1
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Luo Y, Pedersen CET, Eliasen AU, Brustad N, Chen L, Wang N, Jiang J, Trivedi U, Li X, Sørensen SJ, Chawes BL, Stokholm J, Thorsen J, Bønnelykke K. Maternal and child FUT2 secretor status affect gastroenteritis risk and gut microbiota composition in early life. Clin Microbiol Infect 2025:S1198-743X(25)00216-2. [PMID: 40339805 DOI: 10.1016/j.cmi.2025.04.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2024] [Revised: 04/14/2025] [Accepted: 04/26/2025] [Indexed: 05/10/2025]
Abstract
OBJECTIVE To investigate associations between maternal and child secretor status and early-life gastroenteritis risk, considering the roles of gut microbiota, breastfeeding, and daycare attendance. METHODS In the COPSAC2010 cohort (n=700), parents recorded gastroenteritis episodes during the first three years of life. Secretor status, rs601338 in the FUT2 gene, was genotyped in both parents and children. The association between secretor status and gastroenteritis was assessed using quasi-Poisson regression. Fecal samples were collected at 1 week, 1 month, 1 year after birth. The interaction between secretor status, breastfeeding and daycare attendance were analyzed through Cox regression. RESULTS Maternal secretor status increased first-year gastroenteritis risk (incidence rate ratio [IRR]=1.48, 95% confidence interval [CI]:1.05-2.16, p=0.033); child status increased second-year risk (IRR=1.56, 95%CI:1.11-2.27, p=0.015), especially after daycare attendance (interaction p=0.006). Maternal status associated with microbiota differences at 1 week (weighted UniFrac F=2.4, R2=0.47%, p=0.048) and 1 month (F=3.3, R2=0.62%, p=0.026); child status at 1 year (F=2.5, R2=0.45%, p=0.027). Secretor children showed lower Bacteroides vulgatus (Median [interquartile range (IQR)]:1.00% [0.04-12.92] vs. 5.00% [0.09-24.80], p=0.023) but higher Escherichia/Shigella (1.35% [IQR:0.28-7.42] vs. 0.56% [IQR:0.13-2.62], p=0.002). B. vulgatus mediated 14% of child status effects (average causal mediation effect [ACME] IRR=0.95, 95% CI: 0.89-0.99, p=0.014). CONCLUSION Maternal and child FUT2 status demonstrates age-specific impacts on gastroenteritis and microbiota in early life, providing new insights into gastrointestinal health genetics and host-microbiome dynamics.
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Affiliation(s)
- Yang Luo
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
| | - Casper-Emil T Pedersen
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
| | - Anders Ulrik Eliasen
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
| | - Nicklas Brustad
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
| | - Liang Chen
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
| | - Ni Wang
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
| | - Jie Jiang
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
| | - Urvish Trivedi
- Department of Biology, Section of Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Xuanji Li
- Department of Biology, Section of Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Søren Johannes Sørensen
- Department of Biology, Section of Microbiology, University of Copenhagen, Copenhagen, Denmark
| | - Bo L Chawes
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
| | - Jakob Stokholm
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark; Department of Pediatrics, Slagelse Hospital, 4200 Slagelse, Denmark; Department of Food Science, University of Copenhagen, 1958 Frederiksberg, Copenhagen, Denmark
| | - Jonathan Thorsen
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
| | - Klaus Bønnelykke
- COPSAC, Copenhagen Prospective Studies on Asthma in Childhood, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark.
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2
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Li R, Chen P, Zeng YF, Tseng TH, Gannedi V, Krasnova L, Wong CH. Expedient Assembly of Multiantennary N-Glycans from Common N-Glycan Cores with Orthogonal Protection for the Profiling of Glycan-Binding Proteins. J Am Chem Soc 2025; 147:12937-12948. [PMID: 40193327 PMCID: PMC12006998 DOI: 10.1021/jacs.5c02356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 03/21/2025] [Accepted: 03/26/2025] [Indexed: 04/09/2025]
Abstract
Complex-type N-glycans are structurally diverse molecules, responsible for many biological processes, yet the specific sequences of N-glycans involved in biological recognition remain largely unknown. Despite the recent development of many efficient chemoenzymatic approaches, it is still lacking a general approach to produce structurally diverse complex-type N-glycans. Here, we designed two common precursors equipped with orthogonal protecting groups for antennary differentiation and selective glycan elongation. The N-acetyllactosamine (LacNAc) repeat modules were synthesized separately based on iterative Au(I) promoted glycosylation and programmable one-pot strategy and were incorporated into the N-glycan core structure in a site-specific manner. The final removal of benzyl groups was cleanly achieved using pressurized flow chemistry. A total of 51 N-glycans were assembled and presented as an array to study the binding specificity toward a panel of influenza hemagglutinins and other lectins. The established method allows a rapid and previously infeasible synthesis of asymmetric bi- and triantennary N-glycans, especially with the LacNAc repeats residing at a specific arm, bringing in new opportunities to study carbohydrate-receptor interactions.
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Affiliation(s)
- Ruofan Li
- Department
of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States
| | - Pengxi Chen
- Department
of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States
| | - Yi-Fang Zeng
- Department
of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States
| | - Tzu-Hao Tseng
- Department
of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States
| | - Veeranjaneyulu Gannedi
- Department
of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States
| | - Larissa Krasnova
- Department
of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States
| | - Chi-Huey Wong
- Department
of Chemistry, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, California 92037, United States
- Genomics
Research Center, Academia Sinica, Taipei 11529, Taiwan
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3
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Kim H, Lupoli TJ. Defined Glycan Ligands for Detecting Rare l-Sugar-Binding Proteins. J Am Chem Soc 2025; 147:11693-11699. [PMID: 40167164 PMCID: PMC11987014 DOI: 10.1021/jacs.5c03251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2025] [Revised: 03/17/2025] [Accepted: 03/20/2025] [Indexed: 04/02/2025]
Abstract
Most cells are decorated with distinct sugar sequences that can be recognized by carbohydrate-binding proteins (CBPs), such as antibodies and lectins. While humans utilize ten monosaccharide building blocks, bacteria biosynthesize hundreds of activated sugars to assemble diverse glycans. Monosaccharides absent in mammals are termed "rare" and are enriched in deoxy l-sugars beyond the "common" sugar l-fucose (l-Fuc) found across species. While immune proteins recognize microbial surfaces, there are limited probes to identify CBPs for the many rare sugars that may mediate these interactions. Here, we devise chemoenzymatic strategies to defined glycoconjugates containing l-Fuc and its structural analog l-colitose (l-Col), a bacterial dideoxysugar believed to bind immune proteins. We report a concise synthesis of l-Col and semisynthetic routes to several activated l-sugars. Incorporation of these sugars into glycans is evaluated using bacterial and mammalian glycosyltransferases (GTs) annotated to transfer l-Col or l-Fuc, respectively. We find that each GT can transfer both l-sugars, along with the rare hexose l-galactose (l-Gal), onto various glycan acceptors. Incorporation of these l-sugars into the resulting glycoconjugates is confirmed using known CBPs. Finally, these glycan ligands are employed to detect rare sugar-binding proteins in human serum. Overall, this work reveals similarities between bacterial and mammalian GTs that may be exploited for in vitro glycoconjugate construction to unveil novel mediators of host-pathogen interactions.
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Affiliation(s)
- Hanee Kim
- Department of Chemistry, New
York University, New York, New York 10003, United States
| | - Tania J. Lupoli
- Department of Chemistry, New
York University, New York, New York 10003, United States
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4
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Kamitaki N, Handsaker RE, Hujoel MLA, Mukamel RE, Usher CL, McCarroll SA, Loh PR. Human and bacterial genetic variation shape oral microbiomes and health. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2025:2025.03.31.25324952. [PMID: 40236410 PMCID: PMC11998847 DOI: 10.1101/2025.03.31.25324952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/17/2025]
Abstract
It is largely unknown which human genetic variants shape a person's oral microbiome and potentially promote its dysbiosis. We characterized the oral microbiomes of 12,519 people by analyzing whole-genome sequencing reads from previously sequenced saliva-derived DNA. Human genetic variation at 11 loci (10 novel) associated with differences in oral microbiome composition. Nearly all of these associations implicated candidate genes with readily interpretable functions, several related to carbohydrate availability. The strongest association ( p =3.0x10 -188 ) involved the common FUT2 W154X loss-of-function variant, which associated with the abundances of 32 bacterial species. Human host genetics also appeared to powerfully shape within-species genetic variation in oral bacteria. Variation at the 11 human loci associated with variation in gene dosages in 68 regions of bacterial genomes. Several such associations implicated interactions of bacterial proteins with histo-blood group antigens presented on host mucosal cell surfaces and salivary proteins. Common, multi-allelic copy-number variation of AMY1 , which encodes salivary amylase, associated with oral microbiome composition ( p =1.5x10 -53 ) and with dentures use in UK Biobank ( p =5.9x10 -35 , n=418k), suggesting that amylase abundance impacts oral health by influencing the oral microbiome. Two other microbiome composition-associated loci, FUT2 and PITX1 , also significantly associated with dentures risk, collectively nominating numerous microbial taxa that might contribute to tooth decay.
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5
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Iqbal MW, Ahmad M, Shahab M, Sun X, Baig MM, Yu K, Dawoud TM, Bourhia M, Dabiellil F, Zheng G, Yuan Q. Exploring deleterious non-synonymous SNPs in FUT2 gene, and implications for norovirus susceptibility and gut microbiota composition. Sci Rep 2025; 15:10395. [PMID: 40140394 PMCID: PMC11947322 DOI: 10.1038/s41598-025-92220-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 02/26/2025] [Indexed: 03/28/2025] Open
Abstract
Fucosyltransferase 2 (FUT2) gene has been extensively reported to play its role in potential gut microbiota changes and norovirus susceptibility. The normal activity of FUT2 has been found to be disrupted by non-synonymous single nucleotide polymorphisms (nsSNPs) in its gene. To explore the possible mutational changes and their deleterious effects, we employed state-of-the-art computational strategies. Firstly, nine widely-used bioinformatics tools were utilized for initial screening of possibly deleterious nsSNPs. Subsequently, the structural and functional effects of screened nsSNPs on FUT2 were evaluated by utilizing relevant computational tools. Following this, the two shortlisted nsSNPs, including G149S (rs200543547) and V196G (rs367923363), were further validated by their molecular docking with norovirus capsid protein, VP1. As compared to wild-type, the higher stability and lower binding energy scores of the both the mutants indicated their stable binding with VP1, which ultimately leads to norovirus implications. These docking results were further verified by a comprehensive computational approach, molecular dynamic simulation, which gave results in the form of lower RMSD, RMSF, RoG, and hydrogen bond values of both the mutants, depicted in relevant graphs. Overall, this research explores and validated the two FUT2 nsSNPs (G146S and V196G), which may possibly linked with the norovirus susceptibility and gut microbiota changes. Moreover, our findings highlights the value of computational strategies in mutational analysis and welcomes any further experimental validation.
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Affiliation(s)
- Muhammad Waleed Iqbal
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, People's Republic of China
| | - Muneer Ahmad
- College of Medicine and Bioinformation Engineering, Northeastern University, Shenyang, 110819, People's Republic of China
| | - Muhammad Shahab
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, People's Republic of China
| | - Xinxiao Sun
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, People's Republic of China
| | - Mudassar Mehmood Baig
- Institute of Fundamental and Frontier Science, University of Electronic Science and Technology, Chengdu, 611731, People's Republic of China
| | - Kun Yu
- College of Medicine and Bioinformation Engineering, Northeastern University, Shenyang, 110819, People's Republic of China
| | - Turki M Dawoud
- Department of Botany and Microbiology, College of Science, King Saud University, P. O. Box 2455, 11451, Riyadh, Saudi Arabia
| | - Mohammed Bourhia
- Laboratory of Biotechnology and Natural Resources Valorization, Faculty of Sciences, Ibn Zohr University, 80060, Agadir, Morocco
| | - Fakhreldeen Dabiellil
- Laboratory of Biotechnology and Natural Resources Valorization, Faculty of Sciences, Ibn Zohr University, 80060, Agadir, Morocco.
- University of Bahr el Ghazal, Freedom Street, 91113, Wau, South Sudan.
| | - Guojun Zheng
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, People's Republic of China.
| | - Qipeng Yuan
- State Key Laboratory of Chemical Resource Engineering, Beijing University of Chemical Technology, Beijing, 100029, People's Republic of China.
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Downie CG, Highland HM, Alotaibi M, Welch BM, Howard AG, Cheng S, Miller N, Jain M, Kaplan RC, Lilly AG, Long T, Sofer T, Thyagarajan B, Yu B, North KE, Avery CL. Genome-wide association study reveals shared and distinct genetic architecture of fatty acids and oxylipins in the Hispanic Community Health Study/Study of Latinos. HGG ADVANCES 2025; 6:100390. [PMID: 39644095 PMCID: PMC11751521 DOI: 10.1016/j.xhgg.2024.100390] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 12/02/2024] [Accepted: 12/02/2024] [Indexed: 12/09/2024] Open
Abstract
Bioactive fatty acid-derived oxylipin molecules play key roles mediating inflammation and oxidative stress. Circulating levels of fatty acids and oxylipins are influenced by environmental and genetic factors; characterizing the genetic architecture of bioactive lipids could yield new insights into underlying biology. We performed a genome-wide association study (GWAS) of 81 fatty acids and oxylipins in 11,584 Hispanic Community Health Study/Study of Latinos (HCHS/SOL) participants with genetic and lipidomic data measured at study baseline (58.6% female, mean age = 46.1 years (standard deviation 13.8)). Additionally, given the effects of central obesity on inflammation, we examined interactions with waist circumference using two-degree-of-freedom joint tests. Thirty-three of the 81 oxylipins and fatty acids were significantly heritable (heritability range: 0-32.7%). Forty (49.4%) oxylipins and fatty acids had at least one genome-wide significant (p < 6.94E-11) variant resulting in 19 independent genetic loci. Six loci (lead variant minor allele frequency [MAF] range: 0.08-0.50), including desaturase-encoding FADS and OATP1B1 transporter protein-encoding SLCO1B1, exhibited associations with two or more fatty acids and oxylipins. At several of these loci, there was evidence of colocalization of the top variant across fatty acids and oxylipins. The remaining loci were only associated with one oxylipin or fatty acid and included several CYP loci. We also identified an additional rare variant (MAF = 0.002) near CARS2 in two-degree-of-freedom tests. Our analyses revealed shared and distinct genetic architecture underlying fatty acids and oxylipins, providing insights into genetic factors and motivating work to characterize these compounds and elucidate their roles in disease.
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Affiliation(s)
- Carolina G Downie
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Heather M Highland
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Mona Alotaibi
- Division of Pulmonary, Critical Care and Sleep Medicine, University of California, San Diego, San Diego, CA, USA
| | - Barrett M Welch
- School of Public Health, University of Nevada, Reno, Reno, NV, USA
| | - Annie Green Howard
- Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Susan Cheng
- Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | | | - Mohit Jain
- Sapient Bioanalytics, San Diego, CA, USA; Departments of Medicine and Pharmacology, University of California, San Diego, San Diego, CA, USA
| | - Robert C Kaplan
- Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA; Public Health Sciences Division, Fred Hutchison Cancer Center, Seattle, WA, USA
| | - Adam G Lilly
- Department of Sociology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Tao Long
- Sapient Bioanalytics, San Diego, CA, USA
| | - Tamar Sofer
- CardioVascular Institute (CVI), Beth Israel Deaconess Medical Center, Boston, MA, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Bharat Thyagarajan
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical Center, Minneapolis, MN, USA
| | - Bing Yu
- Department of Epidemiology, Human Genetics, and Environmental Sciences, The University of Texas Health Science Center at Houston, School of Public Health, Houston, TX, USA
| | - Kari E North
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Christy L Avery
- Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
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7
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Nagano N, Tagahara A, Shimada T, Miya M, Tamei N, Muto S, Tsutsui T, Saito D, Itami S, Ogawa T, Ito K. Comparison of serum alkaline phosphatase levels between two measurement methods in chronic hemodialysis patients in Japan: involvement of ABO blood group system and relationship with mortality risk. Clin Exp Nephrol 2024; 28:1300-1310. [PMID: 39110345 DOI: 10.1007/s10157-024-02540-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 07/08/2024] [Indexed: 12/07/2024]
Abstract
BACKGROUND Elevated serum alkaline phosphatase (ALP) levels are a risk factor for all-cause mortality in hemodialysis patients. Traditionally in Japan, ALP measurements were conducted using the JSCC method, which yields higher ALP measurement values than the IFCC method, mainly due to its increased sensitivity to intestinal ALP. METHODS Serum total ALP levels before and after switching the assay method from JSCC to IFCC were compared among different blood types in 521 hemodialysis patients (Study 1). The association between ALP levels measured by the JSCC method and 7-year mortality was analyzed, including blood types and liver function parameters as covariates, in 510 hemodialysis patients (Study 2). RESULTS ALP levels measured by the JSCC method were approximately three times higher than those measured by the IFCC method, with significant elevation in patients with blood types B and O compared to those with blood types A and AB. Similarly, ALP levels measured by the IFCC method were significantly higher in patients with blood types B and O compared to those with blood types A and AB (Study 1). The highest tertile of ALP levels showed a significantly increased risk of all-cause mortality, even after adjusting for patient background. However, this significance disappeared when serum liver function-related or inflammatory markers were included as covariates (Study 2). CONCLUSION ALP levels measured by the JSCC method are associated with life prognosis, but caution should be exercised due to their elevation in patients with blood types B and O and in those with hepatic dysfunction or inflammation.
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Affiliation(s)
- Nobuo Nagano
- Kidney Disease and Dialysis Center, Hidaka Hospital, Hidaka-kai, Takasaki, Gunma, Japan.
- Department of Medicine, Tokyo Women's Medical University Adachi Medical Center, Tokyo, Japan.
| | - Ayaka Tagahara
- Kidney Disease and Dialysis Center, Hidaka Hospital, Hidaka-kai, Takasaki, Gunma, Japan
| | - Takahito Shimada
- Kidney Disease and Dialysis Center, Hidaka Hospital, Hidaka-kai, Takasaki, Gunma, Japan
| | - Masaaki Miya
- Kidney Disease and Dialysis Center, Hidaka Hospital, Hidaka-kai, Takasaki, Gunma, Japan
| | - Noriko Tamei
- Kidney Disease and Dialysis Center, Hidaka Hospital, Hidaka-kai, Takasaki, Gunma, Japan
| | - Shigeaki Muto
- Kidney Disease and Dialysis Center, Hidaka Hospital, Hidaka-kai, Takasaki, Gunma, Japan
| | - Takaaki Tsutsui
- Kidney Disease and Dialysis Center, Hidaka Hospital, Hidaka-kai, Takasaki, Gunma, Japan
| | - Daiki Saito
- Department of Medicine, Tokyo Women's Medical University Adachi Medical Center, Tokyo, Japan
| | - Shusaku Itami
- Department of Medicine, Tokyo Women's Medical University Adachi Medical Center, Tokyo, Japan
| | - Tetsuya Ogawa
- Kidney Disease and Dialysis Center, Hidaka Hospital, Hidaka-kai, Takasaki, Gunma, Japan
- Department of Medicine, Tokyo Women's Medical University Adachi Medical Center, Tokyo, Japan
| | - Kyoko Ito
- Kidney Disease and Dialysis Center, Hidaka Hospital, Hidaka-kai, Takasaki, Gunma, Japan
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Kundu S, dos Santos Correia G, Lee YS, Ng S, Sykes L, Chan D, Lewis H, Brown RG, Kindinger L, Dell A, Feizi T, Haslam SM, Liu Y, Marchesi JR, MacIntyre DA, Bennett PR. Secretor status is a modifier of vaginal microbiota-associated preterm birth risk. Microb Genom 2024; 10:001323. [PMID: 39630497 PMCID: PMC11616779 DOI: 10.1099/mgen.0.001323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2024] [Accepted: 10/14/2024] [Indexed: 12/07/2024] Open
Abstract
Mutations in the FUT2 gene that result in a lack of expression of histo-blood group antigens on secreted glycoproteins may shape the vaginal microbiota with consequences for birth outcome. To test this, we analysed the relationship between secretor status, vaginal microbiota and gestational length in an ethnically diverse cohort of 302 pregnant women, including 82 who delivered preterm. Lactobacillus gasseri and L. jensenii were found to have distinct co-occurrence patterns with other microbial taxa in non-secretors. Moreover, non-secretors with Lactobacillus spp. depleted high diversity vaginal microbiota in early pregnancy had significantly shorter gestational length than Lactobacillus spp. dominated non-secretors (mean of 241.54 days (sd=47.14) versus 266.21 (23.61); P-value=0.0251). Similar gestational length differences were observed between non-secretors with high vaginal diversity and secretors with Lactobacillus spp. dominance (mean of 262.52 days (SD=27.73); p-value=0.0439) or depletion (mean of 266.05 days (SD=20.81); p-value=0.0312). Our data highlight secretor status and blood-group antigen expression as being important mediators of vaginal microbiota-host interactions in the context of preterm birth risk.
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Affiliation(s)
- Samit Kundu
- March of Dimes European Prematurity Research Centre, Imperial College London, London, UK
| | - Gonçalo dos Santos Correia
- March of Dimes European Prematurity Research Centre, Imperial College London, London, UK
- Institute for Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
| | - Yun S. Lee
- March of Dimes European Prematurity Research Centre, Imperial College London, London, UK
| | - Sherrianne Ng
- March of Dimes European Prematurity Research Centre, Imperial College London, London, UK
- Institute for Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
| | - Lynne Sykes
- March of Dimes European Prematurity Research Centre, Imperial College London, London, UK
- Institute for Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
- Imperial College Healthcare NHS Trust, Parasol Foundation for Women’s Health, London, UK
| | - Denise Chan
- Institute for Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
| | - Holly Lewis
- Institute for Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
| | - Richard G. Brown
- Institute for Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
| | - Lindsay Kindinger
- Institute for Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
- Institute for Women’s Health, University College London, London, UK
| | - Anne Dell
- March of Dimes European Prematurity Research Centre, Imperial College London, London, UK
- Department of Life Sciences, Imperial College London, London, UK
| | - Ten Feizi
- March of Dimes European Prematurity Research Centre, Imperial College London, London, UK
- Glycosciences Laboratory, Department of Metabolism Digestion and Reproduction, Imperial College London, London, UK
| | - Stuart M. Haslam
- March of Dimes European Prematurity Research Centre, Imperial College London, London, UK
- Department of Life Sciences, Imperial College London, London, UK
| | - Yan Liu
- March of Dimes European Prematurity Research Centre, Imperial College London, London, UK
- Glycosciences Laboratory, Department of Metabolism Digestion and Reproduction, Imperial College London, London, UK
| | - Julian R. Marchesi
- March of Dimes European Prematurity Research Centre, Imperial College London, London, UK
- Division of Digestive Medicine, Department of Metabolism, Digestion and Reproduction, Faculty of Medicine, Imperial College London, London, UK
| | - David A. MacIntyre
- March of Dimes European Prematurity Research Centre, Imperial College London, London, UK
- Institute for Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
- Robinson Research Institute, University of Adelaide, Adelaide, Australia
| | - Phillip R. Bennett
- March of Dimes European Prematurity Research Centre, Imperial College London, London, UK
- Institute for Reproductive and Developmental Biology, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, UK
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9
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Liu S, Chen H, Wen Z, Ouyang Y, Mei B, Li C. Association of fucosyltransferase 2 gene polymorphism with the susceptibility to norovirus infection in Han Chinese population. J Med Virol 2024; 96:e29848. [PMID: 39105389 DOI: 10.1002/jmv.29848] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 07/25/2024] [Accepted: 07/29/2024] [Indexed: 08/07/2024]
Abstract
Fucosyltransferase 2 (FUT2) gene, which regulates the formation of Histoblood group antigens, could determine the human susceptibility to norovirus. This study aimed to investigate the correlation between FUT2 gene polymorphism and susceptibility to norovirus gastroenteritis in Han Chinese population. A total of 212 children patients with acute gastroenteritis were enrolled. The stool and serum samples were collected respectively. We used the qPCR method to detect the norovirus infection status from the stool samples, and we used serum samples to detect the FUT2 polymorphism. A case-control study was conducted to investigate the three common SNPs polymorphisms (rs281377, rs1047781, and rs601338) of FUT2 gene with sanger sequencing method. The results indicated that the homozygous genotypes and mutant allele of rs1047781 (A385T) would downgrade the risk of norovirus gastroenteritis in Chinese Han population (AA vs. TT, odds ratio [OR] = 0.098, 95% confidence interval [CI] = 0.026-0.370, p = 0.001; AA + AT vs. TT, OR = 0.118. 95% CI = 0.033-0.424, p = 0.001; A vs. T, OR = 0.528, 95% CI = 0.351-0.974, p = 0.002). There were no significant difference of rs281377 (C357T) and rs601338 (G428A) polymorphisms between norovirus positive and norovirus negative groups (p > 0.05). The haplotype T-T-G was less susceptible (OR = 0.49, 95% CI = 0.31-0.79, p = 0.0034) to norovirus infection compared to other haplotypes. Our results investigated the relationship between the FUT2 gene polymorphisms and norovirus susceptibility in Han Chinese population, and firstly revealed that children with homozygous genotypes and mutant alleles of FUT2 rs1047781 (A385T) were less susceptible to norovirus gastroenteritis.
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Affiliation(s)
- Shun Liu
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, People's Republic of China
| | - Hanyu Chen
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, People's Republic of China
| | - Zihan Wen
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, People's Republic of China
| | - Yaoling Ouyang
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, People's Republic of China
| | - Bing Mei
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, People's Republic of China
| | - Chengbin Li
- Department of Laboratory Medicine, Jingzhou Hospital Affiliated to Yangtze University, Jingzhou, Hubei, People's Republic of China
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10
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Li C, Gu Z, Hou Y, Gao Q, Xu G, Lu H. A Pedigree Investigation of H-antigen Deletion Caused by Mutation of 658 C to T in the FUT1 Gene. Indian J Hematol Blood Transfus 2024; 40:504-507. [PMID: 39011245 PMCID: PMC11246360 DOI: 10.1007/s12288-023-01669-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 04/10/2023] [Indexed: 07/17/2024] Open
Abstract
H-antigen deletion is often caused by FUT1 gene mutation, which is a very rare blood group. In this case, the H-antigen phenotype, FUT1, FUT2 sequences, and family genetic investigation of a 26-year-old patient (proband) and her three family members were studied. The results showed that the proband and little her brother were H-deficient phenotype, their ABO genotype of both was A/O1, her father was A/B, and her mother was O1/O1. The proband and her little brother's FUT1 phenotype were both h3|h3, with a homozygous mutation 658C > T in their FUT1 gene, and the FUT1 phenotype of their parents' were H|h3, with a heterozygous mutation (658C > T) in their FUT1 gene. The result of whole gene sequencing showed that the father of the proband had a deletion of CHR19.49,255,178-49,257,177 in the FUT1 gene (hg19 was used as the reference). The results of the family investigation showed that the mutation of site 658 in the FUT1 gene between offspring and parents was consistent with Mendelian inheritance law.
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Affiliation(s)
- Chun Li
- Transfusion Department, Chongqing Medical University Affiliated Second Hospital, Linjiang Road 74#,Yu Zhong District, Chongqing, 400010 China
| | - Zelan Gu
- Transfusion Department, Chongqing Medical University Affiliated Second Hospital, Linjiang Road 74#,Yu Zhong District, Chongqing, 400010 China
| | - Yijun Hou
- Transfusion Department, Chongqing Medical University Affiliated Second Hospital, Linjiang Road 74#,Yu Zhong District, Chongqing, 400010 China
| | - Qi Gao
- Transfusion Department, Chongqing Medical University Affiliated Second Hospital, Linjiang Road 74#,Yu Zhong District, Chongqing, 400010 China
| | - Guping Xu
- Transfusion Department, Chongqing Medical University Affiliated Second Hospital, Linjiang Road 74#,Yu Zhong District, Chongqing, 400010 China
| | - Hua Lu
- Transfusion Department, Chongqing Medical University Affiliated Second Hospital, Linjiang Road 74#,Yu Zhong District, Chongqing, 400010 China
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11
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Kotowski MJ, Ostrowski P, Sieńko J, Czerny B, Tejchman K, Machaliński B, Górska A, Mrozikiewicz AE, Bogacz A. The Importance of the FUT2 rs602662 Polymorphism in the Risk of Cardiovascular Complications in Patients after Kidney Transplantation. Int J Mol Sci 2024; 25:6562. [PMID: 38928269 PMCID: PMC11203847 DOI: 10.3390/ijms25126562] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 06/05/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
The FUT2 gene encodes an enzyme called α-1,2-fucosyltransferase, which is involved in the formation of blood group antigens AB0(H) and is also involved in the processes of vitamin B12 absorption and its transport between cells. FUT2 gene polymorphisms are associated with vitamin B12 levels in the body. Vitamin B12 deficiency associated with hyperhomocysteinemia is a major risk factor for cardiovascular diseases (CVDs), which are one of the main causes of death in patients after kidney transplantation. The aim of our study was to determine the impact of the rs602662 (G>A) polymorphism of the FUT2 gene on the functionality of transplanted kidneys and the risk of CVD in patients after kidney transplantation. The study included 402 patients treated with immunosuppression (183 patients taking cyclosporine (CsA) and 219 patients taking tacrolimus (TAC)). The analysis of the FUT2 rs602662 (G>A) polymorphism was performed using real-time PCR. Patients with CsA were more likely to be underweight (1.64% vs. 0.91%) and obese (27.87% vs. 15.98%), while those taking TAC were more likely to be of normal weight (39.27%) or overweight (43.84%). No statistically significant differences were observed comparing the mean blood pressure, both systolic and diastolic. The renal profile showed a higher median urea nitrogen concentration in patients with CsA (26.45 mg/dL (20.60-35.40) vs. 22.95 mg/dL (17.60-33.30), p = 0.004). The observed frequency of rs602662 alleles of the FUT2 gene was similar in the analyzed groups. The A allele was present in 43.7% of patients with CsA and 41.1% of those taking TAC (OR = 0.898; 95% CI: 0.678-1.189; p = 0.453). In the group with CsA, the GG genotype was present in 32.2% of patients, the GA in 48.1% and the AA in 19.7%. A similar distribution was obtained in the TAC group: GG-33.8%, GA-50.2%, and AA-16.0%. An association of genotypes containing the G allele with a higher incidence of hypertension was observed. The G allele was present in 65% of people with hypertension and in 56% of patients with normal blood pressure (p = 0.036). Moreover, the evaluation of the renal parameters showed no effect of the FUT2 polymorphism on the risk of organ rejection because the levels of creatinine, eGFR, potassium, and urea nitrogen were prognostic of successful transplantation. Our results suggest that the rs6022662 FUT2 polymorphism may influence the risk of cardiovascular diseases.
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Affiliation(s)
- Maciej Józef Kotowski
- Department of General Surgery and Transplantology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; (M.J.K.); (P.O.); (K.T.)
| | - Piotr Ostrowski
- Department of General Surgery and Transplantology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; (M.J.K.); (P.O.); (K.T.)
| | - Jerzy Sieńko
- Institute of Physical Culture Sciences, University of Szczecin, 70-453 Szczecin, Poland;
| | - Bogusław Czerny
- Department of Stem Cells and Regenerative Medicine, Institute of Natural Fibres and Medicinal Plants, Kolejowa 2, 62-064 Plewiska, Poland; (B.C.); (A.G.)
- Department of Pharmacology and Pharmacoeconomics, Pomeranian Medical University in Szczecin, Żołnierska 48, 71-230 Szczecin, Poland
| | - Karol Tejchman
- Department of General Surgery and Transplantology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland; (M.J.K.); (P.O.); (K.T.)
| | - Bogusław Machaliński
- Department of General Pathology, Pomeranian Medical University in Szczecin, 70-111 Szczecin, Poland;
| | - Aleksandra Górska
- Department of Stem Cells and Regenerative Medicine, Institute of Natural Fibres and Medicinal Plants, Kolejowa 2, 62-064 Plewiska, Poland; (B.C.); (A.G.)
| | - Aleksandra E. Mrozikiewicz
- Department of Obstetrics and Women’s Diseases, Poznan University of Medical Sciences, Polna 33, 60-535 Poznan, Poland;
| | - Anna Bogacz
- Department of Personalized Medicine and Cell Therapy, Regional Blood Center, Marcelińska 44, 60-354 Poznan, Poland
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12
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Wang D, Madunić K, Mayboroda OA, Lageveen-Kammeijer GSM, Wuhrer M. (Sialyl)Lewis Antigen Expression on Glycosphingolipids, N-, and O-Glycans in Colorectal Cancer Cell Lines is Linked to a Colon-Like Differentiation Program. Mol Cell Proteomics 2024; 23:100776. [PMID: 38670309 PMCID: PMC11128521 DOI: 10.1016/j.mcpro.2024.100776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Revised: 04/03/2024] [Accepted: 04/23/2024] [Indexed: 04/28/2024] Open
Abstract
Alterations in the glycomic profile are a hallmark of cancer, including colorectal cancer (CRC). While, the glycosylation of glycoproteins and glycolipids has been widely studied for CRC cell lines and tissues, a comprehensive overview of CRC glycomics is still lacking due to the usage of different samples and analytical methods. In this study, we compared glycosylation features of N-, O-glycans, and glycosphingolipid glycans for a set of 22 CRC cell lines, all measured by porous graphitized carbon nano-liquid chromatography-tandem mass spectrometry. An overall, high abundance of (sialyl)Lewis antigens for colon-like cell lines was found, while undifferentiated cell lines showed high expression of H blood group antigens and α2-3/6 sialylation. Moreover, significant associations of glycosylation features were found between the three classes of glycans, such as (sialyl)Lewis and H blood group antigens. Integration of the datasets with transcriptomics data revealed positive correlations between (sialyl)Lewis antigens, the corresponding glycosyltransferase FUT3 and transcription factors CDX1, ETS, HNF1/4A, MECOM, and MYB. This indicates a possible role of these transcription factors in the upregulation of (sialyl)Lewis antigens, particularly on glycosphingolipid glycans, via FUT3/4 expression in colon-like cell lines. In conclusion, our study provides insights into the possible regulation of glycans in CRC and can serve as a guide for the development of diagnostic and therapeutic biomarkers.
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Affiliation(s)
- Di Wang
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Katarina Madunić
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands; Department of Cellular and Molecular Medicine, Copenhagen Center for Glycomics, University of Copenhagen, Copenhagen, Denmark
| | - Oleg A Mayboroda
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands
| | - Guinevere S M Lageveen-Kammeijer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands; Division of Analytical Biochemistry, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Manfred Wuhrer
- Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, The Netherlands.
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13
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Jensen M, Stenfelt L, Ricci Hagman J, Pichler MJ, Weikum J, Nielsen TS, Hult A, Morth JP, Olsson ML, Abou Hachem M. Akkermansia muciniphila exoglycosidases target extended blood group antigens to generate ABO-universal blood. Nat Microbiol 2024; 9:1176-1188. [PMID: 38684911 DOI: 10.1038/s41564-024-01663-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 03/04/2024] [Indexed: 05/02/2024]
Abstract
Matching donor and recipient blood groups based on red blood cell (RBC) surface ABO glycans and antibodies in plasma is crucial to avoid potentially fatal reactions during transfusions. Enzymatic conversion of RBC glycans to the universal group O is an attractive solution to simplify blood logistics and prevent ABO-mismatched transfusions. The gut symbiont Akkermansia muciniphila can degrade mucin O-glycans including ABO epitopes. Here we biochemically evaluated 23 Akkermansia glycosyl hydrolases and identified exoglycosidase combinations which efficiently transformed both A and B antigens and four of their carbohydrate extensions. Enzymatic removal of canonical and extended ABO antigens on RBCs significantly improved compatibility with group O plasmas, compared to conversion of A or B antigens alone. Finally, structural analyses of two B-converting enzymes identified a previously unknown putative carbohydrate-binding module. This study demonstrates the potential utility of mucin-degrading gut bacteria as valuable sources of enzymes for production of universal blood for transfusions.
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Affiliation(s)
- Mathias Jensen
- Department of Biotechnology & Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Linn Stenfelt
- Department of Biotechnology & Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
- Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden
| | - Jennifer Ricci Hagman
- Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden
- Department of Clinical Immunology and Transfusion Medicine, Office for Medical Services, Region Skåne, Sweden
| | - Michael Jakob Pichler
- Department of Biotechnology & Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Julia Weikum
- Department of Biotechnology & Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Tine Sofie Nielsen
- Department of Biotechnology & Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Annika Hult
- Department of Clinical Immunology and Transfusion Medicine, Office for Medical Services, Region Skåne, Sweden
| | - Jens Preben Morth
- Department of Biotechnology & Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Martin L Olsson
- Division of Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.
- Department of Clinical Immunology and Transfusion Medicine, Office for Medical Services, Region Skåne, Sweden.
| | - Maher Abou Hachem
- Department of Biotechnology & Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark.
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14
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Donato CM, Handley A, Byars SG, Bogdanovic-Sakran N, Lyons EA, Watts E, Ong DS, Pavlic D, At Thobari J, Satria CD, Nirwati H, Soenarto Y, Bines JE. Vaccine Take of RV3-BB Rotavirus Vaccine Observed in Indonesian Infants Regardless of HBGA Status. J Infect Dis 2024; 229:1010-1018. [PMID: 37592804 PMCID: PMC11011179 DOI: 10.1093/infdis/jiad351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Revised: 08/07/2023] [Accepted: 08/16/2023] [Indexed: 08/19/2023] Open
Abstract
BACKGROUND Histo-blood group antigen (HBGA) status may affect vaccine efficacy due to rotavirus strains binding to HBGAs in a P genotype-dependent manner. This study aimed to determine if HBGA status affected vaccine take of the G3P[6] neonatal vaccine RV3-BB. METHODS DNA was extracted from stool samples collected in a subset (n = 164) of the RV3-BB phase IIb trial in Indonesian infants. FUT2 and FUT3 genes were amplified and sequenced, with any single-nucleotide polymorphisms analyzed to infer Lewis and secretor status. Measures of positive cumulative vaccine take were defined as serum immune response (immunoglobulin A or serum-neutralizing antibody) and/or stool excretion of RV3-BB virus. Participants were stratified by HBGA status and measures of vaccine take. RESULTS In 147 of 164 participants, Lewis and secretor phenotype were determined. Positive vaccine take was recorded for 144 (97.9%) of 147 participants with the combined phenotype determined. Cumulative vaccine take was not significantly associated with secretor status (relative risk, 1.00 [95% CI, .94-1.06]; P = .97) or Lewis phenotype (relative risk, 1.03 [95% CI, .94-1.14]; P = .33), nor was a difference observed when analyzed by each component of vaccine take. CONCLUSIONS The RV3-BB vaccine produced positive cumulative vaccine take, irrespective of HBGA status in Indonesian infants.
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Affiliation(s)
- Celeste M Donato
- Enteric Diseases Group, Murdoch Children's Research Institute
- Department of Paediatrics, The University of Melbourne, Parkville
- Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne
| | - Amanda Handley
- Enteric Diseases Group, Murdoch Children's Research Institute
- Medicines Development for Global Health, Southbank
| | - Sean G Byars
- Florey Institute of Neuroscience and Mental Health, Parkville, Australia
| | | | - Eleanor A Lyons
- Enteric Diseases Group, Murdoch Children's Research Institute
| | - Emma Watts
- Enteric Diseases Group, Murdoch Children's Research Institute
| | - Darren S Ong
- Enteric Diseases Group, Murdoch Children's Research Institute
| | - Daniel Pavlic
- Enteric Diseases Group, Murdoch Children's Research Institute
| | | | | | - Hera Nirwati
- Center for Child Health
- Department of Microbiology, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada
| | - Yati Soenarto
- Center for Child Health
- Department of Child Health, Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Dr Sardjito Hospital, Yogyakarta, Indonesia
| | - Julie E Bines
- Enteric Diseases Group, Murdoch Children's Research Institute
- Department of Paediatrics, The University of Melbourne, Parkville
- Department of Gastroenterology and Clinical Nutrition, Royal Children's Hospital, Parkville, Australia
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15
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Mercer EM, Ramay HR, Moossavi S, Laforest-Lapointe I, Reyna ME, Becker AB, Simons E, Mandhane PJ, Turvey SE, Moraes TJ, Sears MR, Subbarao P, Azad MB, Arrieta MC. Divergent maturational patterns of the infant bacterial and fungal gut microbiome in the first year of life are associated with inter-kingdom community dynamics and infant nutrition. MICROBIOME 2024; 12:22. [PMID: 38326891 PMCID: PMC10848358 DOI: 10.1186/s40168-023-01735-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Accepted: 12/01/2023] [Indexed: 02/09/2024]
Abstract
BACKGROUND The gut microbiome undergoes primary ecological succession over the course of early life before achieving ecosystem stability around 3 years of age. These maturational patterns have been well-characterized for bacteria, but limited descriptions exist for other microbiota members, such as fungi. Further, our current understanding of the prevalence of different patterns of bacterial and fungal microbiome maturation and how inter-kingdom dynamics influence early-life microbiome establishment is limited. RESULTS We examined individual shifts in bacterial and fungal alpha diversity from 3 to 12 months of age in 100 infants from the CHILD Cohort Study. We identified divergent patterns of gut bacterial or fungal microbiome maturation in over 40% of infants, which were characterized by differences in community composition, inter-kingdom dynamics, and microbe-derived metabolites in urine, suggestive of alterations in the timing of ecosystem transitions. Known microbiome-modifying factors, such as formula feeding and delivery by C-section, were associated with atypical bacterial, but not fungal, microbiome maturation patterns. Instead, fungal microbiome maturation was influenced by prenatal exposure to artificially sweetened beverages and the bacterial microbiome, emphasizing the importance of inter-kingdom dynamics in early-life colonization patterns. CONCLUSIONS These findings highlight the ecological and environmental factors underlying atypical patterns of microbiome maturation in infants, and the need to incorporate multi-kingdom and individual-level perspectives in microbiome research to improve our understandings of gut microbiome maturation patterns in early life and how they relate to host health. Video Abstract.
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Affiliation(s)
- Emily M Mercer
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada
- Department of Pediatrics, University of Calgary, Calgary, AB, Canada
- International Microbiome Center, University of Calgary, Calgary, AB, Canada
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
- Alberta Children's Hospital Research Institute (ACHRI), Calgary, AB, Canada
| | - Hena R Ramay
- International Microbiome Center, University of Calgary, Calgary, AB, Canada
| | - Shirin Moossavi
- Department of Microbiology, Immunology and Transplantation, Rega Institute, KU Leuven, Louvain, Belgium
- VIB Center for Microbiology, VIB, Louvain, Belgium
| | | | - Myrtha E Reyna
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
- Department of Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada
| | - Allan B Becker
- Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada
- Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada
| | - Elinor Simons
- Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada
- Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada
| | - Piush J Mandhane
- Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Stuart E Turvey
- Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Theo J Moraes
- Department of Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada
| | - Malcolm R Sears
- Department of Medicine, McMaster University, Hamilton, ON, Canada
| | - Padmaja Subbarao
- Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada
- Department of Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada
| | - Meghan B Azad
- Department of Pediatrics and Child Health, University of Manitoba, Winnipeg, MB, Canada
- Children's Hospital Research Institute of Manitoba, Winnipeg, MB, Canada
- Manitoba Interdisciplinary Lactation Centre (MILC), Winnipeg, MB, Canada
| | - Marie-Claire Arrieta
- Department of Physiology and Pharmacology, University of Calgary, Calgary, AB, Canada.
- Department of Pediatrics, University of Calgary, Calgary, AB, Canada.
- International Microbiome Center, University of Calgary, Calgary, AB, Canada.
- Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.
- Alberta Children's Hospital Research Institute (ACHRI), Calgary, AB, Canada.
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16
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Yamaguchi T, Fukudome H, Higuchi J, Takahashi T, Tsujimori Y, Ueno HM, Toba Y, Sakai F. Label-Free Liquid Chromatography-Mass Spectrometry Quantitation of Relative N- and O-Glycan Concentrations in Human Milk in Japan. Int J Mol Sci 2024; 25:1772. [PMID: 38339050 PMCID: PMC10855831 DOI: 10.3390/ijms25031772] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Revised: 01/26/2024] [Accepted: 01/29/2024] [Indexed: 02/12/2024] Open
Abstract
Human milk is abundant in carbohydrates and includes human milk oligosaccharides (HMOs) and N/O-glycans conjugated to proteins. HMO compositions and concentrations vary in individuals according to the maternal secretor status based on the fucosyltransferase 2 genotype; however, the profile of N/O-glycans remains uninvestigated because of the analytical complexity. Herein, we applied a label-free chromatography-mass spectrometry (LC-MS) technique to elucidate the variation in the composition and concentration of N/O-glycans in human milk. We used label-free LC-MS to relatively quantify 16 N-glycans and 12 O-glycans in 200 samples of Japanese human milk (1-2 months postpartum) and applied high performance anion exchange chromatography with pulsed amperometric detection to absolutely quantify the concentrations of 11 representative HMOs. Cluster analysis of the quantitative data revealed that O-glycans and several HMOs were classified according to the presence or absence of fucose linked to galactose while N-glycans were classified into a different group from O-glycans and HMOs. O-glycans and HMOs with fucose linked to galactose were more abundant in human milk from secretor mothers than from nonsecretor mothers. Thus, secretor status influenced the composition and concentration of HMOs and O-glycans but not those of N-glycans in human milk.
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Affiliation(s)
- Toshiyuki Yamaguchi
- Milk Science Research Institute, Megmilk Snow Brand Co., Ltd., 1-1-2 Minamidai, Kawagoe-shi 350-1165, Saitama, Japan; (T.Y.); (H.F.); (J.H.); (H.M.U.)
| | - Hirofumi Fukudome
- Milk Science Research Institute, Megmilk Snow Brand Co., Ltd., 1-1-2 Minamidai, Kawagoe-shi 350-1165, Saitama, Japan; (T.Y.); (H.F.); (J.H.); (H.M.U.)
| | - Junichi Higuchi
- Milk Science Research Institute, Megmilk Snow Brand Co., Ltd., 1-1-2 Minamidai, Kawagoe-shi 350-1165, Saitama, Japan; (T.Y.); (H.F.); (J.H.); (H.M.U.)
| | - Tomoki Takahashi
- Department of Research and Development, Bean Stalk Snow Co., Ltd., 1-1-2 Minamidai, Kawagoe-shi 350-1165, Saitama, Japan; (T.T.); (Y.T.); (Y.T.)
| | - Yuta Tsujimori
- Department of Research and Development, Bean Stalk Snow Co., Ltd., 1-1-2 Minamidai, Kawagoe-shi 350-1165, Saitama, Japan; (T.T.); (Y.T.); (Y.T.)
| | - Hiroshi M. Ueno
- Milk Science Research Institute, Megmilk Snow Brand Co., Ltd., 1-1-2 Minamidai, Kawagoe-shi 350-1165, Saitama, Japan; (T.Y.); (H.F.); (J.H.); (H.M.U.)
- Department of Research and Development, Bean Stalk Snow Co., Ltd., 1-1-2 Minamidai, Kawagoe-shi 350-1165, Saitama, Japan; (T.T.); (Y.T.); (Y.T.)
| | - Yasuhiro Toba
- Department of Research and Development, Bean Stalk Snow Co., Ltd., 1-1-2 Minamidai, Kawagoe-shi 350-1165, Saitama, Japan; (T.T.); (Y.T.); (Y.T.)
| | - Fumihiko Sakai
- Milk Science Research Institute, Megmilk Snow Brand Co., Ltd., 1-1-2 Minamidai, Kawagoe-shi 350-1165, Saitama, Japan; (T.Y.); (H.F.); (J.H.); (H.M.U.)
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Shi M, Nan XR, Liu BQ. The Multifaceted Role of FUT8 in Tumorigenesis: From Pathways to Potential Clinical Applications. Int J Mol Sci 2024; 25:1068. [PMID: 38256141 PMCID: PMC10815953 DOI: 10.3390/ijms25021068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Revised: 01/07/2024] [Accepted: 01/13/2024] [Indexed: 01/24/2024] Open
Abstract
FUT8, the sole glycosyltransferase responsible for N-glycan core fucosylation, plays a crucial role in tumorigenesis and development. Aberrant FUT8 expression disrupts the function of critical cellular components and triggers the abnormality of tumor signaling pathways, leading to malignant transformations such as proliferation, invasion, metastasis, and immunosuppression. The association between FUT8 and unfavorable outcomes in various tumors underscores its potential as a valuable diagnostic marker. Given the remarkable variation in biological functions and regulatory mechanisms of FUT8 across different tumor types, gaining a comprehensive understanding of its complexity is imperative. Here, we review how FUT8 plays roles in tumorigenesis and development, and how this outcome could be utilized to develop potential clinical therapies for tumors.
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Affiliation(s)
| | | | - Bao-Qin Liu
- Department of Biochemistry & Molecular Biology, School of Life Sciences, China Medical University, Shenyang 110122, China; (M.S.); (X.-R.N.)
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18
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Kofsky JM, Babulic JL, Boddington ME, De León González FV, Capicciotti CJ. Glycosyltransferases as versatile tools to study the biology of glycans. Glycobiology 2023; 33:888-910. [PMID: 37956415 DOI: 10.1093/glycob/cwad092] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 11/05/2023] [Accepted: 11/06/2023] [Indexed: 11/15/2023] Open
Abstract
All cells are decorated with complex carbohydrate structures called glycans that serve as ligands for glycan-binding proteins (GBPs) to mediate a wide range of biological processes. Understanding the specific functions of glycans is key to advancing an understanding of human health and disease. However, the lack of convenient and accessible tools to study glycan-based interactions has been a defining challenge in glycobiology. Thus, the development of chemical and biochemical strategies to address these limitations has been a rapidly growing area of research. In this review, we describe the use of glycosyltransferases (GTs) as versatile tools to facilitate a greater understanding of the biological roles of glycans. We highlight key examples of how GTs have streamlined the preparation of well-defined complex glycan structures through chemoenzymatic synthesis, with an emphasis on synthetic strategies allowing for site- and branch-specific display of glyco-epitopes. We also describe how GTs have facilitated expansion of glyco-engineering strategies, on both glycoproteins and cell surfaces. Coupled with advancements in bioorthogonal chemistry, GTs have enabled selective glyco-epitope editing of glycoproteins and cells, selective glycan subclass labeling, and the introduction of novel biomolecule functionalities onto cells, including defined oligosaccharides, antibodies, and other proteins. Collectively, these approaches have contributed great insight into the fundamental biological roles of glycans and are enabling their application in drug development and cellular therapies, leaving the field poised for rapid expansion.
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Affiliation(s)
- Joshua M Kofsky
- Department of Chemistry, Queen's University, 90 Bader Lane, Kingston, ON K7L 3N6, Canada
| | - Jonathan L Babulic
- Department of Biomedical and Molecular Sciences, Queen's University, 18 Stuart Street, Kingston, ON K7L 2V7, Canada
| | - Marie E Boddington
- Department of Biomedical and Molecular Sciences, Queen's University, 18 Stuart Street, Kingston, ON K7L 2V7, Canada
| | | | - Chantelle J Capicciotti
- Department of Chemistry, Queen's University, 90 Bader Lane, Kingston, ON K7L 3N6, Canada
- Department of Biomedical and Molecular Sciences, Queen's University, 18 Stuart Street, Kingston, ON K7L 2V7, Canada
- Department of Surgery, Queen's University, 76 Stuart Street, Kingston, ON K7L 2V7, Canada
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19
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Yu Y, Han F, Yang M, Zhang X, Chen Y, Yu M, Wang Y. Pseudomonas composti isolate from oyster digestive tissue specifically binds with norovirus GII.6 via Psl extracellular polysaccharide. Int J Food Microbiol 2023; 406:110369. [PMID: 37666026 DOI: 10.1016/j.ijfoodmicro.2023.110369] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/15/2023] [Accepted: 08/21/2023] [Indexed: 09/06/2023]
Abstract
Oysters are recognized as important vectors for human norovirus transmission in the environment. Whether norovirus binds to bacteria in oyster digestive tissues (ODTs) remains unknown. To shed light on this concern, ODT-54 and ODT-32, positive for histo-blood group antigen (HBGA) -like substances, were isolated from ODTs and identified as Pseudomonas composti and Enterobacter cloacae, respectively. The binding of noroviruses (GII.4 and GII.6 P domains) to bacterial cells (ODT-32 and ODT-54; in situ assay) as well as extracted extracellular polysaccharides (EPSs; in vitro assay) was analyzed by flow cytometry, confocal laser scanning microscopy, ELISA, and gene knock-out mutants. ODT-32 bound to neither GII.4 nor GII.6 P domains, while ODT-54 specifically binds with GII.6 P domain through Psl, an exopolysaccharide encoded by the polysaccharide synthesis locus (psl), identified based on gene annotation, gene transcription, Psl specific staining, and ELISAs. These findings attest that ODT bacteria specifically bind with certain norovirus genotypes in a strain-dependent manner, contributing to a better understanding of the transmission and enrichment of noroviruses in the environment.
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Affiliation(s)
- Yongxin Yu
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China; Laboratory of Quality and Safety Risk Assessment for Aquatic Products on Storage and Preservation (Shanghai), Ministry of Agriculture, China
| | - Feng Han
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China; Ministry of Agriculture and Rural Affairs, East China Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, Shanghai, China
| | - Mingshu Yang
- College of Food Science and Engineering, Hainan Tropical Ocean University, Sanya, China
| | - Xiaoya Zhang
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Yunfei Chen
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Mingxia Yu
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China
| | - Yongjie Wang
- College of Food Science and Technology, Shanghai Ocean University, Shanghai, China; Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao, China; Laboratory of Quality and Safety Risk Assessment for Aquatic Products on Storage and Preservation (Shanghai), Ministry of Agriculture, China.
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20
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Zhou S, Wang L, Song W, Xia Y, Shao L, Liang X. A novel allele of FUT2 gene containing a deletion of nine bases (c.461_469delGGACCTTCT) in a Chinese Han blood donor. Vox Sang 2023; 118:988-992. [PMID: 37800389 DOI: 10.1111/vox.13528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 08/08/2023] [Accepted: 08/22/2023] [Indexed: 10/07/2023]
Abstract
BACKGROUND AND OBJECTIVES The FUT2 gene is responsible for the synthesis of the H antigen in body secretions. It is highly polymorphic and population specific. We investigated the FUT2 gene polymorphism in Chinese blood donors and found a novel deletion mutation in one non-secretor individual. This study aimed to identify mutation(s) responsible for a non-secretor phenotype. MATERIALS AND METHODS The Lewis blood group of a Chinese Han blood donor was typed using the standard serological technique and the FUT2 gene of the sample was analysed by Sanger sequencing. Clone sequencing was performed for determining the haplotype of the FUT2 gene. Bioinformatics tools were used for predicting the effect of the deletion on the FUT2 gene. RESULTS A novel nine-base deletion (c.461_469delGGACCTTCT) in the FUT2 gene was identified in a Chinese Han blood donor. Two haplotypes Se390,418 and se204,249,461_469del,772,993 were determined by clone sequencing. According to the prediction of bioinformatics tools, the mutation at c.461_469delGGACCTTCT might not influence the activity of the Se enzyme. CONCLUSION We identified a new FUT2 mutation, the deletion of nine bases (c.461_469delGGACCTTCT), in a Chinese Han blood donor. This deletion was reported for the first time.
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Affiliation(s)
| | - Liying Wang
- College of Laboratory Medicine, Dalian Medical University, Dalian, China
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21
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Soejima M, Koda Y. FUT1 variants responsible for Bombay or para-Bombay phenotypes in a database. Sci Rep 2023; 13:17447. [PMID: 37838738 PMCID: PMC10576827 DOI: 10.1038/s41598-023-44731-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 10/11/2023] [Indexed: 10/16/2023] Open
Abstract
Rare individuals with Bombay and para-Bombay phenotypes lack or have weak expression of the ABO(H) antigens on surface of red blood cells due to no or very weak H-type α(1,2)fucosyltransferase activity encoded by FUT1. These phenotypes are clinically important because subjects with these phenotypes can only accept transfusions of autologous blood or blood from subjects with the same phenotypes due to the anti-H antibody. To survey FUT1 alleles involved in Bombay and para-Bombay phenotypes, the effect of 22 uncharacterized nonsynonymous SNPs in the Erythrogene database on the α(1,2)fucosyltransferase activity were examined by transient expression studies and in silico analysis using four different online software tools. Two nonfunctional alleles (FUT1 with c.503C>G and c.749G>C) and one weakly functional allele (with c.799T>C) were identified in transient expression studies, while the software predicted that the proteins encoded by more alleles including these would be impaired. Because both nonfunctional FUT1 alleles appear to link to the nonsecretor alleles, homozygotes of these alleles would be of the Bombay phenotype. The present results suggest that functional assays are useful for characterization of nonsynonymous SNPs of FUT1 when their phenotypes are not available.
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Affiliation(s)
- Mikiko Soejima
- Department of Forensic Medicine, Kurume University School of Medicine, Kurume, 830-0011, Japan
| | - Yoshiro Koda
- Department of Forensic Medicine, Kurume University School of Medicine, Kurume, 830-0011, Japan.
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22
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Snaebjarnarson AS, Helgadottir A, Arnadottir GA, Ivarsdottir EV, Thorleifsson G, Ferkingstad E, Einarsson G, Sveinbjornsson G, Thorgeirsson TE, Ulfarsson MO, Halldorsson BV, Olafsson I, Erikstrup C, Pedersen OB, Nyegaard M, Bruun MT, Ullum H, Brunak S, Iversen KK, Christensen AH, Olesen MS, Ghouse J, Banasik K, Knowlton KU, Arnar DO, Thorgeirsson G, Nadauld L, Ostrowski SR, Bundgaard H, Holm H, Sulem P, Stefansson K, Gudbjartsson DF. Complex effects of sequence variants on lipid levels and coronary artery disease. Cell 2023; 186:4085-4099.e15. [PMID: 37714134 DOI: 10.1016/j.cell.2023.08.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 05/06/2023] [Accepted: 08/10/2023] [Indexed: 09/17/2023]
Abstract
Many sequence variants have additive effects on blood lipid levels and, through that, on the risk of coronary artery disease (CAD). We show that variants also have non-additive effects and interact to affect lipid levels as well as affecting variance and correlations. Variance and correlation effects are often signatures of epistasis or gene-environmental interactions. These complex effects can translate into CAD risk. For example, Trp154Ter in FUT2 protects against CAD among subjects with the A1 blood group, whereas it associates with greater risk of CAD in others. His48Arg in ADH1B interacts with alcohol consumption to affect lipid levels and CAD. The effect of variants in TM6SF2 on blood lipids is greatest among those who never eat oily fish but absent from those who often do. This work demonstrates that variants that affect variance of quantitative traits can allow for the discovery of epistasis and interactions of variants with the environment.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Magnus O Ulfarsson
- deCODE genetics/Amgen, Inc., Reykjavik 102, Iceland; Faculty of Electrical and Computer Engineering, University of Iceland, Reykjavik 102, Iceland
| | | | - Isleifur Olafsson
- Department of Clinical Biochemistry, Landspitali - National University Hospital of Iceland, Hringbraut, Reykjavik 101, Iceland
| | - Christian Erikstrup
- Department of Clinical Immunology, Aarhus University Hospital, Aarhus 8200, Denmark; Department of Clinical Medicine, Health, Aarhus University, Aarhus 8200, Denmark
| | - Ole B Pedersen
- Department of Clinical Immunology, Zealand University Hospital, Køge 4600, Denmark; Department of Clinical Medicine, University of Copenhagen, Copenhagen 1165, Denmark
| | - Mette Nyegaard
- Department of Health Science and Technology, Faculty of Medicine, Aalborg University, Aalborg 9220, Denmark
| | - Mie T Bruun
- Department of Clinical Immunology, Odense University Hospital, Odense 5000, Denmark
| | - Henrik Ullum
- Statens Serum Institut, Copenhagen 2300, Denmark
| | - Søren Brunak
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Kasper Karmark Iversen
- Department of Clinical Medicine, University of Copenhagen, Copenhagen 1165, Denmark; Department of Emergency Medicine, Copenhagen University Hospital Herlev and Gentofte, Herlev 2900, Denmark; Department of Cardiology, Copenhagen University Hospital, Herlev-Gentofte Hospital, Herlev 2900, Denmark
| | - Alex Hoerby Christensen
- Department of Clinical Medicine, University of Copenhagen, Copenhagen 1165, Denmark; Department of Cardiology, Copenhagen University Hospital, Herlev-Gentofte Hospital, Herlev 2900, Denmark
| | - Morten S Olesen
- Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen 2100, Denmark; Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen 1165, Denmark
| | - Jonas Ghouse
- Laboratory for Molecular Cardiology, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen 2100, Denmark; Laboratory for Molecular Cardiology, Department of Biomedical Sciences, University of Copenhagen, Copenhagen 1165, Denmark
| | - Karina Banasik
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark
| | - Kirk U Knowlton
- Intermountain Medical Center, Intermountain Heart Institute, Salt Lake City, UT 84143, USA
| | - David O Arnar
- deCODE genetics/Amgen, Inc., Reykjavik 102, Iceland; Faculty of Medicine, University of Iceland, Vatnsmyrarvegur, Reykjavik 101, Iceland; Division of Cardiology, Department of Internal Medicine, Landspitali - National University Hospital of Iceland, Hringbraut, Reykjavik 101, Iceland
| | - Gudmundur Thorgeirsson
- deCODE genetics/Amgen, Inc., Reykjavik 102, Iceland; Faculty of Medicine, University of Iceland, Vatnsmyrarvegur, Reykjavik 101, Iceland; Division of Cardiology, Department of Internal Medicine, Landspitali - National University Hospital of Iceland, Hringbraut, Reykjavik 101, Iceland
| | - Lincoln Nadauld
- Precision Genomics, Intermountain Healthcare, Saint George, UT 84790, USA
| | - Sisse Rye Ostrowski
- Department of Clinical Medicine, University of Copenhagen, Copenhagen 1165, Denmark; Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen 2100, Denmark
| | - Henning Bundgaard
- Department of Clinical Medicine, University of Copenhagen, Copenhagen 1165, Denmark; Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen 2100, Denmark
| | - Hilma Holm
- deCODE genetics/Amgen, Inc., Reykjavik 102, Iceland
| | | | - Kari Stefansson
- deCODE genetics/Amgen, Inc., Reykjavik 102, Iceland; Faculty of Medicine, University of Iceland, Vatnsmyrarvegur, Reykjavik 101, Iceland.
| | - Daniel F Gudbjartsson
- deCODE genetics/Amgen, Inc., Reykjavik 102, Iceland; School of Engineering and Natural Sciences, University of Iceland, Reykjavik 102, Iceland.
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23
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Sudarma V, Sunardi D, Marzuki NS, Munasir Z, Asmarinah, Hidayat A, Hegar B. Human Milk Oligosaccharide Profiles and the Secretor and Lewis Gene Status of Indonesian Lactating Mothers. Pediatr Gastroenterol Hepatol Nutr 2023; 26:266-276. [PMID: 37736221 PMCID: PMC10509021 DOI: 10.5223/pghn.2023.26.5.266] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 06/22/2023] [Accepted: 07/27/2023] [Indexed: 09/23/2023] Open
Abstract
Purpose Human milk oligosaccharides (HMOs) may be genetically determined based on the secretor and Lewis status of the mother. This study aims to determine the HMO profile and the secretor and Lewis gene status of Indonesian lactating mothers. Methods Baseline data of 120 mother-infant pairs between 0-4 months post-partum obtained from a prospective longitudinal study was used. The concentrations of 2'-fucosyllactose (2'FL), lacto-N-fucopentaose I (LNFP I), lacto-N-tetraose (LNT), lacto-N-neotetraose (LNnT), 3'-sialyllactose (3'SL), and 6'-sialyllactose (6'SL) were measured. Genetic analysis was performed for mothers using targeted next-generation sequencing and Sanger sequencing. Wild-type AA with the rs1047781 (A385T) polymorphism was categorized as secretor positive, while heterozygous mutant AT was classified as a weak secretor. The presence of rs28362459 (T59G) heterozygous mutant AC and rs3745635 (G508A) heterozygous mutant CT genes indicated a Lewis negative status, and the absence of these genes indicated a positive status. Subsequently, breast milk was classified into various groups, namely Group 1: Secretor+Lewis+ (Se+Le+), Group 2: Secretor-Lewis+ (Se-Le+), Group 3: Secretor+Lewis- (Se+Le-), and Group 4: Secretor-Lewis- (Se-Le-). Data were analyzed using the Mann-Whitney and Kruskal-Wallis rank tests, and a p-value of 0.05 indicated statistical significance. Results A total of 58.3% and 41.7% of the samples had positive and weak secretor statuses, respectively. The proportion of those in Group 1 was 85%, while 15% were Group 3. The results showed that only 2'FL significantly differed according to the secretor status (p-value=0.018). Conclusion All Indonesian lactating mothers in this study were secretor positive, and most of them had a Lewis-positive status.
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Affiliation(s)
- Verawati Sudarma
- Doctorate Program of Nutrition, Faculty of Medicine, Universitas Indonesia – Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
- Department of Nutrition, Faculty of Medicine, Universitas Trisakti, Jakarta, Indonesia
| | - Diana Sunardi
- Department of Nutrition, Faculty of Medicine, Universitas Indonesia – Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
| | - Nanis Sacharina Marzuki
- Eijkman Research Center for Molecular Biology, National Research and Innovation Agency, Jakarta, Indonesia
| | - Zakiudin Munasir
- Department of Child Health, Faculty of Medicine, Universitas Indonesia – Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
| | - Asmarinah
- Department of Medical Biology, Faculty of Medicine, Universitas Indonesia – Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
| | - Adi Hidayat
- Department of Public Health, Faculty of Medicine, Universitas Trisakti, Jakarta, Indonesia
| | - Badriul Hegar
- Department of Child Health, Faculty of Medicine, Universitas Indonesia – Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
- Indonesia Medical Education and Research Institute, Faculty of Medicine, Universitas Indonesia – Dr. Cipto Mangunkusumo General Hospital, Jakarta, Indonesia
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24
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Kim J, Yuan C, Amundadottir LT, Wolpin BM, Pancreatic Cancer Cohort Consortium (PanScan), Klein AP, Pancreatic Cancer Case-Control Consortium (PanC4), Risch HA, Kraft P. Relationship between ABO Blood Group Alleles and Pancreatic Cancer Is Modulated by Secretor (FUT2) Genotype, but Not Lewis Antigen (FUT3) Genotype. Cancer Epidemiol Biomarkers Prev 2023; 32:1242-1248. [PMID: 37342060 PMCID: PMC10527950 DOI: 10.1158/1055-9965.epi-23-0009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 05/15/2023] [Accepted: 06/16/2023] [Indexed: 06/22/2023] Open
Abstract
BACKGROUND In Western populations, pancreatic ductal adenocarcinoma (PDAC) risk has been found to be greater among individuals with non-O blood types than those with O blood type. However, the association has not been fully evaluated with respect to FUT2 (determining secretor status) and FUT3 (determining Lewis antigens) status, two biologically important genes in the expression of ABO blood groups with PDAC. METHODS We examined interactions in data from 8,027 cases and 11,362 controls in large pancreatic cancer consortia (PanScan I-III and PanC4) by using genetic variants to predict ABO blood groups (rs505922 and rs8176746), secretor status (rs601338), and Lewis antigens (rs812936, rs28362459, and rs3894326). Multivariable logistic regression was used to estimate ORs and 95% confidence intervals (CI) of the risk of PDAC adjusted for age and sex. We examined multiplicative interactions of ABO with secretor status and Lewis antigens by considering each product term between ABO and secretor and between ABO and Lewis antigens individually. RESULTS We found that the increased risk associated with non-O blood groups was somewhat stronger among secretors than nonsecretors [ORs, 1.28 (95% CI, 1.15-1.42) and 1.17 (95% CI, 1.03-1.32) respectively; Pinteraction = 0.002]. We did not find any interactions between ABO and Lewis antigens. CONCLUSIONS Our large consortia data provide evidence of effect modification in the association between non-O blood type and pancreatic cancer risk by secretor status. IMPACT Our results indicate that the association between ABO blood type and PDAC risk may vary by secretor status, but not by Lewis antigens.
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Affiliation(s)
- Jihye Kim
- Program in Genetic Epidemiology and Statistical Genetics,
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston,
Massachusetts, United States of America
| | - Chen Yuan
- Department of Medical Oncology, Dana-Farber Cancer
Institute, Boston, Massachusetts, United States of America
| | - Laufey T. Amundadottir
- Laboratory of Translational Genomics, Division of Cancer
Epidemiology and Genetics, National Cancer Institute, National Institutes of Health,
Bethesda, Maryland, United States of America
| | - Brian M. Wolpin
- Department of Medical Oncology, Dana-Farber Cancer
Institute, Boston, Massachusetts, United States of America
| | | | - Alison P. Klein
- Department of Oncology, Sidney Kimmel Comprehensive Cancer
Center, Johns Hopkins School of Medicine, Baltimore, MD, USA
- Department of Pathology, Sol Goldman Pancreatic Cancer
Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland, United
States of America
| | | | - Harvey A. Risch
- Department of Chronic Disease Epidemiology, Yale School of
Public Health, New Haven, Connecticut, United States of America
| | - Peter Kraft
- Program in Genetic Epidemiology and Statistical Genetics,
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston,
Massachusetts, United States of America
- Department of Biostatistics, Harvard T.H. Chan School of
Public Health, Boston, Massachusetts, United States of America
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25
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Fan Y, McMath AL, Donovan SM. Review on the Impact of Milk Oligosaccharides on the Brain and Neurocognitive Development in Early Life. Nutrients 2023; 15:3743. [PMID: 37686775 PMCID: PMC10490528 DOI: 10.3390/nu15173743] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 08/09/2023] [Accepted: 08/24/2023] [Indexed: 09/10/2023] Open
Abstract
Milk Oligosaccharides (MOS), a group of complex carbohydrates found in human and bovine milk, have emerged as potential modulators of optimal brain development for early life. This review provides a comprehensive investigation of the impact of milk oligosaccharides on brain and neurocognitive development of early life by synthesizing current literature from preclinical models and human observational studies. The literature search was conducted in the PubMed search engine, and the inclusion eligibility was evaluated by three reviewers. Overall, we identified 26 articles for analysis. While the literature supports the crucial roles of fucosylated and sialylated milk oligosaccharides in learning, memory, executive functioning, and brain structural development, limitations were identified. In preclinical models, the supplementation of only the most abundant MOS might overlook the complexity of naturally occurring MOS compositions. Similarly, accurately quantifying MOS intake in human studies is challenging due to potential confounding effects such as formula feeding. Mechanistically, MOS is thought to impact neurodevelopment through modulation of the microbiota and enhancement of neuronal signaling. However, further advancement in our understanding necessitates clinical randomized-controlled trials to elucidate the specific mechanisms and long-term implications of milk oligosaccharides exposure. Understanding the interplay between milk oligosaccharides and cognition may contribute to early nutrition strategies for optimal cognitive outcomes in children.
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Affiliation(s)
- Yuting Fan
- Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA;
| | - Arden L. McMath
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA;
| | - Sharon M. Donovan
- Department of Food Science and Human Nutrition, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA;
- Division of Nutritional Sciences, University of Illinois Urbana-Champaign, Urbana, IL 61801, USA;
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26
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Soejima M, Koda Y. Detection of c.375A>G, c.385A>T, c.571C>T, and sedel2 of FUT2 via Real-Time PCR in a Single Tube. Diagnostics (Basel) 2023; 13:2022. [PMID: 37370917 DOI: 10.3390/diagnostics13122022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/01/2023] [Accepted: 06/08/2023] [Indexed: 06/29/2023] Open
Abstract
α(1,2)fucosyltransferase (Se enzyme) encoded by FUT2 is involved in the secretor status of ABH(O) blood group antigens. The sedel2 allele is one of the non-functional FUT2 (se) alleles in which 9.3 kb, containing the entire coding region of FUT2, is deleted by Alu-mediated nonhomologous recombination. In addition to this allele, three SNPs of FUT2, c.375A>G, c.385A>T, and c.571C>T, appear to be prevalent in certain Oceanian populations such as Polynesians. Recently, we developed an endpoint genotyping assay to determine sedel2 zygosity, using a FAM-labeled probe for detection of the sedel2 allele and a VIC-labeled probe for the detection of FUT2. In this study, instead of the VIC probe, a HEX-labeled probe covering both c.375A>G and c.385A>T and a Cy5-labeled probe covering c.571C>T were added to the sedel2 allele assay mixture to allow for the simultaneous detection of these four variations via endpoint genotyping for sedel2 zygosity and fluorescence melting curve analysis for c.375A>G, c.385A>T, and c.571C>T genotyping. The results obtained from 24 Samoan subjects using this method were identical to those obtained using previous methods. Therefore, it appears that the present method can accurately determine these four variations simultaneously.
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Affiliation(s)
- Mikiko Soejima
- Department of Forensic Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Yoshiro Koda
- Department of Forensic Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
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Packer RJ, Shrine N, Hall R, Melbourne CA, Thompson R, Williams AT, Paynton ML, Guyatt AL, Allen RJ, Lee PH, John C, Campbell A, Hayward C, de Vries M, Vonk JM, Davitte J, Hessel E, Michalovich D, Betts JC, Sayers I, Yeo A, Hall IP, Tobin MD, Wain LV. Genome-wide association study of chronic sputum production implicates loci involved in mucus production and infection. Eur Respir J 2023; 61:2201667. [PMID: 37263751 PMCID: PMC10284065 DOI: 10.1183/13993003.01667-2022] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 02/17/2023] [Indexed: 06/03/2023]
Abstract
BACKGROUND Chronic sputum production impacts on quality of life and is a feature of many respiratory diseases. Identification of the genetic variants associated with chronic sputum production in a disease agnostic sample could improve understanding of its causes and identify new molecular targets for treatment. METHODS We conducted a genome-wide association study (GWAS) of chronic sputum production in UK Biobank. Signals meeting genome-wide significance (p<5×10-8) were investigated in additional independent studies, were fine-mapped and putative causal genes identified by gene expression analysis. GWASs of respiratory traits were interrogated to identify whether the signals were driven by existing respiratory disease among the cases and variants were further investigated for wider pleiotropic effects using phenome-wide association studies (PheWASs). RESULTS From a GWAS of 9714 cases and 48 471 controls, we identified six novel genome-wide significant signals for chronic sputum production including signals in the human leukocyte antigen (HLA) locus, chromosome 11 mucin locus (containing MUC2, MUC5AC and MUC5B) and FUT2 locus. The four common variant associations were supported by independent studies with a combined sample size of up to 2203 cases and 17 627 controls. The mucin locus signal had previously been reported for association with moderate-to-severe asthma. The HLA signal was fine-mapped to an amino acid change of threonine to arginine (frequency 36.8%) in HLA-DRB1 (HLA-DRB1*03:147). The signal near FUT2 was associated with expression of several genes including FUT2, for which the direction of effect was tissue dependent. Our PheWAS identified a wide range of associations including blood cell traits, liver biomarkers, infections, gastrointestinal and thyroid-associated diseases, and respiratory disease. CONCLUSIONS Novel signals at the FUT2 and mucin loci suggest that mucin fucosylation may be a driver of chronic sputum production even in the absence of diagnosed respiratory disease and provide genetic support for this pathway as a target for therapeutic intervention.
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Affiliation(s)
- Richard J Packer
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Nick Shrine
- Department of Population Health Sciences, University of Leicester, Leicester, UK
| | - Robert Hall
- Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | - Carl A Melbourne
- Department of Population Health Sciences, University of Leicester, Leicester, UK
| | - Rebecca Thompson
- Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | - Alex T Williams
- Department of Population Health Sciences, University of Leicester, Leicester, UK
| | - Megan L Paynton
- Department of Population Health Sciences, University of Leicester, Leicester, UK
| | - Anna L Guyatt
- Department of Population Health Sciences, University of Leicester, Leicester, UK
| | - Richard J Allen
- Department of Population Health Sciences, University of Leicester, Leicester, UK
| | - Paul H Lee
- Department of Population Health Sciences, University of Leicester, Leicester, UK
| | - Catherine John
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Archie Campbell
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, Western General Hospital, Edinburgh, UK
| | - Caroline Hayward
- Medical Research Council Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
| | - Maaike de Vries
- University of Groningen, University Medical Center Groningen, Department of Epidemiology and Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands
| | - Judith M Vonk
- University of Groningen, University Medical Center Groningen, Department of Epidemiology and Groningen Research Institute for Asthma and COPD (GRIAC), Groningen, The Netherlands
| | | | | | | | | | - Ian Sayers
- Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | | | - Ian P Hall
- Centre for Respiratory Research, NIHR Nottingham Biomedical Research Centre, School of Medicine, Biodiscovery Institute, University of Nottingham, Nottingham, UK
| | - Martin D Tobin
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
| | - Louise V Wain
- Department of Population Health Sciences, University of Leicester, Leicester, UK
- Leicester NIHR Biomedical Research Centre, Glenfield Hospital, Leicester, UK
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Berry A, Kapelus D, Singh P, Groome M, de Assis Rosa D. ABO blood types, but not Secretor or Lewis blood types, influence strength of antibody response to Hepatitis B vaccine in Black South African children. Vaccine 2023:S0264-410X(23)00465-6. [PMID: 37169653 DOI: 10.1016/j.vaccine.2023.04.051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Revised: 03/24/2023] [Accepted: 04/19/2023] [Indexed: 05/13/2023]
Abstract
Subunit vaccines for the Hepatitis B virus (HBV) have greatly reduced the prevalence of infection and morbidity through HBV-related liver cirrhosis and cancer. However, strength of immune response to vaccination varies considerably. While it is known that ABO blood types may influence HBV infection risk, the role of ABO and related blood types in strength of immune response to HBV vaccine has not been investigated. We examined 16 polymorphisms in the ABO, FUT2, and FUT3 genes and their related phenotypes for associations with strength of antibody response to HBV vaccine in Black South African infants. Anti-HBc and anti-HBs antibody levels were measured by CMIA assay 1-3 months after the last dose of HBV vaccine. Prior infection occurred in 8/207 individuals (3.86%) who were removed from further study. Of the remaining 199 individuals, 83.4% individuals were strong responders (anti-HBs ≥ 100 mIU/ml, median 973 mIU/ml), another 15.6% were weak responders (anti-HBs < 100 mIU/ml, median 50 mIU/ml) and 1% were non-responders (anti-HBs < 10 mIU/ml). The frequency of weak responders to HBV vaccine was not significantly affected by sex, birthweight, use of an additional booster dose of vaccine or cohort of origin. We characterised patterns of genetic variation present at the ABO, FUT2 and FUT3 loci by use of MassArray genotyping and used these data to predict ABO, Secretor and Lewis phenotypes. We observed significant association of ABO blood type with strength of antibody response to HBV vaccine in a Black South African cohort (p = 0.002). In particular, presence of rs8176747G and expression of B antigen (whether in B blood type or AB blood type) was associated with decreased antibody response to HBV vaccine. Secretor and Lewis blood types were not associated with antibody response to HBV vaccine. This work increases our understanding of the impact that host genetic variation may have on vaccine immunogenicity.
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Affiliation(s)
- Adam Berry
- School of Molecular and Cell Biology, Faculty of Science, University of the Witwatersrand, Jhb, South Africa
| | - Daniel Kapelus
- School of Molecular and Cell Biology, Faculty of Science, University of the Witwatersrand, Jhb, South Africa
| | - Payal Singh
- School of Molecular and Cell Biology, Faculty of Science, University of the Witwatersrand, Jhb, South Africa
| | - Michelle Groome
- Vaccines and Infectious Diseases Analytics (VIDA) Research Unit, SA Medical Research Council and University of the Witwatersrand, Jhb, South Africa; National Institute for Communicable Diseases, Jhb, South Africa
| | - Debra de Assis Rosa
- School of Molecular and Cell Biology, Faculty of Science, University of the Witwatersrand, Jhb, South Africa.
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Fan Y, Vinjamuri A, Tu D, Lebrilla CB, Donovan SM. Determinants of human milk oligosaccharides profiles of participants in the STRONG kids 2 cohort. Front Nutr 2023; 10:1105668. [PMID: 37057069 PMCID: PMC10086122 DOI: 10.3389/fnut.2023.1105668] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Accepted: 03/10/2023] [Indexed: 03/30/2023] Open
Abstract
IntroductionHuman milk oligosaccharides (HMOS) are indigestible carbohydrates that support infant development by establishing a healthy microbiota, preventing infectious diseases, and promoting immune and cognitive development. Individual HMOS have distinct functions based on their chemical structures. HMO profiles can vary largely among mothers, but the research on factors other than genetic background affecting HMO composition are limited.MethodsIn the present analysis, we examined the relationships between maternal characteristics and the HMO profiles of breastfeeding mothers (n = 392) in the STRONG kids 2 with the following demographic characteristics: average age: 30.8 y, 74.5% White, and 75.5% exclusively breastfeeding. Human milk samples were collected at 6 weeks postpartum and maternal information was obtained from self-reported surveys. Information on dietary intake changes since the participants have been breastfeeding was collected. HMO profiles were analyzed by high performance liquid chromatography coupled with mass spectrometry and secretor status was determined by the presence of four secretor markers [2′-fucosyllactose (2′-FL), LNFP I, LDFT, and TFLNH]. Spearmen correlation test was utilized to determine the relationships between individual HMOS and associations with maternal factors. Between-group differences in HMO relative abundances were examined with Kruskal-Wallis test.ResultsAmong all participants, 71.9% were secretors and 28.1% were non-secretors. The relative abundances of all HMOS differed (p < 0.05) by secretor status, with the exception for 6′-SL and 3′-SL. Positive correlations were observed among HMOS with similar structures, such as the 1,2-fucosylated HMOS. The abundances of selected HMOS were associated with maternal body weight, pregnancy complications, and dietary characteristics. Based on pre-pregnancy BMI, in all mothers, relative abundance of 3′-SL was significantly higher in overweight mothers than obese mothers (p = 0.013). In milk produced by non-secretor mothers, LNPF I + III abundances were greater in overweight than normal weight mothers (p = 0.020). Several HMO abundances were found to be associated with Gestational diabetes mellitus (GDM). Variations of HMO abundances were also observed with dietary food intake. In all mothers, egg consumption was positively correlated with LNT + LNnT (R = 0.13; p = 0.012) and cheese intake was positively associated with 2′-FL (R = 0.10; p = 0.046) and S-LNnH II (R = 0.11; p = 0.026) abundances.DiscussionHMO profiles were found to be associated with maternal characteristics and intake. Future research will investigate associations between HMOS and maternal and infant outcomes.
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Affiliation(s)
- Yuting Fan
- Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL, United States
| | - Anita Vinjamuri
- Department of Chemistry, University of California, Davis, Davis, CA, United States
| | - Diane Tu
- Department of Chemistry, University of California, Davis, Davis, CA, United States
| | - Carlito B. Lebrilla
- Department of Chemistry, University of California, Davis, Davis, CA, United States
| | - Sharon M. Donovan
- Department of Food Science and Human Nutrition, University of Illinois, Urbana, IL, United States
- *Correspondence: Sharon M. Donovan,
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Fu C, Xu X, Xie Y, Liu Y, Liu M, Chen A, Blamey JM, Shi J, Zhao S, Sun J. Rational design of GDP‑D‑mannose mannosyl hydrolase for microbial L‑fucose production. Microb Cell Fact 2023; 22:56. [PMID: 36964553 PMCID: PMC10037897 DOI: 10.1186/s12934-023-02060-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 03/11/2023] [Indexed: 03/26/2023] Open
Abstract
BACKGROUND L‑Fucose is a rare sugar that has beneficial biological activities, and its industrial production is mainly achieved with brown algae through acidic/enzymatic fucoidan hydrolysis and a cumbersome purification process. Fucoidan is synthesized through the condensation of a key substance, guanosine 5'‑diphosphate (GDP)‑L‑fucose. Therefore, a more direct approach for biomanufacturing L‑fucose could be the enzymatic degradation of GDP‑L‑fucose. However, no native enzyme is known to efficiently catalyze this reaction. Therefore, it would be a feasible solution to engineering an enzyme with similar function to hydrolyze GDP‑L‑fucose. RESULTS Herein, we constructed a de novo L‑fucose synthetic route in Bacillus subtilis by introducing heterologous GDP‑L‑fucose synthesis pathway and engineering GDP‑mannose mannosyl hydrolase (WcaH). WcaH displays a high binding affinity but low catalytic activity for GDP‑L‑fucose, therefore, a substrate simulation‑based structural analysis of the catalytic center was employed for the rational design and mutagenesis of selected positions on WcaH to enhance its GDP‑L‑fucose‑splitting efficiency. Enzyme mutants were evaluated in vivo by inserting them into an artificial metabolic pathway that enabled B. subtilis to yield L‑fucose. WcaHR36Y/N38R was found to produce 1.6 g/L L‑fucose during shake‑flask growth, which was 67.3% higher than that achieved by wild‑type WcaH. The accumulated L‑fucose concentration in a 5 L bioreactor reached 6.4 g/L. CONCLUSIONS In this study, we established a novel microbial engineering platform for the fermentation production of L‑fucose. Additionally, we found an efficient GDP‑mannose mannosyl hydrolase mutant for L‑fucose biosynthesis that directly hydrolyzes GDP‑L‑fucose. The engineered strain system established in this study is expected to provide new solutions for L‑fucose or its high value‑added derivatives production.
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Affiliation(s)
- Cong Fu
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xuexia Xu
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
- iHuman Institute, ShanghaiTech University, Shanghai, 201210, China
| | - Yukang Xie
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yufei Liu
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Min Liu
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
| | - Ai Chen
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jenny M Blamey
- Fundación Biociencia, José Domingo Cañas, 2280, Ñuñoa, Santiago, Chile
- Facultad de Química Y Biología, Universidad de Santiago de Chile, 3363, Alameda, Estación Central, Santiago, Chile
| | - Jiping Shi
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210, China
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Suwen Zhao
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
- iHuman Institute, ShanghaiTech University, Shanghai, 201210, China.
| | - Junsong Sun
- Shanghai Advanced Research Institute, Chinese Academy of Sciences, Shanghai, 201210, China.
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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Nanthakumar NN, Meng D, Newburg DS. Fucosylated TLR4 mediates communication between mutualist fucotrophic microbiota and mammalian gut mucosa. Front Med (Lausanne) 2023; 10:1070734. [PMID: 37007789 PMCID: PMC10061023 DOI: 10.3389/fmed.2023.1070734] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2022] [Accepted: 01/26/2023] [Indexed: 03/18/2023] Open
Abstract
Objective The glycans on the mucosa of suckling mice are predominantly sialylated; upon weaning, fucosylated glycans preponderate. This manifestation of mutualism between fucotrophic bacteria and the mature host utilizes a sentinel receptor in the intestinal mucosa; this receptor was isolated to distinguish its structural and functional features. Design Provisional identification of the sentinel gut receptor as fuc-TLR4 was through colonization of germ-free mutant mice. Conventional mice whose microbiota was depleted with a cocktail of antibiotics were used to further define the nature and functions of fuc-TLR4 sentinel, and to define the role of the fucotrophic microbiota in gut homeostasis and recovery from insult. The nature of the sentinel was confirmed in cultured human HEL cells. Results Fuc-TLR4 activity is distinct from that of TLR4. Activated mucosal fuc-TLR4 induces a fuc-TLR4 dependent non-inflammatory (ERK and JNK dependent, NF-κB independent) signaling cascade, initiating induction of fucosyltransferase 2 (secretor) gene transcription. In vitro, either defucosylation or TLR4 knockdown abrogates FUT2 induction, indicating that fuc-TLR4 activity requires both the peptide and glycan moieties. In vivo, fucose-utilizing bacteria and fucose-binding ligands induce mucosal fucosylation. Activation of this pathway is essential for recovery from chemically induced mucosal injury in vivo. Conclusion In mature mice, fucosyl-TLR4 mediated gut fucosylation creates a niche that supports the healthy fucose-dependent mutualism between the mammalian gut and its fucotrophic microbes. Such microbiota-induced Fuc-TLR4 signaling supports initial colonization of the secretor gut, recovery from dysbiosis, and restoration or preservation of intestinal homeostasis.
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Affiliation(s)
| | | | - David S. Newburg
- Department of Pediatrics, Harvard Medical School and GI Unit, Massachusetts General Hospital, Boston, MA, United States
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Estimation of Lewis Blood Group Status by Fluorescence Melting Curve Analysis in Simultaneous Genotyping of c.385A>T and Fusion Gene in FUT2 and c.59T>G and c.314C>T in FUT3. Diagnostics (Basel) 2023; 13:diagnostics13050931. [PMID: 36900072 PMCID: PMC10000471 DOI: 10.3390/diagnostics13050931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 02/15/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Lewis blood group status is determined by two fucosyltransferase activities: those of FUT2-encoded fucosyltransferase (Se enzyme) and FUT3-encoded fucosyltransferase (Le enzyme). In Japanese populations, c.385A>T in FUT2 and a fusion gene between FUT2 and its pseudogene SEC1P are the cause of most Se enzyme-deficient alleles (Sew and sefus), and c.59T>G and c.314C>T in FUT3 are tag SNPs for almost all nonfunctional FUT3 alleles (le59, le59,508, le59,1067, and le202,314). In this study, we first conducted a single-probe fluorescence melting curve analysis (FMCA) to determine c.385A>T and sefus using a pair of primers that collectively amplify FUT2, sefus, and SEC1P. Then, to estimate Lewis blood group status, a triplex FMCA was performed with a c.385A>T and sefus assay system by adding primers and probes to detect c.59T>G and c.314C>T in FUT3. We also validated these methods by analyzing the genotypes of 96 selected Japanese people whose FUT2 and FUT3 genotypes were already determined. The single-probe FMCA was able to identify six genotype combinations: 385A/A, 385T/T, sefus/sefus, 385A/T, 385A/sefus, and 385T/sefus. In addition, the triplex FMCA successfully identified both FUT2 and FUT3 genotypes, although the resolutions of the analysis of c.385A>T and sefus were somewhat reduced compared to that of the analysis of FUT2 alone. The estimation of the secretor status and Lewis blood group status using the form of FMCA used in this study may be useful for large-scale association studies in Japanese populations.
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Thorman AW, Adkins G, Conrey SC, Burrell AR, Yu Y, White B, Burke R, Haslam D, Payne DC, Staat MA, Morrow AL, Newburg DS. Gut Microbiome Composition and Metabolic Capacity Differ by FUT2 Secretor Status in Exclusively Breastfed Infants. Nutrients 2023; 15:471. [PMID: 36678342 PMCID: PMC9866411 DOI: 10.3390/nu15020471] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2022] [Revised: 12/29/2022] [Accepted: 01/14/2023] [Indexed: 01/18/2023] Open
Abstract
A major polymorphism in the fucosyltransferase2 (FUT2) gene influences risk of multiple gut diseases, but its impact on the microbiome of breastfed infants was unknown. In individuals with an active FUT2 enzyme (“secretors”), the intestinal mucosa is abundantly fucosylated, providing mutualist bacteria with a rich endogenous source of fucose. Non-secretors comprise approximately one-fifth of the population, and they lack the ability to create this enzyme. Similarly, maternal secretor status influences the abundance of a breastfeeding mother’s fucosylated milk oligosaccharides. We compared the impact of maternal secretor status, measured by FUT2 genotype, and infant secretor status, measured by FUT2 genotype and phenotype, on early infant fecal microbiome samples collected from 2-month-old exclusively breastfed infants (n = 59). Infant secretor status (19% non-secretor, 25% low-secretor, and 56% full-secretor) was more strongly associated with the infant microbiome than it was with the maternal FUT2 genotype. Alpha diversity was greater in the full-secretors than in the low- or non-secretor infants (p = 0.049). Three distinct microbial enterotypes corresponded to infant secretor phenotype (p = 0.022) and to the dominance of Bifidobacterium breve, B. longum, or neither (p < 0.001). Infant secretor status was also associated with microbial metabolic capacity, specifically, bioenergetics pathways. We concluded that in exclusively breastfed infants, infant—but not maternal—secretor status is associated with infant microbial colonization and metabolic capacity.
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Affiliation(s)
- Alexander W. Thorman
- Department of Environmental and Public Health Sciences, Division of Epidemiology, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
| | - Grace Adkins
- St. Jude’s Graduate School of Biomedical Sciences, Memphis, TN 38105, USA
| | - Shannon C. Conrey
- Department of Environmental and Public Health Sciences, Division of Epidemiology, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Department of Pediatrics, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45220, USA
| | - Allison R. Burrell
- Department of Environmental and Public Health Sciences, Division of Epidemiology, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Department of Pediatrics, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45220, USA
| | - Ying Yu
- Department of Pharmaceutical Sciences, College of Pharmacy, The University of Tennessee Health Science Center, Memphis, TN 38163, USA
| | - Brendon White
- Department of Pediatrics, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45220, USA
| | - Rachel Burke
- Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA
| | - David Haslam
- Department of Pediatrics, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45220, USA
| | - Daniel C. Payne
- Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA
| | - Mary A. Staat
- Department of Pediatrics, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45220, USA
| | - Ardythe L. Morrow
- Department of Environmental and Public Health Sciences, Division of Epidemiology, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
- Department of Pediatrics, Division of Infectious Diseases, University of Cincinnati College of Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45220, USA
| | - David S. Newburg
- Department of Environmental and Public Health Sciences, Division of Epidemiology, University of Cincinnati College of Medicine, Cincinnati, OH 45220, USA
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Lin SJH, Helm ET, Gabler NK, Burrough ER. Acute infection with Brachyspira hyodysenteriae affects mucin expression, glycosylation, and fecal MUC5AC. Front Cell Infect Microbiol 2023; 12:1042815. [PMID: 36683692 PMCID: PMC9852840 DOI: 10.3389/fcimb.2022.1042815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Accepted: 11/28/2022] [Indexed: 01/08/2023] Open
Abstract
Introduction Infection with strongly β-hemolytic strains of Brachyspira hyodysenteriae leads to swine dysentery (SD), a production-limiting disease that causes mucohemorrhagic diarrhea and typhlocolitis in pigs. This pathogen has strong chemotactic activity toward mucin, and infected pigs often have a disorganized mucus layer and marked de novo expression of MUC5AC, which is not constitutively expressed in the colon. It has been shown that fucose is chemoattractant for B. hyodysenteriae, and a highly fermentable fiber diet can mitigate and delay the onset of SD. Methods We used lectins targeting sialic acids in α-2,6 or α-2,3 linkages, N-acetylglucosamine (GlcNAc), α-linked L-fucose, and an immunohistochemical stain targeting N-glycolylneuraminic acid (NeuGc) to investigate the local expression of these mucin glycans in colonic tissues of pigs with acute SD. We used a commercial enzyme-linked immunosorbent assay (ELISA) to quantify fecal MUC5AC in infected pigs and assess its potential as a diagnostic monitoring tool and RNA in situ hybridization to detect IL-17A in the colonic mucosa. Results Colonic mucin glycosylation during SD has an overall increase in fucose, a spatially different distribution of GlcNAc with more expression within the crypt lumens of the upper colonic mucosa, and decreased expression or a decreased trend of sialic acids in α-2,6 or α-2,3 linkages, and NeuGc compared to the controls. The degree of increased fucosylation was less in the colonic mucosa of pigs with SD and fed the highly fermentable fiber diet. There was a significant increase in MUC5AC in fecal and colonic samples of pigs with SD at the endpoint compared to the controls, but the predictive value for disease progression was limited. Discussion Fucosylation and the impact of dietary fiber may play important roles in the pathogenesis of SD. The lack of predictive value for fecal MUC5AC quantification by ELISA is possibly due to the presence of other non-colonic sources of MUC5AC in the feces. The moderate correlation between IL-17A, neutrophils and MUC5AC confirms its immunoregulatory and mucin stimulatory role. Our study characterizes local alteration of mucin glycosylation in the colonic mucosa of pigs with SD after B. hyodysenteriae infection and may provide insight into host-pathogen interaction.
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Affiliation(s)
- Susanne Je-Han Lin
- Department of Veterinary Pathology, Iowa State University, Ames, IA, United States
| | - Emma T Helm
- Department of Animal Science, Iowa State University, Ames, IA, United States
| | - Nicholas K Gabler
- Department of Animal Science, Iowa State University, Ames, IA, United States
| | - Eric R Burrough
- Department of Veterinary Diagnostic and Production Animal Medicine, Iowa State University, Ames, IA, United States
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Raev S, Amimo J, Saif L, Vlasova A. Intestinal mucin-type O-glycans: the major players in the host-bacteria-rotavirus interactions. Gut Microbes 2023; 15:2197833. [PMID: 37020288 PMCID: PMC10078158 DOI: 10.1080/19490976.2023.2197833] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 03/28/2023] [Indexed: 04/07/2023] Open
Abstract
Rotavirus (RV) causes severe diarrhea in young children and animals worldwide. Several glycans terminating in sialic acids (SAs) and histo-blood group antigens (HBGAs) on intestinal epithelial cell (IEC) surface have been recognized to act as attachment sites for RV. IECs are protected by the double layer of mucus of which O-glycans (including HBGAs and SAs) are a major organic component. Luminal mucins, as well as bacterial glycans, can act as decoy molecules removing RV particles from the gut. The composition of the intestinal mucus is regulated by complex O-glycan-specific interactions among the gut microbiota, RV and the host. In this review, we highlight O-glycan-mediated interactions within the intestinal lumen prior to RV attachment to IECs. A better understanding of the role of mucus is essential for the development of alternative therapeutic tools including the use of pre- and probiotics to control RV infection.
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Affiliation(s)
- S.A. Raev
- Center for Food Animal Health, Department of Animal Sciences, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, USA
| | - J.O. Amimo
- Center for Food Animal Health, Department of Animal Sciences, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, USA
- Department of Animal Production, Faculty of Veterinary Medicine, University of Nairobi, Nairobi, Kenya
| | - L.J. Saif
- Center for Food Animal Health, Department of Animal Sciences, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, USA
| | - A.N. Vlasova
- Center for Food Animal Health, Department of Animal Sciences, College of Food, Agricultural and Environmental Sciences, The Ohio State University, Wooster, OH, USA
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Barmania F, Mellet J, Holborn MA, Pepper MS. Genetic Associations with Coronavirus Susceptibility and Disease Severity. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1412:119-140. [PMID: 37378764 DOI: 10.1007/978-3-031-28012-2_6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/29/2023]
Abstract
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) global public health emergency, and the disease it causes is highly variable in its clinical presentation. Host genetic factors are increasingly recognised as a determinant of infection susceptibility and disease severity. Several initiatives and groups have been established to analyse and review host genetic epidemiology associated with COVID-19 outcomes. Here, we review the genetic loci associated with COVID-19 susceptibility and severity focusing on the common variants identified in genome-wide association studies.
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Affiliation(s)
- Fatima Barmania
- Institute for Cellular and Molecular Medicine, Department of Immunology, SAMRC Extramural Unit for Stem Cell Research and Therapy, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Juanita Mellet
- Institute for Cellular and Molecular Medicine, Department of Immunology, SAMRC Extramural Unit for Stem Cell Research and Therapy, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Megan A Holborn
- Institute for Cellular and Molecular Medicine, Department of Immunology, SAMRC Extramural Unit for Stem Cell Research and Therapy, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa
| | - Michael S Pepper
- Institute for Cellular and Molecular Medicine, Department of Immunology, SAMRC Extramural Unit for Stem Cell Research and Therapy, Faculty of Health Sciences, University of Pretoria, Pretoria, South Africa.
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Moslemi C, Sækmose S, Larsen R, Brodersen T, Didriksen M, Hjalgrim H, Banasik K, Nielsen KR, Bruun MT, Dowsett J, Kasperen KA, Mikkelsen S, Hansen TF, Ullum H, Erikstrup C, Olsson ML, Ostrowski SR, Pedersen OB. A large cohort study of the effects of Lewis, ABO, 13 other blood groups, and secretor status on COVID-19 susceptibility, severity, and long COVID-19. Transfusion 2023; 63:47-58. [PMID: 36271437 PMCID: PMC9874484 DOI: 10.1111/trf.17170] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 08/15/2022] [Accepted: 09/14/2022] [Indexed: 01/27/2023]
Abstract
BACKGROUND Previous studies have reported Blood type O to confer a lower risk of SARS-CoV-2 infection, while secretor status and other blood groups have been suspected to have a similar effect as well. STUDY DESIGN AND METHODS To determine whether any other blood groups influence testing positive for SARS-CoV-2, COVID-19 severity, or prolonged COVID-19, we used a large cohort of 650,156 Danish blood donors with varying available data for secretor status and blood groups ABO, Rh, Colton, Duffy, Diego, Dombrock, Kell, Kidd, Knops, Lewis, Lutheran, MNS, P1PK, Vel, and Yt. Of these, 36,068 tested positive for SARS-CoV-2 whereas 614,088 tested negative between 2020-02-17 and 2021-08-04. Associations between infection and blood groups were assessed using logistic regression models with sex and age as covariates. RESULTS The Lewis blood group antigen Lea displayed strongly reduced SARS-CoV-2 susceptibility OR 0.85 CI[0.79-0.93] p < .001. Compared to blood type O, the blood types B, A, and AB were found more susceptible toward infection with ORs 1.1 CI[1.06-1.14] p < .001, 1.17 CI[1.14-1.2] p < .001, and 1.2 CI[1.14-1.26] p < .001, respectively. No susceptibility associations were found for the other 13 blood groups investigated. There was no association between any blood groups and COVID-19 hospitalization or long COVID-19. No secretor status associations were found. DISCUSSION This study uncovers a new association to reduced SARS-CoV-2 susceptibility for Lewis type Lea and confirms the previous link to blood group O. The new association to Lea could be explained by a link between mucosal microbiome and SARS-CoV-2.
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Affiliation(s)
- Camous Moslemi
- Department of Clinical ImmunologyZealand University HospitalKøgeDenmark
| | - Susanne Sækmose
- Department of Clinical ImmunologyZealand University HospitalKøgeDenmark
| | - Rune Larsen
- Department of Clinical ImmunologyZealand University HospitalKøgeDenmark
| | | | - Maria Didriksen
- Department of Clinical ImmunologyCopenhagen University Hospital, RigshopitaletCopenhagenDenmark
| | - Henrik Hjalgrim
- Department of Clinical ImmunologyAarhus University HospitalSkejbyDenmark
| | - Karina Banasik
- Novo Nordisk Foundation Center for Protein ResearchUniversity of CopenhagenCopenhagenDenmark
| | - Kaspar R. Nielsen
- Department of Clinical ImmunologyAalborg University HospitalAalborgDenmark
| | - Mie T. Bruun
- Department of Clinical ImmunologyOdense University HospitalOdenseDenmark
| | - Joseph Dowsett
- Department of Clinical ImmunologyCopenhagen University Hospital, RigshopitaletCopenhagenDenmark
| | - Kathrine A. Kasperen
- Danish Cancer Society Research CenterCopenhagenDenmark,Danish Big Data Centre for Environment and Health (BERTHA)Aarhus UniversityRoskildeDenmark
| | | | - Thomas F. Hansen
- Novo Nordisk Foundation Center for Protein ResearchUniversity of CopenhagenCopenhagenDenmark,Department of NeurologyNeuroGenomic group, RigshospitaletGlostrupDenmark
| | | | | | - Martin L. Olsson
- Department of Laboratory MedicineLund UniversityLundSweden,Department of Clinical Immunology and Transfusion MedicineOffice for Medical ServicesLundSweden
| | - Sisse R. Ostrowski
- Department of Clinical ImmunologyCopenhagen University Hospital, RigshopitaletCopenhagenDenmark,Department of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
| | - Ole B. Pedersen
- Department of Clinical ImmunologyZealand University HospitalKøgeDenmark,Department of Clinical Medicine, Faculty of Health and Medical SciencesUniversity of CopenhagenCopenhagenDenmark
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38
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Nguyen MTT, Seo N, Kim YK, Jung JA, An HJ, Kim JM, Song YH, Kim J, Yoon JW. The analysis of 2'-fucosyllactose concentration in Korean maternal milk using LC-MS/MS. Food Sci Biotechnol 2022; 31:1661-1666. [PMID: 36312994 PMCID: PMC9596627 DOI: 10.1007/s10068-022-01154-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/02/2022] [Accepted: 08/05/2022] [Indexed: 11/27/2022] Open
Abstract
Despite health benefits reported recently, 2'-fucosyllactose (2'-FL) concentration in maternal milk was not conclusively reported because it varies between countries and mothers. Particularly, its distribution among Korean mothers was not obtained from a reliable sample group yet. Thus, a dynamic range for 2'-FL concentration in Korean mothers' milk was investigated from 102 samples. A quantitative method using multiple reaction monitoring (MRM) by triple-quadrupole-mass spectrometry has been evaluated by a standard procedure of method validation. The 2'-FL concentration was in the range of 0.4 to 2.6 g/L overall. While the samples from secretor mothers (n = 80) contained 1.0 to 2.8 g/L of 2'-FL, the maternal milk from non-secretor mothers (n = 22) had 0.01 to 0.06 g/L of 2'-FL only. In addition to the genetic variation of mothers, the lactation period impacted the 2'-FL concentration. The average 2'-FL concentration of the late-stage group (> 60 days) was 78% of that obtained from the first month of postpartum mothers. Supplementary Information The online version contains supplementary material available at 10.1007/s10068-022-01154-4.
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Affiliation(s)
- My Tuyen T. Nguyen
- Department of Food and Nutrition, Chungnam National University, Daejeon, 34134 Korea
- College of Agriculture, Can Tho University, Can Tho City, 900000 Vietnam
| | - Nari Seo
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 34134 Korea
| | - Yong-Ki Kim
- Maeil Asia Human Milk Research Center, Maeil Dairies Co. Ltd, 63 Jinwiseo-ro, Jinwi-myeon, Pyeongtaek, 17706 Gyeonggi-do Korea
| | - Ji A. Jung
- Maeil Asia Human Milk Research Center, Maeil Dairies Co. Ltd, 63 Jinwiseo-ro, Jinwi-myeon, Pyeongtaek, 17706 Gyeonggi-do Korea
| | - Hyun Joo An
- Graduate School of Analytical Science and Technology, Chungnam National University, Daejeon, 34134 Korea
| | - Jung-Min Kim
- Advanced Protein Technologies Corporation, Suwon, Gyeonggi-do 16229 Korea
| | - Young-Ha Song
- Advanced Protein Technologies Corporation, Suwon, Gyeonggi-do 16229 Korea
| | - Jaehan Kim
- Department of Food and Nutrition, Chungnam National University, Daejeon, 34134 Korea
| | - Jong-Won Yoon
- Advanced Protein Technologies Corporation, Suwon, Gyeonggi-do 16229 Korea
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39
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Saikia K, Saharia N, Singh CS, Borah PP, Namsa ND. Association of histo-blood group antigens and predisposition to gastrointestinal diseases. J Med Virol 2022; 94:5149-5162. [PMID: 35882942 DOI: 10.1002/jmv.28028] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 06/26/2022] [Accepted: 07/23/2022] [Indexed: 12/15/2022]
Abstract
Infectious gastroenteritis is a common illness afflicting people worldwide. The two most common etiological agents of viral gastroenteritis, rotavirus and norovirus are known to recognize histo-blood group antigens (HBGAs) as attachment receptors. ABO, Lewis, and secretor HBGAs are distributed abundantly on mucosal epithelia, red blood cell membranes, and also secreted in biological fluids, such as saliva, intestinal content, milk, and blood. HBGAs are fucosylated glycans that have been implicated in the attachment of some enteric pathogens such as bacteria, parasites, and viruses. Single nucleotide polymorphisms in the genes encoding ABO (H), fucosyltransferase gene FUT2 (Secretor/Se), FUT3 (Lewis/Le) have been associated with changes in enzyme expression and HBGAs production. The highly polymorphic HBGAs among different populations and races influence genotype-specific susceptibility or resistance to enteric pathogens and its epidemiology, and vaccination seroconversion. Therefore, there is an urgent need to conduct population-based investigations to understand predisposition to enteric infections and gastrointestinal diseases. This review focuses on the relationship between HBGAs and predisposition to common human gastrointestinal illnesses caused by viral, bacterial, and parasitic agents.
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Affiliation(s)
- Kasturi Saikia
- Department of Molecular Biology and Biotechnology, Tezpur University, Napaam, Assam, India
| | - Niruprabha Saharia
- Department of Paediatrics, Tezpur Medical College and Hospital, Bihaguri, Tezpur, Assam, India
| | - Chongtham S Singh
- Department of Paediatrics, Regional Institute of Medical Sciences, Imphal, India
| | - Partha P Borah
- Department of Paediatrics and Neonatology, Pratiksha Hospital, Guwahati, Assam, India
| | - Nima D Namsa
- Department of Molecular Biology and Biotechnology, Tezpur University, Napaam, Assam, India.,Centre for Multi-disciplinary Research, Tezpur University, Napaam, Assam, India
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40
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Genetic Aspects of Micronutrients Important for Inflammatory Bowel Disease. Life (Basel) 2022; 12:life12101623. [PMID: 36295058 PMCID: PMC9604584 DOI: 10.3390/life12101623] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 10/07/2022] [Accepted: 10/08/2022] [Indexed: 11/16/2022] Open
Abstract
Inflammatory bowel disease (IBD), Crohn’s disease (CD) and ulcerative colitis (UC) are complex diseases whose etiology is associated with genetic and environmental risk factors, among which are diet and gut microbiota. To date, IBD is an incurable disease and the main goal of its treatment is to reduce symptoms, prevent complications, and improve nutritional status and the quality of life. Patients with IBD usually suffer from nutritional deficiency with imbalances of specific micronutrient levels that contribute to the further deterioration of the disease. Therefore, along with medications usually used for IBD treatment, therapeutic strategies also include the supplementation of micronutrients such as vitamin D, folic acid, iron, and zinc. Micronutrient supplementation tailored according to individual needs could help patients to maintain overall health, avoid the triggering of symptoms, and support remission. The identification of individuals’ genotypes associated with the absorption, transport and metabolism of micronutrients can modify future clinical practice in IBD and enable individualized treatment. This review discusses the personalized approach with respect to genetics related to micronutrients commonly used in inflammatory bowel disease treatment.
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41
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Ren Z, Fan H, Gu S, Liu H, Wu Z, Wang H, Bao W, Wu S. Expression Analysis and the Roles of the Sec1 Gene in Regulating the Composition of Mouse Gut Microbiota. Genes (Basel) 2022; 13:1858. [PMID: 36292744 PMCID: PMC9601920 DOI: 10.3390/genes13101858] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 10/07/2022] [Accepted: 10/11/2022] [Indexed: 11/16/2022] Open
Abstract
The Sec1 gene encodes galactose 2-L-fucosyltransferase, whereas expression during development of the Sec1 gene mouse and its effect on the composition of the gut microbiota have rarely been reported. In this study, we examined Sec1 gene expression during mouse development, constructed Sec1 knockout mice, and sequenced their gut microbial composition. It was found that Sec1 was expressed at different stages of mouse development. Sec1 knockout mice have significantly higher intraperitoneal fat accumulation and body weight than wild-type mice. Analysis of gut microbial composition in Sec1 knockout mice revealed that at the phylum level, Bacteroidetes accounted for 68.8%and 68.3% of gut microbial composition in the Sec1-/- and Sec1+/+ groups, respectively, and Firmicutes accounted for 27.1% and 19.7%, respectively; while Firmicutes/Bacteroidetes were significantly higher in Sec1-/- mice than in Sec1+/+ mice (39.4% vs. 28.8%). In verucomicrobia, it was significantly higher in Sec1-/- mice than in Sec1+/+ group mice. At the family level, the dominant bacteria Prevotellaceae, Akkermansiaceae, Bacteroidaceae, and Lacilltobacaceae were found to be significantly reduced in the gut of Sec1-/- mice among Sec1+/+ gut microbes, while Lachnospiraceae, Ruminococcaceae, Rikenellaceae, Helicobacteraceae, and Tannerellaceae were significantly increased. Indicator prediction also revealed the dominant bacteria Akkermansiaceae and Lactobacillaceae in Sec1+/+ gut microorganisms, while the dominant bacteria Rikenellaceae, Marinifilaceae, ClostridialesvadinBB60aceae, Erysipelotrichaceae, Saccharimonadaceae, Clostridiaceae1, and Christensenellaceae in Sec1-/- group. This study revealed that the Sec1 gene was expressed in different tissues at different time periods in mice, and Sec1 knockout mice had significant weight gain, significant abdominal fat accumulation, and significant changes in gut microbial flora abundance and metabolic function, providing a theoretical basis and data support for the study of Sec1 gene function and effects on gut microbiota-related diseases.
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Affiliation(s)
- Zhanshi Ren
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Hairui Fan
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Shanshen Gu
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Haoyu Liu
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Zhengchang Wu
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
| | - Haifei Wang
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University, Yangzhou 225009, China
| | - Wenbin Bao
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University, Yangzhou 225009, China
| | - Shenglong Wu
- Key Laboratory for Animal Genetics, Breeding, Reproduction and Molecular Design of Jiangsu Province, College of Animal Science and Technology, Yangzhou University, Yangzhou 225009, China
- Joint International Research Laboratory of Agriculture & Agri-Product Safety, Yangzhou University, Yangzhou 225009, China
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42
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Intestinal Norovirus Binding Patterns in Nonsecretor Individuals. J Virol 2022; 96:e0086522. [PMID: 36121297 PMCID: PMC9555158 DOI: 10.1128/jvi.00865-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Human norovirus (HuNoV) infection is associated with an active FUT2 gene, which characterizes the secretor phenotype. However, nonsecretor individuals are also affected by HuNoV infection although in a lesser proportion. Here, we studied GII.3, GII.4, and GII.17 HuNoV interactions in nonsecretor individuals using virus-like particles (VLPs). Only GII.4 HuNoV specifically interacted with nonsecretor saliva. Competition experiments using histo-blood group antigen (HBGA)-specific monoclonal antibodies (MAbs) demonstrate that GII.4 VLPs recognized the Lewis a (Lea) antigen. We also analyzed HuNoV VLP interactions on duodenum tissue blocks from healthy nonsecretor individuals. VLP binding was observed for the three HuNoV genotypes in 10 of the 13 individuals, and competition experiments demonstrated that VLP recognition was driven by an interaction with the Lea antigen. In 3 individuals, binding was restricted to either GII.4 alone or GII.3 and GII.17. Finally, we performed a VLP binding assay on proximal and distal colon tissue blocks from a nonsecretor patient with Crohn's disease. VLP binding to inflammatory tissues was genotype specific since GII.4 and GII.17 VLPs were able to interact with regenerative mucosa, whereas GII.3 VLP was not. The binding of GII.4 and GII.17 HuNoV VLPs was linked to Lea in regenerative mucosae from the proximal and distal colon. Overall, our data clearly showed that Lea has a pivotal role in the recognition of HuNoV in nonsecretors. We also showed that Lea is expressed in inflammatory/regenerative tissues and interacts with HuNoV in a nonsecretor individual. The physiological and immunological consequences of such interactions in nonsecretors have yet to be elucidated. IMPORTANCE Human norovirus (HuNoV) is the main etiological agent of viral gastroenteritis in all age classes. HuNoV infection affects mainly secretor individuals where ABO(H) and Lewis histo-blood group antigens (HBGAs) are present in the small intestine. Nonsecretor individuals, who only express Lewis (Le) antigens, are less susceptible to HuNoV infection. Here, we studied the interaction of common HuNoV genotypes (GII.3, GII.4, and GII.17) in nonsecretor individuals using synthetic viral particles. Saliva binding assays showed that only GII.4 interacted with nonsecretor saliva via the Lewis a (Lea) antigen Surprisingly, the three genotypes interacted with nonsecretor enterocytes via the Lea antigen on duodenal tissue blocks, which were more relevant for HuNoV/HBGA studies. The Lea antigen also played a pivotal role in the recognition of GII.4 and GII.17 particles by inflammatory colon tissue from a nonsecretor Crohn's disease patient. The implications of HuNoV binding in nonsecretors remain to be elucidated in physiological and pathological conditions encountered in other intestinal diseases.
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Khoruddin NA, Lim WF, Teh LK, Noorizhab MNF, Mohd Yusof FZ, Salleh MZ. Toward precision nutrition: A cross‐sectional study on the genetic risks of nutrients deficiencies and eating behaviors among the Orang Asli and Malays. PRECISION MEDICAL SCIENCES 2022. [DOI: 10.1002/prm2.12081] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Affiliation(s)
- Nurul Ain Khoruddin
- Integrative Pharmacogenomics Institute (iPROMISE) Universiti Teknologi MARA (UiTM) Selangor Bandar Puncak Alam Malaysia
- Faculty of Applied Sciences Universiti Teknologi MARA (UiTM) Selangor Shah Alam Malaysia
| | - Wai Feng Lim
- Integrative Pharmacogenomics Institute (iPROMISE) Universiti Teknologi MARA (UiTM) Selangor Bandar Puncak Alam Malaysia
| | - Lay Kek Teh
- Integrative Pharmacogenomics Institute (iPROMISE) Universiti Teknologi MARA (UiTM) Selangor Bandar Puncak Alam Malaysia
- Faculty of Pharmacy Universiti Teknologi MARA (UiTM) Selangor Bandar Puncak Alam Malaysia
| | - Mohd Nur Fakhruzzaman Noorizhab
- Integrative Pharmacogenomics Institute (iPROMISE) Universiti Teknologi MARA (UiTM) Selangor Bandar Puncak Alam Malaysia
- Faculty of Pharmacy Universiti Teknologi MARA (UiTM) Selangor Bandar Puncak Alam Malaysia
| | - Farida Zuraina Mohd Yusof
- Integrative Pharmacogenomics Institute (iPROMISE) Universiti Teknologi MARA (UiTM) Selangor Bandar Puncak Alam Malaysia
- Faculty of Applied Sciences Universiti Teknologi MARA (UiTM) Selangor Shah Alam Malaysia
| | - Mohd Zaki Salleh
- Integrative Pharmacogenomics Institute (iPROMISE) Universiti Teknologi MARA (UiTM) Selangor Bandar Puncak Alam Malaysia
- Faculty of Pharmacy Universiti Teknologi MARA (UiTM) Selangor Bandar Puncak Alam Malaysia
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Palit P, Ahmed MMM, Gazi MA, Haque MA, Alam MA, Haque R, Mahfuz M, Ahmed T. Association of Secretor Status with Enteropathy and Growth among Children in Bangladesh Aged 1-24 Months. Am J Trop Med Hyg 2022; 107:449-456. [PMID: 35895378 PMCID: PMC9393443 DOI: 10.4269/ajtmh.22-0183] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 04/30/2022] [Indexed: 11/24/2022] Open
Abstract
Secretor status refers to the ability of an individual to secrete blood group antigens into body fluids and onto the different epithelial surfaces. Concurrent findings have demonstrated an association of the secretor status of children with susceptibility to a plethora of enteropathogens. We aimed to determine a possible association of secretor status of children with childhood enteropathy, an important causal factor for childhood growth failure. Participants of the Malnutrition and Enteric Disease (MAL-ED) birth cohort study from the Bangladesh site were enrolled along with their mothers. Saliva was analyzed for determining blood groups and secretor status of the children and their mothers by using an in-house ELISA. Approximately 59% of children and 65% of mothers were found to be secretor positive. Secretor-positive children were found to have a significantly positive association with alpha-1-antitrypsin (β-coefficient: 0.11, 95% CI: 0.07, 0.21, P < 0.01) and with environmental enteric dysfunction score (β-coefficient: 0.32, 95% CI: 0.29, 0.65, P = 0.05). However, despite a negative effect size, secretor-positive children did not show any statistical significance with length-for-age and weight-for-age z scores (LAZ and WAZ), respectively. Our findings indicate toward the genetic factor of secretor status of children being associated with childhood growth faltering, through increased susceptibility to distinct enteropathogens and the consequent development of enteric inflammation and enteropathy among children. However, these findings are only applicable in Bangladeshi settings and thus need to be validated in several other similar settings, to establish a possible relationship between the secretor status of children with enteropathy and resulting childhood growth failure.
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Affiliation(s)
- Parag Palit
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Diseases Research, Dhaka, Bangladesh (icddr,b)
| | - Mondar Maruf Moin Ahmed
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Diseases Research, Dhaka, Bangladesh (icddr,b)
| | - Md Amran Gazi
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Diseases Research, Dhaka, Bangladesh (icddr,b)
| | - Md Ahshanul Haque
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Diseases Research, Dhaka, Bangladesh (icddr,b)
| | - Md Ashraful Alam
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Diseases Research, Dhaka, Bangladesh (icddr,b)
| | - Rashidul Haque
- Emerging Infections and Parasitology Laboratory, International Centre for Diarrhoeal Diseases Research, Dhaka, Bangladesh (icddr,b)
| | - Mustafa Mahfuz
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Diseases Research, Dhaka, Bangladesh (icddr,b)
| | - Tahmeed Ahmed
- Nutrition and Clinical Services Division, International Centre for Diarrhoeal Diseases Research, Dhaka, Bangladesh (icddr,b)
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45
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Hu M, Zhang X, Li J, Chen L, He X, Sui T. Fucosyltransferase 2: A Genetic Risk Factor for Intestinal Diseases. Front Microbiol 2022; 13:940196. [PMID: 35923409 PMCID: PMC9339987 DOI: 10.3389/fmicb.2022.940196] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 06/20/2022] [Indexed: 12/26/2022] Open
Abstract
The fucosyltransferase 2 gene (FUT2) mediates the synthesis of histoblood group antigens (HBGA) that occur in vivo from multiple organs, particularly on the surface of intestinal epithelial cells and body fluids. To date, many studies have demonstrated that the interaction of HBGA with the host microbiota is the cause of pathogenesis of intestinal diseases, making FUT2 non-secretor a risk factor for inflammatory bowel disease (IBD) due to the lack of HBGA. As HBGA also acts as an attachment site for norovirus (NoV) and rotavirus (RV), the non-secretor becomes a protective factor for both viral infections. In addition, the interaction of norovirus and rotavirus with symbiotic bacteria has been found to play an important role in regulating enteroviral infection in IBD. Given the current incomplete understanding of the complex phenomenon and the underlying pathogenesis of intestinal diseases such as IBD, it has recently been hypothesized that the FUT2 gene regulates intestinal bacteria through attachment sites, may help to unravel the role of FUT2 and intestinal flora in the mechanism of intestinal diseases in the future, and provide new ideas for the prevention and treatment of intestinal diseases through more in-depth studies.
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46
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Guo K, Huang J, Zhou Z. Host gene effects on gut microbiota in type 1 diabetes. Biochem Soc Trans 2022; 50:1133-1142. [PMID: 35521897 PMCID: PMC9246325 DOI: 10.1042/bst20220004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Revised: 04/07/2022] [Accepted: 04/12/2022] [Indexed: 12/03/2022]
Abstract
Type 1 diabetes (T1D) is an organ-specific autoimmune disease characterized by progressive pancreatic β-cell loss. Both a predisposing genetic background, that may encompass mutations in several genes, as well as exposure to environmental factors can affect the progression of autoimmune responses to multiple pancreatic islet autoantigens. Many genetic variants that increase the risk of T1D are found in immunity genes involved in sensing and responding to microorganisms. Although increasing evidence indicates that the gut microbiome composition may promote or prevent T1D development, little is known about the link between gut microbiota and T1D susceptibility genes in patients with T1D. Recent studies in the inbred non-obese diabetic (NOD) mouse, a widely used model of T1D, have suggested that many genetic loci can influence gut microbiome composition to modulate islet autoimmunity. This review summarizes evidence that examines the effect of host genes on gut microbiota diversity and function during T1D development. Knowledge of the host gene-gut microbiota interactions at play during T1D progression may help us identify new diagnostic and prognostic tools and help also design effective strategies for disease treatment.
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Affiliation(s)
- Keyu Guo
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
| | - Juan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
- Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, CT, U.S.A
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, China
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Ge X, Pereira FC, Mitteregger M, Berry D, Zhang M, Hausmann B, Zhang J, Schintlmeister A, Wagner M, Cheng JX. SRS-FISH: A high-throughput platform linking microbiome metabolism to identity at the single-cell level. Proc Natl Acad Sci U S A 2022; 119:e2203519119. [PMID: 35727976 PMCID: PMC9245642 DOI: 10.1073/pnas.2203519119] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Accepted: 04/08/2022] [Indexed: 12/26/2022] Open
Abstract
One of the biggest challenges in microbiome research in environmental and medical samples is to better understand functional properties of microbial community members at a single-cell level. Single-cell isotope probing has become a key tool for this purpose, but the current detection methods for determination of isotope incorporation into single cells do not allow high-throughput analyses. Here, we report on the development of an imaging-based approach termed stimulated Raman scattering-two-photon fluorescence in situ hybridization (SRS-FISH) for high-throughput metabolism and identity analyses of microbial communities with single-cell resolution. SRS-FISH offers an imaging speed of 10 to 100 ms per cell, which is two to three orders of magnitude faster than achievable by state-of-the-art methods. Using this technique, we delineated metabolic responses of 30,000 individual cells to various mucosal sugars in the human gut microbiome via incorporation of deuterium from heavy water as an activity marker. Application of SRS-FISH to investigate the utilization of host-derived nutrients by two major human gut microbiome taxa revealed that response to mucosal sugars tends to be dominated by Bacteroidales, with an unexpected finding that Clostridia can outperform Bacteroidales at foraging fucose. With high sensitivity and speed, SRS-FISH will enable researchers to probe the fine-scale temporal, spatial, and individual activity patterns of microbial cells in complex communities with unprecedented detail.
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Affiliation(s)
- Xiaowei Ge
- Department of Electrical & Computer Engineering, Boston University, Boston, MA 02215
| | - Fátima C. Pereira
- Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, University of Vienna, 1030 Vienna, Austria
| | - Matthias Mitteregger
- Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, University of Vienna, 1030 Vienna, Austria
| | - David Berry
- Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, University of Vienna, 1030 Vienna, Austria
| | - Meng Zhang
- Department of Electrical & Computer Engineering, Boston University, Boston, MA 02215
| | - Bela Hausmann
- Joint Microbiome Facility of the Medical University of Vienna and the University of Vienna, 1030 Vienna, Austria
- Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria
| | - Jing Zhang
- Department of Biomedical Engineering, Photonics Center, Boston University, Boston, MA 02215
| | - Arno Schintlmeister
- Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, University of Vienna, 1030 Vienna, Austria
| | - Michael Wagner
- Centre for Microbiology and Environmental Systems Science, Department of Microbiology and Ecosystem Science, University of Vienna, 1030 Vienna, Austria
- Department of Chemistry and Bioscience, Aalborg University, 9220 Aalborg, Denmark
| | - Ji-Xin Cheng
- Department of Electrical & Computer Engineering, Boston University, Boston, MA 02215
- Department of Biomedical Engineering, Photonics Center, Boston University, Boston, MA 02215
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Alharbi AF, Sheng N, Nicol K, Strömberg N, Hollox EJ. Balancing selection at the human salivary agglutinin gene (DMBT1) driven by host-microbe interactions. iScience 2022; 25:104189. [PMID: 35494225 PMCID: PMC9038570 DOI: 10.1016/j.isci.2022.104189] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 02/07/2022] [Accepted: 03/30/2022] [Indexed: 11/19/2022] Open
Abstract
Discovering loci under balancing selection in humans can identify loci with alleles that affect response to the environment and disease. Genome variation data have identified the 5′ region of the DMBT1 gene as undergoing balancing selection in humans. DMBT1 encodes the pattern-recognition glycoprotein DMBT1, also known as SALSA, gp340, or salivary agglutinin. DMBT1 binds to a variety of pathogens through a tandemly arranged scavenger receptor cysteine-rich (SRCR) domain, with the number of domains polymorphic in humans. We show that the signal of balancing selection is driven by one haplotype usually carrying a shorter SRCR repeat and another usually carrying a longer SRCR repeat. DMBT1 encoded by a shorter SRCR repeat allele does not bind a cariogenic and invasive Streptococcus mutans strain, in contrast to the long SRCR allele that shows binding. Our results suggest that balancing selection at DMBT1 is due to host-microbe interactions of encoded SRCR tandem repeat alleles.
Clear evidence from many analyses show balancing selection at DMBT1 Scavenger-receptor cysteine-rich domain array associated with balancing selection Genetic variation, not alternative splicing, responsible for protein isoforms Long, but not short, DMBT1 isoforms bind a cariogenic strain of Streptococcus mutans
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Affiliation(s)
- Adel F. Alharbi
- Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
- Medina Regional Laboratory, General Directorate of Health Affairs, Ministry of Health, Medina, Saudi Arabia
| | - Nongfei Sheng
- Department of Odontology, Umeå University, Umeå, Sweden
| | - Katie Nicol
- Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
| | | | - Edward J. Hollox
- Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
- Corresponding author
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Soejima M, Koda Y. Simultaneous genotyping of three major Se enzyme inactivating SNPs of FUT2 based on a triplex probe-based fluorescence melting-curve analysis. Clin Chim Acta 2022; 530:50-54. [PMID: 35271838 DOI: 10.1016/j.cca.2022.03.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/04/2022] [Indexed: 11/03/2022]
Abstract
BACKGROUND The ABO(H) secretor status is controlled by FUT2-encoded α(1,2)fucosyltransferase (Se enzyme) activity. Three SNPs of FUT2, 302C>T (rs200157007), 385A>T (rs1047781), and 428G>A (rs601338), cause three major variants of nonsecretor (se) or weak-secretor (Sew) alleles. Evidence has been accumulating that suggests the secretor status is associated with various conditions including infectious diseases but a robust multiplex method for assaying relatively large-scale samples to determine the genotype of these three SNPs simultaneously has not been developed yet. METHODS By combined usage of two Eprobes and a dual-labeled fluorescence probe, we developed a real-time PCR, followed by triplex probe-based fluorescent melting-curve analysis (FMCA) for genotyping of 302C>T, 385A>T, and 428G>A of FUT2 in a single tube. RESULTS Three genotypes of each of three variants of FUT2 were accurately determined by the triplex probe-based FMCA. We then validated this method using genomic DNA samples of 47 Bangladeshis, and the results obtained by using this method were fully concordant with those by previous Sanger sequencing. CONCLUSIONS Since the present single triplex probe-based FMCA is robust, fast, and cost-effective, we are able to effectively estimate the secretor status of subjects on a large scale in many populations around the world.
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Affiliation(s)
- Mikiko Soejima
- Department of Forensic Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan
| | - Yoshiro Koda
- Department of Forensic Medicine, Kurume University School of Medicine, Kurume 830-0011, Japan.
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Elling CL, Scholes MA, Streubel SO, Larson ED, Wine TM, Bootpetch TC, Yoon PJ, Kofonow JM, Gubbels SP, Cass SP, Robertson CE, Jenkins HA, Prager JD, Frank DN, Chan KH, Friedman NR, Ryan AF, Santos-Cortez RLP. The FUT2 Variant c.461G>A (p.Trp154*) Is Associated With Differentially Expressed Genes and Nasopharyngeal Microbiota Shifts in Patients With Otitis Media. Front Cell Infect Microbiol 2022; 11:798246. [PMID: 35096646 PMCID: PMC8798324 DOI: 10.3389/fcimb.2021.798246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 12/20/2021] [Indexed: 12/30/2022] Open
Abstract
Otitis media (OM) is a leading cause of childhood hearing loss. Variants in FUT2, which encodes alpha-(1,2)-fucosyltransferase, were identified to increase susceptibility to OM, potentially through shifts in the middle ear (ME) or nasopharyngeal (NP) microbiotas as mediated by transcriptional changes. Greater knowledge of differences in relative abundance of otopathogens in carriers of pathogenic variants can help determine risk for OM in patients. In order to determine the downstream effects of FUT2 variation, we examined gene expression in relation to carriage of a common pathogenic FUT2 c.461G>A (p.Trp154*) variant using RNA-sequence data from saliva samples from 28 patients with OM. Differential gene expression was also examined in bulk mRNA and single-cell RNA-sequence data from wildtype mouse ME mucosa after inoculation with non-typeable Haemophilus influenzae (NTHi). In addition, microbiotas were profiled from ME and NP samples of 65 OM patients using 16S rRNA gene sequencing. In human carriers of the FUT2 variant, FN1, KMT2D, MUC16 and NBPF20 were downregulated while MTAP was upregulated. Post-infectious expression in the mouse ME recapitulated these transcriptional differences, with the exception of Fn1 upregulation after NTHi-inoculation. In the NP, Candidate Division TM7 was associated with wildtype genotype (FDR-adj-p=0.009). Overall, the FUT2 c.461G>A variant was associated with transcriptional changes in processes related to response to infection and with increased load of potential otopathogens in the ME and decreased commensals in the NP. These findings provide increased understanding of how FUT2 variants influence gene transcription and the mucosal microbiota, and thus contribute to the pathology of OM.
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Affiliation(s)
- Christina L. Elling
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Human Medical Genetics and Genomics Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Melissa A. Scholes
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of Pediatric Otolaryngology, Children’s Hospital Colorado, Aurora, CO, United States
| | - Sven-Olrik Streubel
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of Pediatric Otolaryngology, Children’s Hospital Colorado, Aurora, CO, United States
| | - Eric D. Larson
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Todd M. Wine
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of Pediatric Otolaryngology, Children’s Hospital Colorado, Aurora, CO, United States
| | - Tori C. Bootpetch
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Patricia J. Yoon
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of Pediatric Otolaryngology, Children’s Hospital Colorado, Aurora, CO, United States
| | - Jennifer M. Kofonow
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Samuel P. Gubbels
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Stephen P. Cass
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Charles E. Robertson
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Herman A. Jenkins
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Jeremy D. Prager
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of Pediatric Otolaryngology, Children’s Hospital Colorado, Aurora, CO, United States
| | - Daniel N. Frank
- Division of Infectious Diseases, Department of Medicine, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Kenny H. Chan
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of Pediatric Otolaryngology, Children’s Hospital Colorado, Aurora, CO, United States
| | - Norman R. Friedman
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of Pediatric Otolaryngology, Children’s Hospital Colorado, Aurora, CO, United States
| | - Allen F. Ryan
- Division of Otolaryngology, Department of Surgery, San Diego School of Medicine and Veterans Affairs Medical Center, University of California, La Jolla, CA, United States
| | - Regie Lyn P. Santos-Cortez
- Department of Otolaryngology-Head and Neck Surgery, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Human Medical Genetics and Genomics Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Center for Children’s Surgery, Children’s Hospital Colorado, Aurora, CO, United States
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