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Adu F, Aniakwaa-Bonsu E, Badu Nyarko S, Obeng AS, Ateko RO, Anyanful A, Thomford NE. Host cytokine genetic polymorphisms in a selected population of persons living with hepatitis B virus infection in the central region of Ghana. BMC Gastroenterol 2024; 24:374. [PMID: 39434005 PMCID: PMC11494869 DOI: 10.1186/s12876-024-03456-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2024] [Accepted: 10/09/2024] [Indexed: 10/23/2024] Open
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a public health concern in resource limited settings like Ghana. Over the past decades, it is noted that the natural course of HBV in persons infected are taking a worse turn leading to liver cirrhosis and cancer. The outcome of HBV infection is influenced by viral and host factors including genetics. Cytokine variations affect virus survival and progression and may even influence associated complications. Cytokines such as tumor necrosis factor alpha (TNF-α), interleukins (IL-4, IL-6, IL-8, IL-10, IL-18), interferon gamma (IFN)-γ, and tumor growth factor-beta (TGF-β) have key roles in HBV infection and modulation. In this study, polymorphisms occurring in five cytokines were analysed to understand how they can influence prognosis of HBV infection. METHODS The study is a single centre cross-sectional study involving 227 participants made up of HBV infected participants and HBV-negative controls. Recruitment was from March 2021 to April 2022. Blood samples were taken for full blood count, HBV antigen profile, liver function tests, HBV DNA quantification and cytokine genotyping. FIB score was calculated using available tools. Statistical analysis was undertaken with p < 0.05 set as statistically significant. RESULTS The 20-39-year-old group formed majority of the HBV infected participants with 60% of all participants being classified as healthy HBsAg carriers. IL2 rs1479920 GG carriers ((1258.93; 0.00-5011.87) IU/mL had reduced HBV DNA in comparison to IL2 rs1479920 AA ((5011.87; 2113.49-5956.62) /AG (3548.13; 0.00-6309.57) IU/mL carriers. TNF-α rs1800629 AA carriers (1258.93; 0.00-3981.07) IU/mL had a reduction in HBV DNA levels in comparison to TNF-α rs1800629 GG carriers (1584.89; 0.00-5011.87) IU/mL. The results of univariate (OR = 0.08, 0.00-0.93; p = 0.043) and multivariate (OR = 0.02, 0.00-0.67; p = 0.029) analysis, showed that carrying TNF-α rs1800629 AA genotype reduce susceptibility to high FIB score compared with GG genotypes. In univariate analysis, subjects aged 20-39 years (OR = 5.00, 1.13-6.10; p = 0.034) and 40-59 years (OR = 41.99, 3.74-47.21; p = 0.0002) were more susceptible to high FIB score compared to subjects aged 1-19 years. Being female (OR = 2.42, 1.03-5.71; p = 0.043) in the univariate models showed higher odds of having high levels of HBV DNA in the multivariate model. There was a reduced likelihood of herbal medicine usage influencing HBV DNA levels significantly (OR = 0.29, 0.10-0.86; p = 0.025). CONCLUSION In conclusion, variations in IL2 rs1479920 GG and IL2 rs1479921 AA could offer protective effects by reducing HBV DNA. TNF-α rs179924CT may also cause elevation in HBV DNA levels whiles TNF-α -308A/G, showed a potential protective effect on liver scarring in HBV infected participants. It is therefore important to take a further look at such variations for understanding of HBV modulation in the Ghanaian population.
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Affiliation(s)
- Faustina Adu
- Department of Medical Biochemistry, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
- Pharmacogenomics and Genomic Medicine Group & Lab, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Ebenezer Aniakwaa-Bonsu
- Department of Microbiology & Immunology, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Samuel Badu Nyarko
- Department of Medical Biochemistry, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
- Pharmacogenomics and Genomic Medicine Group & Lab, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Aikins Sarpong Obeng
- Department of Medical Biochemistry, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Richmond Owusu Ateko
- Department of Chemical Pathology, University of Ghana Medical School University of Ghana, Legon, Accra, Ghana
- Division of Chemical Pathology, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Akwasi Anyanful
- Department of Medical Biochemistry, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana
| | - Nicholas Ekow Thomford
- Department of Medical Biochemistry, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana.
- Pharmacogenomics and Genomic Medicine Group & Lab, School of Medical Sciences, College of Health and Allied Sciences, University of Cape Coast, Cape Coast, Ghana.
- Division of Human Genetics, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town, 7925, South Africa.
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Naderi M, Hosseini SM, Behnampour N, Shahramian I, Moradi A. Association of HLADQ-B1 polymorphisms in three generations of chronic hepatitis B patients. Virus Res 2023; 325:199036. [PMID: 36592642 DOI: 10.1016/j.virusres.2022.199036] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 12/28/2022] [Accepted: 12/29/2022] [Indexed: 12/31/2022]
Abstract
The presence of polymorphisms in the human leukocyte antigen (HLA)-DQB1 gene, along with its expression, has been demonstrated to be correlated with spontaneous clearance and susceptibility to HBV infection. The present study aimed to evaluate the possible role of genetic polymorphisms in HLA-DQB1 in three generations of patients with chronic hepatitis B (CHB). Based on the inclusion criteria, 90 CHB patients, 18 individuals recovered from HBV infection, and 40 healthy subjects were chosen. The DNA contents of the whole blood samples were extracted in order to perform HLA-DQB1 typing by the PCR technique. Besides whole blood samples, sera were applied to measure liver function tests (LFTs), as well as the titers of anti-HDV and anti-HCV. Also, in all CHB patients were measured liver stiffness (LSM) by Fibro Scan. The results of HLA-DQB1 polymorphisms (rs2856718 and rs7453920) demonstrated that the majority of polymorphisms in CHB patients were HLA-DQB1*03, HLA-DQB1*05, HLA-DQB1*04:01 and HLA-DQB1*03:01 that associated with HBV persistence and chronicity. Among the patients who showed these polymorphisms, the mean±SD, LSM was 4±1.57 KPa and most of them, F grade was reported as F2, which was a sign of disease progression towards chronicity. HLA polymorphisms imputation revealed that HLA-DQB1*06:04 (3.4%, P-Value= 0.2) was detected only in healthy subjects as protective polymorphism, while the allele HLA-DQB1*03:03 was reported in both healthy subjects (P-Value= 0.06) and recovered patients (P-Value= 0.1) as suppressor of CHB formation. The allele HLA-DQB1*05:02 was found in both healthy subjects (3.4%) and CHB patients (4.5%) which was associated with risk to liver cirrhosis (P-Value= 0, OR: 0.002 0.95CI: 0.000-0.15). HLA polymorphism analysis indicated that 17.39% of patients who were seropositive for anti-HCV carried the HLA-DQB1*03:01. HBV resistance or infection risk could be assessed by DBQ1 typing. The existence of polymorphisms in HLA gene could influence the clearance (HLA-DQB1*03:03) or susceptibility and persistence of infection (HLA-DQB1*03, HLA-DQB1*05, HLA-DQB1*04:01 and HLA-DQB1*03:01). These results have the potential to improve personalized therapy and prognosis for HBV infection.
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Affiliation(s)
- Malihe Naderi
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran; Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran
| | - Seyed Masoud Hosseini
- Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran.
| | - Naser Behnampour
- Biostatistics and Epidemiology Department, Faculty of Health, Health Management and Social Development Research Center, Golestan University of Medical Sciences, Golestan, Iran
| | - Iraj Shahramian
- Department of Pediatrics, Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Abdolvahab Moradi
- Department of Microbiology, Faculty of Medicine, Golestan University of Medical Sciences, Gorgan, Iran.
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Tuncel B, Kaygusuz S, Sayın Kocakap DB, Aksoy E, Azkur AK. Do CCR5 (CCR5Δ32) and TLR3 (RS5743313) gene polymorphisms prevent chronic hepatitis B infection? J Med Virol 2023; 95:e28376. [PMID: 36478230 DOI: 10.1002/jmv.28376] [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: 08/26/2022] [Revised: 11/07/2022] [Accepted: 12/03/2022] [Indexed: 12/12/2022]
Abstract
Hepatitis B virus (HBV) is still a significant health problem in human. HBV severity or sensitivity of patients may be based on the individual genetic factors significantly. The aim of this study is to investigate the association of CCR5 (CCR5Δ32), TLR3 (rs5743313) functional gene polymorphisms, interferon-gamma (IFN-ɣ) level in HBV infection, which are thought to play an important role in innate and acquired immunity in patients who have undergone HBV seroconversion and those who have chronic hepatitis B disease and receive treatment. One hundred patients who are became naturally immune against HBV infection (HBsAg negative, anti-HBc IgG, and anti-HBs IgG positive), and 100 patients with chronic hepatitis B infection (>6 months HBsAg positive) who are receiving oral antiviral therapy were compared for CCR5Δ32, TLR3 (rs5743313) genotypes and serum IFN-ɣ level. It was found that CCR5Δ32 polymorphism (Wt/Δ32 and Δ32/Δ32) was significantly higher in the chronic hepatitis B group (p = 0.048) but not for TLR3 gene polymorphism. However, serum IFN-ɣ level was significantly higher in the HBV seroconversion group (75 ± 89 ng/ml) than in the chronic hepatitis B group (4.35 ± 17.27 ng/ml) (p < 0.001). In conclusion, a higher CCR5Δ32 allele frequency in patients with chronic hepatitis B might be considered as a marker of progression to chronic hepatitis.
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Affiliation(s)
- Burçin Tuncel
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Kırıkkale University, Kırıkkale, Türkiye
| | - Sedat Kaygusuz
- Department of Infectious Diseases and Clinical Microbiology, Faculty of Medicine, Kırıkkale University, Kırıkkale, Türkiye
| | | | - Emel Aksoy
- Department of Virology, Faculty of Veterinary Medicine, Kırıkkale University, Kırıkkale, Türkiye
| | - Ahmet Kürşat Azkur
- Department of Virology, Faculty of Veterinary Medicine, Kırıkkale University, Kırıkkale, Türkiye
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Zeng Z, Liu H, Xu H, Lu H, Yu Y, Xu X, Yu M, Zhang T, Tian X, Xi H, Guan L, Zhang J, O'Brien SJ. Genome-wide association study identifies new loci associated with risk of HBV infection and disease progression. BMC Med Genomics 2021; 14:84. [PMID: 33736632 PMCID: PMC7977299 DOI: 10.1186/s12920-021-00907-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 02/17/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Recent studies have identified susceptibility genes of HBV clearance, chronic hepatitis B, liver cirrhosis, hepatocellular carcinoma, and showed the host genetic factors play an important role in these HBV-related outcomes. METHODS Collected samples from different outcomes of HBV infection and performed genotyping by Affymetrix 500 k SNP Array. GCTA tool, PLINK, and Bonferroni method were applied for analysis of genotyping and disease progression. ANOVA was used to evaluate the significance of the association between biomarkers and genotypes in healthy controls. PoMo, FST, Vcftools and Rehh package were used for building the racial tree and population analysis. FST statistics accesses 0.15 was used as a threshold to detect the signature of selection. RESULTS There are 1031 participants passed quality control from 1104 participants, including 275 HBV clearance, 92 asymptomatic persistence infection (ASPI), 93 chronic hepatitis B (CHB), 188 HBV-related decompensated cirrhosis (DC), 214 HBV-related hepatocellular carcinoma (HCC) and 169 healthy controls (HC). In the case-control study, one novel locus significantly associated with CHB (SNP: rs1264473, Gene: GRHL2, P = 1.57 × 10-6) and HCC (SNP: rs2833856, Gene: EVA1C, P = 1.62 × 10-6; SNP: rs4661093, Gene: ETV3, P = 2.26 × 10-6). In the trend study across progressive stages post HBV infection, one novel locus (SNP: rs1537862, Gene: LACE1, P = 1.85 × 10-6), and three MHC loci (HLA-DRB1, HLA-DPB1, HLA-DPA2) showed significant increased progressive risk from ASPI to CHB. Underlying the evolutionary study of HBV-related genes in public database, the derived allele of two HBV clearance related loci, rs3077 and rs9277542, are under strong selection in European population. CONCLUSIONS In this study, we identified several novel candidate genes associated with individual HBV infectious outcomes, progressive stages, and liver enzymes. Two SNPs that show selective significance (HLA-DPA1, HLA-DPB1) in non-East Asian (European, American, South Asian) versus East Asian, indicating that host genetic factors contribute to the ethnic disparities of susceptibility of HBV infection. Taken together, these findings provided a new insight into the role of host genetic factors in HBV related outcomes and progression.
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Affiliation(s)
- Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China.
| | | | | | - Haiying Lu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Yanyan Yu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Xiaoyuan Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Min Yu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Tao Zhang
- BGI-Shenzhen, Shenzhen, 518083, China
| | - Xiulan Tian
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Hongli Xi
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | | | | | - Stephen J O'Brien
- Laboratory of Genomic Diversity, Center for Computer Technologies, ITMO University, St. Petersburg, Russia, 197101.
- Guy Harvey Oceanographic Center, Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Ft Lauderdale, FL, 33004, USA.
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Ben Selma W, Alibi S, Smach MA, Saad A, Boukadida J. IL-18 variant increases risk of enhanced HBV DNA replication in chronic hepatitis. Immunol Lett 2020; 228:70-75. [DOI: 10.1016/j.imlet.2020.10.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 09/24/2020] [Accepted: 10/01/2020] [Indexed: 12/13/2022]
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Identification and characterization of SEC24D as a susceptibility gene for hepatitis B virus infection. Sci Rep 2019; 9:13425. [PMID: 31530870 PMCID: PMC6748997 DOI: 10.1038/s41598-019-49777-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 08/30/2019] [Indexed: 12/15/2022] Open
Abstract
Single nucleotide polymorphisms (SNPs) and genes associated with susceptibility to hepatitis B virus (HBV) infection that have been identified by genome-wide association studies explain only a limited portion of the known heritability, indicating more genetic variants remain to be discovered. In this study, we adopted a new research strategy to identify more susceptibility genes and variants for HBV infection. We first performed genetic association analysis of 300 sib-pairs and 3,087 case-control samples, which revealed that 36 SNPs located in 31 genes showed nominal associations with HBV infection in both samples. Of these genes, we selected SEC24D for further molecular analysis according to the following two main lines of evidence. First, a time course analysis of the expression profiles from HBV-infected primary human hepatocytes (PHH) demonstrated that SEC24D expression increased markedly as time passed after HBV infection (P = 4.0 × 10−4). Second, SNP rs76459466 in SEC24D was adversely associated with HBV risk (ORmeta = 0.82; Pmeta = 0.002), which again indicated that SEC24D represents a novel susceptibility gene for HBV infection. Moreover, SEC24D appeared to be protective against HBV infection in vitro. Consistently, we found that SEC24D expression was significantly enhanced in non-infected liver tissues (P = 0.002). We conclude that SEC24D is a novel candidate gene linked to susceptibility to HBV infection.
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Al-Saffar OB, Bajlan JS, Ad'hiah AH. Association analysis of interleukin-1 single nucleotide polymorphisms in viral hepatitis of Iraqi patients. Meta Gene 2019. [DOI: 10.1016/j.mgene.2019.100546] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
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Jiang H, Cao F, Cao H, Rao Q, Yang Y. Associations of human leukocyte antigen and interleukin-18 gene polymorphisms with viral load in patients with hepatitis B infection. Medicine (Baltimore) 2018; 97:e11249. [PMID: 30045250 PMCID: PMC6078658 DOI: 10.1097/md.0000000000011249] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
This study aimed to assess the associations of human leukocyte antigen (HLA)-DR and interleukin (IL)-18 gene polymorphisms with hepatitis B virus (HBV).Clinical data were retrospectively reviewed between December 2006 and December 2015 at Xiangyang Central Hospital. HBV patients were assigned to the high and low viral load groups, respectively, according to HBV copies. HLA-DRB1*03 polymorphisms and IL-18 polymorphisms were detected by sequence-specific primer-polymerase chain reaction (PCR-SSP) and PCR-ligase detection reaction (PCR-LDR), respectively. T cell subgroups were identified by flow cytometry, and IL-18, IL-12, interferon-γ (IFN-γ), IL-4, and IL-10 expression levels were assessed by ELISA. A total of 630 subjects were included in the analysis.Compared with healthy controls, the chronic HBV group showed significantly lower IL-18 (P < .001), IL-12 (P < .001), and IFN-γ (P < .001) expression levels, and markedly increased IL-4 (P < .001) and IL-10 (P < .001) amounts. Th2 cytokine expression was high in HLA-DRB1*03 positive (+) HBV patients, with low Th1 cytokine levels. The ratios of CD4+/CD8+ and Th1/Th2 cells decreased with increasing HBV DNA levels. The chronic HBV group showed a relatively high frequency of -137G in the IL-18 gene, while IL-18 expression was low in homozygous GG genotype individuals.Polymorphisms in the HLA-DRB1*03 and IL-18 genes are associated with viral load in HBV. HLA-DRB1 and IL-18 gene polymorphisms are involved in the regulation of the Th1/Th2 balance and expression of relevant cytokines that influence immune responses in HBV.
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Affiliation(s)
| | | | - Hong Cao
- Department of Clinical Laboratory
| | - Qun Rao
- Department of Clinical Laboratory
| | - Ying Yang
- Department of Gastroenterology, Hospital Affiliated to Hubei University of Arts and Science, Xiangyang, Hubei, People's Republic of China
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Zhang C, He Y, Shan KR, Tan K, Zhang T, Wang CJ, Guan ZZ. Correlations between polymorphisms in the uridine diphosphate-glucuronosyltransferase 1A and C-C motif chemokine receptor 5 genes and infection with the hepatitis B virus in three ethnic groups in China. J Int Med Res 2018; 46:739-751. [PMID: 29239247 PMCID: PMC5971517 DOI: 10.1177/0300060517730174] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 08/16/2017] [Indexed: 12/23/2022] Open
Abstract
Objective To determine whether genetic polymorphisms in the uridine diphosphate-glucuronosyltransferase 1A ( UGT1A) and the C-C motif chemokine receptor 5 ( CCR5) genes are associated with hepatitis B virus (HBV) infection in Yi, Yao and Han ethnic groups in the Guizhou Province of China. Methods The study enrolled subjects with and without HBV infection. Whole blood was used for DNA genotyping using standard techniques. The study determined the frequencies of several polymorphic alleles ( UGT1A6 [rs2070959], UGT1A1 [rs8175347], CCR5-59029 [rs1799987] and CCR5Δ32 [rs333]) and then characterized their relationship with HBV infection. Results A total of 404 subjects were enrolled in the study: 138 from the Yao group, 101 from the Yi group and 165 from the Han group. There was a significant difference in the frequency of UGT1A1 rs8175347 polymorphisms among the three groups. The rates of 7TA carriers of UGT1A1 rs8175347 in all three groups were significantly higher than the other genotypes. Individuals with genotype AA of UGT1A6 rs2070959 in the Yi group had a higher risk for HBV infection than in the Yao and Han groups. The frequency of genotype GG in CCR5-59029 in the Yao group was significantly higher than in the Yi group. The genotypes of CCR5Δ32 were not associated with HBV infection. Conclusion These findings provide genetic and epidemiological evidence for an association of UGT1A and CCR5-59029 polymorphisms with HBV infection in Chinese Yi and Yao populations.
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Affiliation(s)
- Chan Zhang
- The Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education of PR China (Guizhou Medical University), Guiyang, Guizhou Province, China
- Reproduction Centre of Luoyang Centre Hospital Affiliated to Zhengzhou University, Zhengzhou, Henan Province, China
| | - Yan He
- The Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education of PR China (Guizhou Medical University), Guiyang, Guizhou Province, China
| | - Ke-Ren Shan
- The Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education of PR China (Guizhou Medical University), Guiyang, Guizhou Province, China
| | - Kui Tan
- The Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education of PR China (Guizhou Medical University), Guiyang, Guizhou Province, China
| | - Ting Zhang
- The Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education of PR China (Guizhou Medical University), Guiyang, Guizhou Province, China
| | - Chan-Juan Wang
- The Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education of PR China (Guizhou Medical University), Guiyang, Guizhou Province, China
| | - Zhi-Zhong Guan
- The Key Laboratory of Endemic and Ethnic Diseases of the Ministry of Education of PR China (Guizhou Medical University), Guiyang, Guizhou Province, China
- Department of Pathology, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou Province, China
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Quantitative assessment of HLA-DQ gene polymorphisms with the development of hepatitis B virus infection, clearance, liver cirrhosis, and hepatocellular carcinoma. Oncotarget 2017; 9:96-109. [PMID: 29416599 PMCID: PMC5787527 DOI: 10.18632/oncotarget.22941] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 11/03/2017] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B is one of the most common infectious diseases, which leads to public health problems in the world, especially in Asian counties. In recent years, extensive human genetic association studies have been carried out to identify susceptible genes and genetic polymorphisms to understand the genetic contributions to the disease progression of HBV infection. HLA-DQ gene variations have been reported to be associated with HBV infection/clearance, disease progression and the development of hepatitis B-related complications, including liver cirrhosis (LC) and hepatocellular carcinoma (HCC). However, the results are either inconclusive or controversial. Therefore, to derive a more precise estimation of the association, a meta-analysis was performed. Our data revealed that the HLA-DQ alleles rs2856718-G, rs7453920-A and rs9275319-G were significantly associated with decreased risk of HBV infection and HBV natural clearance. Logistic regression analyses showed that HLA-DQ alleles rs9275572-A significantly increased HBV infection clearance, and decreased HBV natural clearance. However, rs2856718-G and rs9275572-A were not associated with development of cirrhosis. The HLA-DQ polymorphisms (rs2856718 and rs9275572) were associated with a decreased HBV-related HCC risk in all genetic models, but rs9272105-A increased the risk of HBV-related HCC. In addition, no significant association was observed between HLA-DQ rs9275319-G polymorphism and HBV-related HCC. These stratified analyses were limited due to relatively modest size of correlational studies. In future, further investigation on a large population and different ethnicities are warranted. Our findings contribute to the personalized care and prognosis in hepatitis B.
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Tong S, Liu G, Li M, Li X, Liu Q, Peng H, Li S, Ren H, Yin W. Natural killer cell activation contributes to hepatitis B viral control in a mouse model. Sci Rep 2017; 7:314. [PMID: 28331190 PMCID: PMC5428210 DOI: 10.1038/s41598-017-00387-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 02/23/2017] [Indexed: 02/07/2023] Open
Abstract
The roles of CD4 + T cells and CD8 + T cells in hepatitis B virus (HBV) infection have been well documented. However, the role of innate immunity in HBV infection remains obscure. Here we examined the effect of activation of innate immunity by polyinosinic: polycytidylic acid (PolyI:C) on HBV infection. A chronic HBV replication mouse model was established by hydrodynamical injection of pAAV/HBV1.2 plasmid into C57BL/6 mice. We found that HBV did not seem to induce an active NK-cell response in the mouse model. Early PolyI:C treatment markedly decreased serum HBV levels and led to HBV clearance. Following PolyI:C injection, NK cells were activated and accumulated in the liver. Depletion of NK cells markedly attenuated the anti-HBV activity of PolyI:C. Moreover, we found that IFN-γ production from NK cells was essential for the antiviral effect of PolyI:C in the model. Importantly, activation of NK cells by PolyI:C could also lead to HBV suppression in HBV-tolerant mice and HBV-transgenic mice. These results suggest that activated NK cells might suppress HBV and contribute to HBV clearance during natural HBV infection. In addition, therapeutic activation of NK cells may represent a new strategy for the treatment of chronic HBV infection.
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Affiliation(s)
- Shiwen Tong
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.,Department of Clinical Nutrition, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Guangze Liu
- Center of Infectious Diseases, 458th Hospital of PLA, No. 801 Dongfengdong Road, Guangzhou, China
| | - Minghong Li
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Xiumei Li
- Center of Infectious Diseases, 458th Hospital of PLA, No. 801 Dongfengdong Road, Guangzhou, China
| | - Qian Liu
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hong Peng
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Shiying Li
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Hong Ren
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China
| | - Wenwei Yin
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, China.
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Wasityastuti W, Yano Y, Ratnasari N, Triyono T, Triwikatmani C, Indrarti F, Heriyanto DS, Yamani LN, Liang Y, Utsumi T, Hayashi Y. Protective effects of HLA-DPA1/DPB1 variants against Hepatitis B virus infection in an Indonesian population. INFECTION, GENETICS AND EVOLUTION : JOURNAL OF MOLECULAR EPIDEMIOLOGY AND EVOLUTIONARY GENETICS IN INFECTIOUS DISEASES 2016; 41:177-184. [PMID: 27051043 DOI: 10.1016/j.meegid.2016.03.034] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/12/2015] [Revised: 03/07/2016] [Accepted: 03/30/2016] [Indexed: 01/01/2023]
Abstract
Human leukocyte antigen (HLA) DPA1/DPB1 variants have been reported to influence Hepatitis B virus (HBV) infection. HLA-DPA1/DPB1 plays a pivotal role in antigen presentation to CD4(+) helper T cells and influences the outcome of HBV infection. To investigate the influence of HLA-DP variants on the outcome of HBV infection in an Indonesian population where it has the third-highest prevalence of HBV infection worldwide, we performed a case-control study of 686 participants, including patients with HBV-related advanced or nonadvanced liver disease, patients with spontaneously resolved HBV, and healthy controls. Single-nucleotide polymorphisms in HLA-DPA1 (rs3077) and HLA-DPB1 (rs3135021, rs9277535, and rs228388) were genotyped using real-time TaqMan® genotyping assays. Because rs2281388 deviated from Hardy-Weinberg equilibrium, it was excluded from subsequent analyses. The results of logistic regression analyses showed that the HLA-DPB1 rs9277535 variants were associated with a reduced risk of persistent HBV infection (odds ratio [OR] 0.70, 95% confidence interval [95% CI] 0.52-0.96, P=0.026, additive genetic model; OR 0.60, 95% CI 0.38-0.96, P=0.033, dominant genetic model). The HLA-DPA1 rs3077 variant was associated with a protective effect increasing the spontaneously resolved HBV infection (OR 0.64, 95% CI 0.41-0.98, P=0.039, dominant genetic model). By contrast, the HLA-DPB1 rs3135021 variant was not associated with the outcome of HBV infection, including susceptibility, spontaneously resolved, or disease progression. Combinations of haplotype markers were also associated with HBV susceptibility (CA for rs3077-rs9277535, OR 0.57, 95% CI 0.36-0.92, P=0.021; GA for rs3135021-rs9277535, OR 0.56, 95% CI 0.36-0.86, P=0.0087). In conclusion, these findings confirm that HLA-DPA1/DPB1 variants were associated with the outcomes of HBV infection in an Indonesian population.
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Affiliation(s)
- Widya Wasityastuti
- Division of Molecular Medicine & Medical Genetics, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Division of Infectious Disease Pathology, Department of Microbiology and Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Department of Physiology, Faculty of Medicine, Gadjah Mada University, Yogyakarta 55281, Indonesia
| | - Yoshihiko Yano
- Department of Gastroenterology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan.
| | - Neneng Ratnasari
- Subdivision of Gastroenterohepatology, Department of Internal Medicine, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University, Yogyakarta 55281, Indonesia
| | - Teguh Triyono
- Department of Clinical Pathology, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University, Yogyakarta 55281, Indonesia
| | - Catharina Triwikatmani
- Subdivision of Gastroenterohepatology, Department of Internal Medicine, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University, Yogyakarta 55281, Indonesia
| | - Fahmi Indrarti
- Subdivision of Gastroenterohepatology, Department of Internal Medicine, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University, Yogyakarta 55281, Indonesia
| | - Didik Setyo Heriyanto
- Department of Anatomical Pathology, Dr. Sardjito Hospital, Faculty of Medicine, Gadjah Mada University, Yogyakarta 55281, Indonesia
| | - Laura Navika Yamani
- Division of Molecular Medicine & Medical Genetics, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Division of Infectious Disease Pathology, Department of Microbiology and Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Yujiao Liang
- Division of Molecular Medicine & Medical Genetics, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Division of Infectious Disease Pathology, Department of Microbiology and Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
| | - Takako Utsumi
- Center for Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Indonesia-Japan Collaborative Research Centre for Emerging and Re-emerging Infectious Disease, Institute of Tropical Disease, Airlangga University, Surabaya 60115, Indonesia
| | - Yoshitake Hayashi
- Division of Molecular Medicine & Medical Genetics, Department of Pathology, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan; Division of Infectious Disease Pathology, Department of Microbiology and Infectious Diseases, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan
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Laaribi AB, Zidi I, Hannachi N, Ben Yahia H, Chaouch H, Bortolotti D, Zidi N, Letaief A, Yacoub S, Boudabous A, Rizzo R, Boukadida J. Association of an HLA-G 14-bp Insertion/Deletion polymorphism with high HBV replication in chronic hepatitis. J Viral Hepat 2015; 22:835-41. [PMID: 25619305 DOI: 10.1111/jvh.12395] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2014] [Accepted: 12/07/2014] [Indexed: 12/27/2022]
Abstract
Identification of an HLA-G 14-bp Insertion/Deletion (Ins/Del) polymorphism at the 3' untranslated region of HLA-G revealed its importance in HLA-G mRNA stability and HLA-G protein level variation. We evaluated the association between the HLA-G 14-bp Ins/Del polymorphism in patients with chronic Hepatitis B virus (HBV) infection in a case-control study. Genomic DNA was extracted from 263 patients with chronic HBV hepatitis and 246 control subjects and was examined for the HLA-G 14-bp Ins/Del polymorphism by PCR. The polymorphic variants were genotyped in chronic HBV seropositive cases stratified according to HBV DNA levels, fibrosis stages and in a control population. There was no statistical significant association between the 14-bp Ins/Del polymorphism and increased susceptibility to HBV infection neither for alleles (P = 0.09) nor for genotypes (P = 0.18). The stratification of HBV patients based on HBV DNA levels revealed an association between the 14-bp Ins/Del polymorphism and an enhanced HBV activity with high HBV DNA levels. In particular, the Ins allele was significantly associated with high HBV DNA levels (P = 0.0024, OR = 1.71, 95% CI 1.2-2.4). The genotype Ins/Ins was associated with a 2.5-fold (95% CI, 1.29-4.88) increased risk of susceptibility to high HBV replication compared with the Del/Del and Ins/Del genotypes. This susceptibility is linked to the presence of two Ins alleles. No association was observed between the 14-bp Ins/Del polymorphism and fibrosis stage of HBV infection. We observed an association between the 14-bp Ins/Del polymorphism and high HBV replication characterized by high HBV DNA levels in chronic HBV patients. These results suggest a potential prognostic value for disease outcome evaluation.
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Affiliation(s)
- A B Laaribi
- Laboratory Microorganisms and Active Biomolecules, Sciences Faculty of Tunis, University of Tunis El Manar, Tunis, Tunisia.,Laboratory of Microbiology-Immunology, UR02SP13, University Hospital Farhat Hached, Sousse, Tunisia
| | - I Zidi
- Laboratory Microorganisms and Active Biomolecules, Sciences Faculty of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - N Hannachi
- Laboratory of Microbiology-Immunology, UR02SP13, University Hospital Farhat Hached, Sousse, Tunisia
| | - H Ben Yahia
- Laboratory Microorganisms and Active Biomolecules, Sciences Faculty of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - H Chaouch
- Department of Internal Medicine and Infectious Diseases, University Hospital Farhat Hached, Sousse, Tunisia
| | - D Bortolotti
- Department of Experimental and Diagnostic Medicine, Section Microbiology, University of Ferrara, Ferrara, Italy
| | - N Zidi
- Faculty of Medcine Ibn Al Jazzar, University of Sousse, Sousse, Tunisia
| | - A Letaief
- Department of Internal Medicine and Infectious Diseases, University Hospital Farhat Hached, Sousse, Tunisia
| | - S Yacoub
- Regional Center of Blood Transfusion, University Hospital Farhat Hached, Sousse, Tunisia
| | - A Boudabous
- Laboratory Microorganisms and Active Biomolecules, Sciences Faculty of Tunis, University of Tunis El Manar, Tunis, Tunisia
| | - R Rizzo
- Department of Experimental and Diagnostic Medicine, Section Microbiology, University of Ferrara, Ferrara, Italy
| | - J Boukadida
- Laboratory of Microbiology-Immunology, UR02SP13, University Hospital Farhat Hached, Sousse, Tunisia
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Zhang W, Lv F, Gao YF, Zou GZ, Pan FM, Li X. Association between BTLA polymorphisms and genetic susceptibility to chronic HBV infection. Shijie Huaren Xiaohua Zazhi 2015; 23:2373-2381. [DOI: 10.11569/wcjd.v23.i15.2373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the association between BTLA polymorphisms and genetic susceptibility to chronic hepatitis B virus (HBV) infection in a Chinese Han population.
METHODS: The rs2633562 and rs2952323 single nucleotide polymorphisms (SNPs) of the BTLA gene were genotyped by Multiplex SNaPshot technique in patients with chronic HBV infection and other family members (HBsAg negative). Genotype and allele frequencies were calculated and analyzed. The association between the gene polymorphisms of BTLA and genetic susceptibility to chronic HBV infection was analyzed by a family-based association method.
RESULTS: Association or linkage was detected among 431 patients. Univariate family-based association tests (FBATs) demonstrated that the G/G genotype in rs2952323 of the BTLA gene was associated with chronic HBV infection, and the variant allele G at rs2952323 was significantly associated with genetic susceptibility to chronic HBV infection in additive model (Z = 2.689, P = 0.0007174) and recessive model (Z = 2.731, P = 0.006308). Transmission/disequilibrium test (TDT) and sibship disequilibuium test (SDT) analysis showed no increased transmission for the major alleles (A, C or G) from heterozygous parents to affected offspring (P = 1.000000, P = 0.151590, respectively). Furthermore, haplotype-specific FBATs showed that AG haplotype (70.0%) was more frequently transmitted in chronic HBV infection than other haplotypes in additive model (Z = 3.093, P = 0.001979) and recessive model (Z = 2.825, P = 0.004721).
CONCLUSION: The gene polymorphisms of BTLA may participate in chronicity of HBV infection in the Chinese Han population.
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Ülger Y, Bayram S, Sandıkçı MÜ, Akgöllü E, Bekar A. Relationship between programmed cell death-1 polymorphisms and clearance of hepatitis B virus. Int J Immunogenet 2015; 42:133-9. [PMID: 25736598 DOI: 10.1111/iji.12187] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 02/02/2015] [Accepted: 02/05/2015] [Indexed: 12/19/2022]
Abstract
Programmed cell death-1 (PD-1) plays a critical role in regulating T-cell function during hepatitis B virus (HBV) infection. This study investigated the relationship between the polymorphisms of PD-1 gene and the susceptibility to HBV infection. Single nucleotide polymorphisms (SNPs) in PD-1 gene at positions +7146 G>A (guanine to adenine substitution) and +7209 C>T (cytosine to thymine substitution) were analysed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method in 220 subjects with chronic hepatitis B infection and 165 spontaneous clearance of HBV subjects. However, no statistically significant differences were found in the genotype distributions of the PD-1 +7146 G>A and PD-1 +7209 C>T polymorphisms among chronic hepatitis B and spontaneous clearance subjects. According to stratified analyses, borderline significance was observed between PD-1 +7146 GA genotype and risk of HBV chronicity in the subgroup of male gender (OR = 1.88, 95% 0.95-3.71; P = 0.07). Our findings demonstrate for the first time that the PD-1 +7146 G>A and PD-1 +7209 C>T polymorphisms have not been any major role in genetic susceptibility to chronicity of HBV infection, at least in the population studied here. Independent studies are needed to validate our findings in a larger series, as well as in patients of different ethnic origins.
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Affiliation(s)
- Y Ülger
- Department of Gastroenterology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - S Bayram
- Department of Nursing, Adıyaman School of Health, Adıyaman University, Adıyaman, Turkey
| | - M Ü Sandıkçı
- Department of Gastroenterology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - E Akgöllü
- Department of Gastroenterology, Faculty of Medicine, Çukurova University, Adana, Turkey
| | - A Bekar
- Department of Gastroenterology, Faculty of Medicine, Çukurova University, Adana, Turkey
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Thio CL, Hawkins C. Hepatitis B Virus and Hepatitis Delta Virus. MANDELL, DOUGLAS, AND BENNETT'S PRINCIPLES AND PRACTICE OF INFECTIOUS DISEASES 2015:1815-1839.e7. [DOI: 10.1016/b978-1-4557-4801-3.00148-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Jiang X, Ma Y, Cui W, Li MD. Association of variants in HLA-DP on chromosome 6 with chronic hepatitis B virus infection and related phenotypes. Amino Acids 2014; 46:1819-26. [DOI: 10.1007/s00726-014-1767-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2014] [Accepted: 04/21/2014] [Indexed: 01/07/2023]
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Kao JH. HBeAg-positive chronic hepatitis B: why do I treat my patients with pegylated interferon? Liver Int 2014; 34 Suppl 1:112-9. [PMID: 24373087 DOI: 10.1111/liv.12400] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2013] [Accepted: 10/18/2013] [Indexed: 02/06/2023]
Abstract
Although chronic hepatitis B (CHB) is a global health threat, it is now a preventable and treatable disease. Seven agents have been approved for the treatment of CHB. Although many patients prefer potent long-term nucleos(t)ide analogues (NAs) as the first-line therapy because they are convenient to use and well-tolerated, a finite duration of pegylated interferon (PEG-IFN) is still an attractive strategy because it provides higher rates of off-therapy host immune control over hepatitis B virus (HBV) compared with NAs. In addition, the rates of HBeAg/HBsAg loss or seroconversion increase over time in patients who respond to PEG-IFN therapy. Nevertheless, these benefits are limited to 30% of all patients, and significant adverse effects are still a concern. Therefore, patients who can benefit most from PEG-IFN therapy should be more carefully selected according to baseline host and viral predictors, such as age, ALT level, viral load, HBV genotype and HBV mutants. In addition, on-treatment predictors including HBV DNA, HBeAg and HBsAg kinetics, can help decide who should continue or discontinue PEG-IFN and shift to NA. Understanding these factors can help determine personalized PEG-IFN therapy for CHB patients. In the near future, the treatment paradigm of CHB should be tailored on the basis of viral (HBV DNA level, HBV genotype and HBV mutants) and host (age, gender, ALT level and host genetic polymorphisms) factors, disease status (stage of fibrosis and comorbidities) and the selection of antiviral agents (immunomodulatory effect, antiviral potency, adverse effects and rate of drug resistance).
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Affiliation(s)
- Jia-Horng Kao
- Department of Internal Medicine, Department of Medical Research, Graduate Institute of Clinical Medicine, and Hepatitis Research Center, National Taiwan University College of Medicine and Hospital, Taipei, Taiwan
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Zhao XM, Gao YF, Zhou Q, Pan FM, Li X. Relationship between interleukin-6 polymorphism and susceptibility to chronic hepatitis B virus infection. World J Gastroenterol 2013; 19:6888-6893. [PMID: 24187466 PMCID: PMC3812490 DOI: 10.3748/wjg.v19.i40.6888] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/05/2013] [Revised: 09/06/2013] [Accepted: 09/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To identify the relationship between tag single nucleotide polymorphisms (tag SNPs) of interleukin-6 (IL-6) gene and susceptibility to chronic hepatitis B virus (HBV) infection in a Han Chinese population.
METHODS: We performed a case-control study of 501 Chinese patients with chronic HBV infection and 301 self-limiting HBV-infected individuals as controls. Genomic DNA was isolated from the whole blood of all subjects using phenol/chloroform with MaXtract high-density tubes. Tag SNPs were identified using genotype data from the panel (Han Chinese in Beijing) of the phase II HapMap Project. Four tag SNPs in IL-6 (rs17147230A/T, rs2066992G/T, rs2069837A/G and rs2069852A/G) were genotyped by the Multiplex Snapshot technique. The genotype and allele frequencies were calculated and analyzed.
RESULTS: Five haplotypes were involved in the analysis, with frequencies higher than 0.03. One of the haplotypes, TTAA, was significantly different between the two groups. Overall haplotype P values were: ATAA, P = 0.605, OR (95%CI) = 1.056 (0.860-1.297); TGAG, P = 0.385, OR (95%CI) = 1.179 (0.813-1.709); TGGG, P = 0.549, OR (95%CI) = 1.087 (0.827-1.429); TTAA, P = 0.004, OR (95%CI) = 0.655 (0.491-0.873); TTAG, P = 0.266, OR (95%CI) = 1.272 (0.832-1.944). However, the four SNPs showed no significant genotype/allele associations with susceptibility to chronic HBV infection. Overall allele P values were: rs17147230, P = 0.696, OR (95%CI) = 1.041 (0.850-1.276); rs2066992, P = 0.460, OR (95%CI) = 1.090 (0.868-1.369); rs2069837, P = 0.898, OR (95%CI) = 0.983 (0.759-1.274); rs2069852, P = 0.165, OR (95%CI) = 0.859 (0.693-1.064). Overall genotype P values were: rs17147230, P = 0.625; rs2066992, P = 0.500; rs2069837, P = 0.853; and rs2069852, P = 0.380.
CONCLUSION: The four tag SNPs of IL-6 gene may be associated with susceptibility to chronic HBV infection in the Han Chinese population.
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Zhang K, Pan X, Shu X, Cao H, Chen L, Zou Y, Deng H, Li G, Xu Q. Relationship between MIF-173 G/C polymorphism and susceptibility to chronic hepatitis B and HBV-induced liver cirrhosis. Cell Immunol 2013; 282:113-6. [PMID: 23770720 DOI: 10.1016/j.cellimm.2013.04.013] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2012] [Revised: 03/15/2013] [Accepted: 04/24/2013] [Indexed: 11/27/2022]
Abstract
Macrophage migration inhibitory factor (MIF), a pro-inflammatory cytokine, played an important role in immune-mediated diseases. The promoter region of MIF, which had functional polymorphisms, controlled MIF expression. MIF polymorphism was associated with many inflammatory diseases. But the association of MIF polymorphism with chronic hepatitis B (CHB) or HBV-induced liver cirrhosis (HC) had not yet been reported. In present study, polymorphism of MIF-173 was genotyped in 95 CHB patients, 73 HC patients and 90 healthy controls in southern China. The frequency of MIF-173 C/C genotype in patients with CHB or HC was statistically significantly higher than that in healthy controls, respectively. Moreover, difference in the distribution of MIF-173 C allele between CHB patients and healthy controls was statistically significant. However, there was no statistical relationship between MIF-173 genotype and clinical features in patients with CHB or HC. Our results suggest that MIF-173 C/C polymorphism might be associated with increased risk of CHB or HC in Chinese southern population.
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Affiliation(s)
- Ka Zhang
- Department of Infectious Diseases, The 3rd Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, People's Republic of China
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Lal JA, Malogajski J, Verweij SP, de Boer P, Ambrosino E, Brand A, Ouburg S, Morré SA. Chlamydia trachomatis infections and subfertility: opportunities to translate host pathogen genomic data into public health. Public Health Genomics 2013; 16:50-61. [PMID: 23548718 DOI: 10.1159/000346207] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Chlamydia trachomatis (CT) infections in women can result in tubal pathology (TP). Worldwide 10-15% of all couples are subfertile, meaning they did not get pregnant after 1 year. Part of the routine subfertility diagnostics is the Chlamydia Antibody Test (CAT) to decide for laparoscopy or not in order to diagnose TP. The CAT positive and negative predictive value is such that many unneeded laparoscopies are done and many TP cases are missed. Addition of host genetic markers related to infection susceptibility and severity could potentially improve the clinical management of couples who suffer from subfertility. In the present study, the potential translational and clinical value of adding diagnostic host genetic marker profiles on the basis of infection and inflammation to the current clinical management of subfertility was investigated. This review provides an overview of the current state of the art of host genetic markers in relation to CT infection, proposes a new clinical diagnostic approach, and investigates how the Learning-Adapting-Leveling model (LAL, a public health genomic (PHG) model) can be of value and provide insight to see whether these host genetic markers can be translated into public health. This review shows that the preliminary basis of adding host genetic marker profiles to the current diagnostic procedures of subfertility is present but has to be further developed before implementation into health care can be achieved. CT infection is an example in the field of PHG with potential diagnostic to be taken up in the future in the field of subfertility diagnosis with a time line for integration to be dependent on enhanced participation of many stakeholders in the field of PHG which could be advanced through the LAL model.
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Affiliation(s)
- J A Lal
- Institute for Public Health Genomics, Department of Genetics and Cell Biology, Faculty of Health, Medicine and Life Sciences, University of Maastricht, Maastricht, The Netherlands
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Qiu B, Huang B, Wang X, Liang J, Feng J, Chang Y, Li D. Association of TAP1 and TAP2 polymorphisms with the outcome of persistent HBV infection in a northeast Han Chinese population. Scand J Gastroenterol 2012; 47:1368-74. [PMID: 22989262 DOI: 10.3109/00365521.2012.725090] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVE Transporter associated with antigen processing (TAP) plays a central role in a cellular immune response against HBV. Polymorphisms exist at the coding region of TAP and alter its structure and function. The aim of this study was to evaluate the potential relationship between polymorphisms of TAP and different outcomes of persistent HBV infection in a Han population in northeastern China. MATERIAL AND METHODS 189 HBV spontaneously recovered (SR) subjects, 571 HBV-infected patients including 180 chronic hepatitis B (CHB), 196 liver cirrhosis (LC) and 195 hepatocellular carcinoma (HCC) individuals were included in this study. TAP1-333 Ile/Val and -637 Asp/Gly, TAP2-651 Arg/Cys and -687 Stop/Gln were genotyped in all the samples by using a PCR-RFLP method. RESULTS The frequency of TAP1-637-Gly (allele G) was significantly higher in persistently HBV-infected individuals (CHB and LC) than that of SR subjects (OR = 1.58, 95% CI 1.12-2.45, p = 0.024; OR = 1.78, 95% CI 1.27-2.68, p = 0.002) by a logistic regression analysis. In addition, the statistically significant difference in the distribution of TAP2-651-Cys (allele T) was observed between HCC cases and SR controls (OR = 2.30, 95% CI 1.51-3.72, p < 0.001), and TAP2-687-Gln (allele C) in CHB patients was more common than that in SR subjects (OR = 1.41, 95% CI 1.13-1.97, p = 0.021). The data also revealed that haplotype 687 Gln-651 Cys-637 Gly-333 Ile was strongly associated with persistent HBV infection (CHB, LC and HCC) (p < 0.001, < 0.05 and < 0.001, respectively). CONCLUSION These results suggested that TAP variants were likely to play a substantial role in different outcomes of persistent HBV infection in the studied population.
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Affiliation(s)
- Bing Qiu
- Department of Gastroenterology, Heilongjiang Province Hospital, Harbin, China
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Qiu B, Wang X, Zhang P, Shi C, Zhang J, Qiu W, Wang W, Li D. Association of TNF-α promoter polymorphisms with the outcome of persistent HBV infection in a northeast Chinese Han population. Acta Biochim Biophys Sin (Shanghai) 2012; 44:712-8. [PMID: 22695741 DOI: 10.1093/abbs/gms046] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Tumor necrosis factor-α (TNF-α) plays an important role in the pathogenesis and clinical outcome of chronic hepatitis B virus (HBV) infection. The objective of this study was to evaluate the relationship between functional polymorphisms of TNF-α and different outcomes of persistent HBV infection in a northeast Chinese Han population. Here 189 HBV spontaneously recovered subjects (SR), 571 HBV-infected patients including 180 chronic hepatitis B (CHB), 196 liver cirrhosis (LC), and 195 hepatocellular carcinoma (HCC) individuals were enrolled in this study. All the samples were genotyped for TNF-α -857C/T and -863C/A using the polymerase chain reaction-restriction fragment length polymorphism method. The frequency of -857CC genotype was significantly higher in CHB and LC individuals compared with that of SR subjects (P= 0.03, OR = 1.57, 95% CI 1.04-2.39 and P= 0.03, OR = 1.57, 95% CI 1.04-2.35, respectively). A significant difference in the distribution of the allele -857C was observed for both CHB vs. SR (P= 0.01, OR = 1.52, 95% CI 1.08-2.13) and LC vs. SR (P= 0.02, OR = 1.47, 95% CI 1.06-2.04) cohorts. In addition, the frequency of -863AA genotype was significantly higher in CHB and LC patients than that of SR subjects (P= 0.01, OR = 3.90, 95% CI 1.35-11.23 and P= 0.01, OR = 3.83, 95% CI 1.34-10.96, respectively), and allele -863A frequency was significantly more common in CHB, LC, and HCC cohorts than that of SR controls (P= 0.004, OR = 1.72, 95% CI 1.19-2.50; P= 0.001, OR = 1.81, 95% CI 1.26-2.61 and P= 0.001, OR = 1.90, 95% CI 1.33-2.73, respectively). Our data also revealed that haplotype CA was strongly associated with persistent HBV infection. These results suggest an association between the TNF-α promoter variants and different outcomes of persistent HBV infection in the studied population.
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Affiliation(s)
- Bing Qiu
- Department of Gastroenterology, Heilongjiang Province Hospital, Harbin 150036, China.
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Park GH, Kim KY, Cheong JY, Cho SW, Kwack K. Association of GNLY genetic polymorphisms with chronic liver disease in a Korean population. DNA Cell Biol 2012; 31:1492-8. [PMID: 22788687 DOI: 10.1089/dna.2012.1709] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Granulysin (GNLY) is found in cytotoxic granules of cytolytic T lymphocytes and natural killer (NK) cells, which are critical for hepatitis B virus (HBV) clearance. GNLY cytotoxicity plays an important role in the defense against viruses or intracellular bacteria. We hypothesized that genetic variation in the GNLY gene could affect the resistance of hosts against HBV infection. We compared the distribution frequencies of GNLY polymorphisms between an HBV-induced chronic liver disease (CLD) group and a spontaneous recovery (SR) control group to determine whether GNLY polymorphisms play a role in HBV clearance. A total of 117 patients in the SR group and 230 patients in the CLD group were enrolled. Samples derived from complex infections, including hepatitis C and human immunodeficiency virus, and those associated with insufficient clinical information (10 samples in SR and 24 samples in CLD) were excluded from the study. The final analysis included 107 SR and 206 CLD samples. DNA was extracted from peripheral blood, and GNLY genotypes were determined by the GoldenGate(®) method. The genotype distribution of the single-nucleotide polymorphisms (SNPs) rs2886767 (C>T), rs1561285 (G>C), and rs11127 (T>C) were significantly different between the SR and CLD groups in a recessive model (p<0.015). These three SNPs were in a complete linkage disequilibrium (LD) block. Diplotype distributions of haplotype (HT) 1 (C-G-T) and HT2 (T-C-C) were significantly different between the SR and CLD groups in a recessive model (p=0.025) and a dominant model (p=0.008). All p-values remained significant after multiple comparisons. GNLY polymorphism genotypes and diplotypes were associated with the chronicity of HBV. These data suggested that genetic variation of GNLY may be an important factor in HBV clearance through the CD8+ T or NK cell-mediated removal of HBV-infected cells from the host.
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Affiliation(s)
- Geun-Hee Park
- Department of Biomedical Science, College of Life Science, CHA University, Seongnam, Republic of Korea
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Yan ZH, Fan Y, Wang XH, Mao Q, Deng GH, Wang YM. Relationship between HLA-DR gene polymorphisms and outcomes of hepatitis B viral infections: A meta-analysis. World J Gastroenterol 2012; 18:3119-28. [PMID: 22791948 PMCID: PMC3386326 DOI: 10.3748/wjg.v18.i24.3119] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2011] [Revised: 11/26/2011] [Accepted: 12/03/2011] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the rigorous relationship between human leukocyte antigens (HLA)-DR alleles and outcomes of hepatitis B virus (HBV) infections by means of meta-analysis.
METHODS: Medline/PubMed, EMBASE, CNKI and VIP were searched to identify relevant studies. Study quality was evaluated using the Newcastle-Ottawa Scale. Odds ratios (OR) and 95% confidence interval (95% CI) were pooled using Stata 11.0. Subgroup analyses were performed by ethnicity. Heterogeneity and publication bias analyses were performed to validate the credibility.
RESULTS: A total of 2609 patients with chronic hepatitis B and 2606 controls spontaneously recovering from prior HBV infection were included. Meta-analysis showed that HLA-DR*04 (OR = 0.72, 95% CI: 0.60-0.85) and DR*13 (OR = 0.27, 95% CI: 0.19-0.37) alleles were significantly associated with HBV clearance while patients carrying HLA-DR*03 (OR = 1.47, 95% CI: 1.16-1.87) or DR*07 (OR = 1.59, 95% CI: 1.24-2.03) alleles had a significantly increased risk of chronic HBV persistence. For the HLA-DR*01 polymorphism, a significantly association with HBV clearance was found in Chinese Han group (OR = 0.48, 95% CI: 0.26-0.86), but not found in other ethnic groups (P = 0.191). For other polymorphisms, no association with the HBV infection outcome was found.
CONCLUSION: HLA-DR*04 and DR*13 alleles may be the protective factors for HBV clearance and HLA-DR*03, and DR*07 alleles may be the risk factors for HBV persistence.
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Yan Z, Tan S, Dan Y, Sun X, Deng G, Wang Y. Relationship between HLA-DP gene polymorphisms and clearance of chronic hepatitis B virus infections: case-control study and meta-analysis. INFECTION GENETICS AND EVOLUTION 2012; 12:1222-8. [PMID: 22543033 DOI: 10.1016/j.meegid.2012.03.026] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2012] [Revised: 03/28/2012] [Accepted: 03/29/2012] [Indexed: 01/02/2023]
Abstract
Hepatitis B virus (HBV) infection is a serious public health problem worldwide. Two common genetic variants (rs3077 and rs9277535) of human leukocyte antigen DP (HLA-DP) have been reported to be associated with persistent HBV infection in populations of Japan and Thailand. To confirm whether the association can be replicated in Chinese populations, an independent case-control study were conducted, and two polymorphisms (rs3077 and rs9277535) were genotyped using the TaqMan SNP genotyping assay in 282 persistent chronic HBV carriers and 64 spontaneously HBV recovered carriers. To provide a more definitive conclusion, a meta-analysis combining and summarizing five studies was performed by random-effects model using the DerSimonian and Laird's method. By using logistic regression analysis with adjustment for covariates, including age, sex, and alcohol consumption, the results of our independent case-control study showed that the minor allele's homozygote (AA genotype) of rs3077 and rs9277535 was significantly associated with decreasing risk/protection of HBV persistent chronic infection (for rs3077: P=0.0017, OR=0.29, 95% CI=0.13-0.62; for rs9277535, P=0.0004, OR=0.26, 95% CI=0.12-0.54). The results of meta-analysis pooling all eligible studies also showed that rs3077-A and rs9277535-A alleles were associated with an increased clearance rate to HBV infection (rs3077: OR=0.57, 95% CI=0.44-0.75; rs9277535: OR=0.56, 95% CI=0.47-0.63). These results further confirmed the strong influence of HLA-DP gene variants on risk of spontaneous HBV clearance from persistent HBV infection. Both A alleles of HLA-DP SNP rs3077 and rs9277535 showed strong protective effects for spontaneous HBV clearance from persistent HBV infection in the Han Chinese population.
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Affiliation(s)
- Zehui Yan
- Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, 30 Gao Tan Yan Street, Sha Ping Ba District, Chongqing 400038, PR China
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Hennig BJ, Hall AJ. Host genetic factors in hepatitis B infection, liver cancer and vaccination response: a review with a focus on Africa. THE SCIENCE OF THE TOTAL ENVIRONMENT 2012; 423:202-209. [PMID: 20970823 DOI: 10.1016/j.scitotenv.2010.09.036] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2009] [Revised: 09/21/2010] [Accepted: 09/21/2010] [Indexed: 05/30/2023]
Abstract
The disease burden due to hepatitis B virus (HBV) infection remains significant; 350 million people are infected world-wide, and around half a million deaths each year are due to HBV-related liver disease and hepatocellular carcinoma (HCC). Infant immunisation against infection was introduced in the early 1980s, the vaccine is routinely administered across regions where the disease is endemic and has been shown to be safe and effective. However, the large number of older individuals with persistent infection means that disease will not be reduced significantly for several decades. Furthermore, failure to respond to the vaccination has been observed in about 5% of vaccinees and to date we have limited information on the durability of vaccine protection against infection. Hepatitis B infection and disease pathogenesis are known to be influenced by a number of factors including host genetics factors. This review aims to give an overview of the role of genetic variation in persistent HBV infection and the development of liver disease including HCC. Vaccine-induced immunity is, at least in part, heritable and we also discuss findings on the genetic control of responses to HBV vaccination. The epidemiology of HBV infection differs by world region, as does the genetic makeup of individuals originating from different regions. This review focuses on the situation in Africa, where hepatitis B is highly endemic.
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Affiliation(s)
- Branwen J Hennig
- Department of Epidemiology and Population Health, London School of Hygiene & Tropical Medicine, Keppel Street, London WC1E 7HT, UK.
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Li N, Gao YF, Zhang TC, Chen P, Li X, Su F. Relationship between interleukin 18 polymorphisms and susceptibility to chronic hepatitis B virus infection. World J Hepatol 2012; 4:105-9. [PMID: 22489263 PMCID: PMC3321489 DOI: 10.4254/wjh.v4.i3.105] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2011] [Revised: 02/29/2012] [Accepted: 03/17/2012] [Indexed: 02/06/2023] Open
Abstract
AIM To identify the relationship between the tagging single nucleotide polymorphism sites (tagSNPs) of the Interleukin-18 (IL-18) gene and genetic susceptibility to chronic hepatitis B virus infection in Chinese patients. METHODS Five hundred and one cases of chronic hepatitis B virus (HBV) infection and 301 HBV natural clearance controls were studied. Two tagSNPs in the IL-18 gene (rs1946518A/C and rs574424C/G) were genotyped by the Multiplex Snapshot technique. The genotype and allele frequencies were calculated and analyzed. RESULTS In the genotypes of rs1946518, the AA type was present at a higher frequency in the patients compared to those in the controls. Odds ratio (OR) of the AA genotype for the comparison with that of the AC and the CC genotype was 1.537 (95% confidence intervals (CI): 1.116-2.218, P = 0.009 < 0.025). In phenotypes, the allele C at rs1946518 was of a significantly lower frequency in the patients with chronic hepatitis B than that in the controls (P = 0.017 < 0.025). OR of the allele A for the comparison with that of the allele C was 1.279 (95% CI: 1.045-1.567). As for the rs574424 genotypes, no significant difference in this genotype distribution or in this allele frequency between the patients and the control subjects was observed. No significant difference in the haplotype frequencies between the patients with chronic hepatitis B and HBV natural clearance individuals was displayed. CONCLUSION The data suggest that genotype AA and the allele A of the IL-18 at position rs1946518 are closely associated with the resistance to chronic hepatitis B and may be the dangerous gene. However, no statistical association was found between polymorphisms of rs574424 for IL-18 and hepatitis B.
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Affiliation(s)
- Na Li
- Na Li, Ping Chen, Xu Li, Fei Su, Department of Infectious Diseases, the First Affiliated Hospital of Anhui Medical University, Hefei 230032, Anhui Province, China
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Vermehren J, Lötsch J, Susser S, Wicker S, Berger A, Zeuzem S, Sarrazin C, Doehring A. A common HLA-DPA1 variant is associated with hepatitis B virus infection but fails to distinguish active from inactive Caucasian carriers. PLoS One 2012; 7:e32605. [PMID: 22448225 PMCID: PMC3308944 DOI: 10.1371/journal.pone.0032605] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Accepted: 01/28/2012] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND AND AIMS Chronic infection with the hepatitis B virus (HBV) is a major health issue worldwide. Recently, single nucleotide polymorphisms (SNPs) within the human leukocyte antigen (HLA)-DP locus were identified to be associated with HBV infection in Asian populations. Most significant associations were observed for the A alleles of HLA-DPA1 rs3077 and HLA-DPB1 rs9277535, which conferred a decreased risk for HBV infection. We assessed the implications of these variants for HBV infection in Caucasians. METHODS Two HLA-DP gene variants (rs3077 and rs9277535) were analyzed for associations with persistent HBV infection and with different clinical outcomes, i.e., inactive HBsAg carrier status versus progressive chronic HBV (CHB) infection in Caucasian patients (n = 201) and HBsAg negative controls (n = 235). RESULTS The HLA-DPA1 rs3077 C allele was significantly associated with HBV infection (odds ratio, OR = 5.1, 95% confidence interval, CI: 1.9-13.7; p = 0.00093). However, no significant association was seen for rs3077 with progressive CHB infection versus inactive HBsAg carrier status (OR = 2.7, 95% CI: 0.6-11.1; p = 0.31). In contrast, HLA-DPB1 rs9277535 was not associated with HBV infection in Caucasians (OR = 0.8, 95% CI: 0.4-1.9; p = 1). CONCLUSIONS A highly significant association of HLA-DPA1 rs3077 with HBV infection was observed in Caucasians. However, as a differentiation between different clinical courses of HBV infection was not possible, knowledge of the HLA-DPA1 genotype cannot be translated into personalized anti-HBV therapy approaches.
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Affiliation(s)
- Johannes Vermehren
- pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der J. W. Goethe Universität, Frankfurt am Main, Germany
| | - Jörn Lötsch
- pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der J. W. Goethe Universität, Frankfurt am Main, Germany
| | - Simone Susser
- Medizinische Klinik 1, Klinikum der J. W. Goethe Universität, Frankfurt am Main, Germany
| | - Sabine Wicker
- Betriebsärztlicher Dienst, Klinikum der J. W. Goethe Universität, Frankfurt am Main, Germany
| | - Annemarie Berger
- Institut für Medizinische Virologie, Klinikum der J. W. Goethe Universität, Frankfurt am Main, Germany
| | - Stefan Zeuzem
- Medizinische Klinik 1, Klinikum der J. W. Goethe Universität, Frankfurt am Main, Germany
| | - Christoph Sarrazin
- Medizinische Klinik 1, Klinikum der J. W. Goethe Universität, Frankfurt am Main, Germany
| | - Alexandra Doehring
- pharmazentrum frankfurt/ZAFES, Institut für Klinische Pharmakologie, Klinikum der J. W. Goethe Universität, Frankfurt am Main, Germany
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Panassié L, Borentain P, Nafati C, Bernardin G, Doudier B, Thibault V, Gerolami R, Colson P. Fatal fulminant primary hepatitis B virus infections with G1896A precore viral mutants in southeastern France. Clin Res Hepatol Gastroenterol 2012; 36:e1-8. [PMID: 22037043 DOI: 10.1016/j.clinre.2011.09.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2011] [Revised: 09/05/2011] [Accepted: 09/13/2011] [Indexed: 02/04/2023]
Abstract
Fulminant hepatitis has been shown to occur in about 1% of acute hepatitis B virus (HBV) infections, and its mortality rate is nearly 70%. Specific HBV genotypic features have been pointed out in fulminant acute hepatitis B worldwide, but these associations remain controversial. We describe all four primary HBV infections diagnosed in 2008 in our institution in Marseille, southeastern France, including two fatal cases. HBV genotypes were D or E. Precore G1896A HBV mutants were detected in both fatal fulminant primary HBV infections. Hepatitis B surface antigen and hepatitis B e antigen (HBeAg) were negative in two and three cases, respectively, despite HBV DNA detection. Primary HBV infection remains a cause of death in France. The impact of the precore G1896A mutation on the severity of AHB deserves to be assessed in larger studies in this country.
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Affiliation(s)
- Laure Panassié
- Laboratoire de virologie, pôle des maladies infectieuses et tropicales clinique et biologique, fédération de bactériologie-hygiène-virologie, CHU Timone, 264, rue Saint-Pierre, 13385 Marseille cedex 05, France
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Effects of variant rs346473 in ARHGAP24 gene on disease progression of HBV infection in Han Chinese population. ACTA ACUST UNITED AC 2011; 31:482. [PMID: 21823009 DOI: 10.1007/s11596-011-0477-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2011] [Indexed: 01/17/2023]
Abstract
Host genetic, environmental and viral factors are classified as three categories that determine clinical outcomes of hepatitis B virus (HBV) infection. The objective of this study was to detect the associations between polymorphisms rs346473 and rs346482 in Rho GTPase-activating protein 24 (ARHGAP24) gene and disease progression of HBV infection in Han Chinese population. These two SNPs were found by our DNA pooling using Affymetrix Genome-Wide Human Mapping SNP6.0 Array in HBV carriers, and verified by using TaqMan 7900HT Sequence Detection System with 758 progressed HBV carriers versus 300 asymptomatic HBV carriers (AsC) in a discovery phase and 971 progressed HBV carriers versus 328 AsC in a replication phase. Multivariable logistic regression revealed that individuals with genotype TT at variant rs346473 displayed remarkable correlations with disease progression of HBV infection both in the discovery phase (OR, 2.693; 95% CI, 1.928-3.760; P=6.2×10(-9); additive model) and the replication phase (OR, 1.490; 95% CI, 1.104-2.012; P=9.0×10(-3); additive model). These two SNPs were in strong linkage disequilibrium with D'=0.99 and r (2)=0.951, and haplotype TT disclosed an increased susceptibility to HBV progression (OR, 1.980; 95% CI, 1.538-2.545; P=8.1×10(-8)). These findings suggest that polymorphism rs346473 in the ARHGAP24 gene might be a part of the genetic variants underlying the susceptibility of HBV carriers to disease progression.
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Host genetic variants and hepatitis B virologic features in HBeAg-negative hepatitis B carriers with long-term biochemical remission. Hepatol Int 2011; 6:598-605. [DOI: 10.1007/s12072-011-9297-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2011] [Accepted: 06/24/2011] [Indexed: 12/15/2022]
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Abstract
INTRODUCTION At present, two strategies exist for the treatment of chronic hepatitis B (CHB): i) standard or pegylated interferon alpha (IFN) with mainly immune modulatory effects; and ii) nucleos(t)ide analogues (NA) with direct antiviral effects. The optimal treatment for an individual patient remains controversial. AREAS COVERED The treatment efficacy and prediction of response to antiviral agents for chronic hepatitis B are reviewed and discussed. EXPERT OPINION The rates of hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg) loss or seroconversion are continuously increasing in CHB patients after stopping a finite course of IFN, whereas long-term NA therapy is usually required to improve the adverse outcomes of CHB. Lower baseline HBV DNA level is a strong predictor for both sustained viral suppression and HBeAg seroconversion in patients receiving IFN-based as well as NAs therapy. In addition, HBeAg-positive patients with genotype A or B infection have better responses to IFN-based therapy than those with genotypes C or D infection. Furthermore, on-treatment predictors such as declines of serum HBV DNA, HBsAg and HBeAg levels may be helpful in making decisions of subsequent therapy. Regarding the association of host genetic factors with responses to antiviral therapy, current evidence is limited.
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Affiliation(s)
- Chih-Lin Lin
- Department of Gastroenterology, Ren-Ai branch, Taipei City Hospital, Taipei, Taiwan
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Li JR, Li JG, Deng GH, Zhao WL, Dan YJ, Wang YM, Chen S. A common promoter variant of TBX21 is associated with allele specific binding to Yin-Yang 1 and reduced gene expression. Scand J Immunol 2011; 73:449-58. [PMID: 21272048 DOI: 10.1111/j.1365-3083.2011.02520.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
T-bet is a key regulator for the lineage commitment in CD4 T helper (Th) 1 cells by activating the hallmark production of interferon-γ, and its expression level is linked to autoimmune, infectious, and allergic diseases. A T to C base substitution has been identified at position -1993 in the TBX21 (encoding T-bet) promoter and has been associated with asthma and systemic lupus erythematosus. This study aimed to investigate the molecular mechanisms responsible for the influence of the T-1993C polymorphism on transcription and its functional effect by luciferase reporter, EMSAs, Chromatin immunoprecipitation assay, and flow cytometric analysis of intracellular T-bet, IFN-γ and IL-4 expression in activated CD4(+) T cells. The presence of a -1993T allele obviously increases promoter activity compared with that of a promoter with a -1993C allele. TBX21 promoter carrying -1993C allele possesses significantly stronger binding affinity to the Yin Yang 1 (YY1) transcription factor than that carrying -1993T allele. YY1 overexpression decreased TBX21 promoter function in a T cell line, demonstrating that this element functions as a repressor. The C to T base exchange relieves the repression mediated by YY1. The individuals carrying -1993C allele were determined to have significantly diminished expression of TBX21 and IFN-γ and increased IL-4 production in cells compared with the individuals carrying -1993T allele (P < 0.05). These findings demonstrate that the TBX21 T-1993C polymorphism represses TBX21 expression and Th1 cytokine production through control of YY1, which might result in the imbalance between Th1 and Th2 immune responses in autoimmune or allergic diseases.
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Affiliation(s)
- J-R Li
- Institute of Infectious Diseases, Southwest Hospital, Third Military Medical University, Chongqing, China
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Cui MF, Gao YF, Lv F, Li N, Zhang ZH, Li X, Su F. Association between polymorphisms of the T cell immunoglobulin musin-3 gene and outcome of hepatitis B virus infection. Shijie Huaren Xiaohua Zazhi 2011; 19:1506-1510. [DOI: 10.11569/wcjd.v19.i14.1506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the relationship between single nucleotide polymorphisms (SNPs) of the T cell immunoglobulin musin-3 (Tim-3) gene and outcome of hepatitis B virus (HBV) infection in a Chinese Han population.
METHODS: Two tagSNPs of the Tim-3 gene (rs11741184 and rs13170556) were genotyped using the SNaPshot method in 996 patients with chronic HBV infection group and 301 patients with acute self-limiting HBV infection. The genotypes, allele frequencies and haplotypes of the two Tim-3 tagSNPs were compared between the two groups of patients.
RESULTS: The frequencies of CC, CG and GG genotypes at the rs11741184 locus were 84.39% (254/301), 15.28% (46/301) and 0.3% (1/301) in patients with acute self-limiting HBV infection, and 86.04% (857/996), 13.65% (136/996) and 0.3% (3/996) in patients with chronic HBV infection, respectively. There were no statistical differences in the genotype frequencies at the rs11741184 locus between the two groups of patients (all P > 0.05). The frequencies of AA, GA and GG genotypes at the rs13170556 locus were 68.77% (207/301), 28.57% (6/301) and 2.66% (8/301) in patients with acute self-limiting HBV infection, and 68.07% (678/996), 28.41% (283/996) and 3.51% (35/996) in patients with chronic HBV infection, respectively. There were also no statistical differences in the genotype frequencies at the rs13170556 locus between the two groups of patients (all P > 0.05). Three haplotypes for Tim-3 tagSNPs (C-A, C-G, G-A) were found in the Chinese Han population, and their haplotype frequencies were similar between patients with acute self-limiting HBV infection (75.08%, 16.94%, 7.97%) and those with chronic HBV infection (75.08% vs 75.15%, 16.94% vs 17.72%, 7.97% vs 7.13%, all P > 0.05).
CONCLUSION: The two Tim-3 tagSNPs may not be associated with outcome of HBV infection in Chinese Han population.
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Lv F, Gao YF, Zhang ZH, Zhang TC, Pan FM, Cui MF, Xia SL, Li X, Yin HF. Polymorphisms in programmed death-1 gene are not associated with chronic HBV infection in Chinese patients. World J Hepatol 2011; 3:72-78. [PMID: 21487538 PMCID: PMC3074088 DOI: 10.4254/wjh.v3.i3.72] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/26/2010] [Revised: 12/23/2010] [Accepted: 12/30/2010] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the association between the programmed death-1(PD-1) polymorphisms and genetic susceptibility of chronic hepatitis B virus (HBV) infection in Chinese patients. METHODS Two single nucleotide polymorphisms (SNPs), PD-1.1 G > A and PD-1.2 G > A, were genotyped in 539 patients with chronic HBV infection and 353 other family members (HbsAg-) from 256 nuclear families using polymerase chain reactiorestriction fragment length polymorphisms assay. The associations between PD-1 polymorphisms and genetic susceptibility of chronic HBV infection were analyzed usng the family-based association analysis method. RESULTS No association or linkage was detected among 539 patients. Univariate (single-marker) family-based association tests demonstrated that PD-1 genotypes, alleles and transmitted haplotypes are not associated with chronic HBV infection (all with P value more than 0.05). Transmission/disequilibrium test and sibship disequilibrium test analysis showed no excess of the alleles from heterozygous parents to affected offspring (P = 0.688880, P = 1.000000 respectively). CONCLUSION The data demonstrated that PD-1.1 and PD-1.2 polymorphisms are not associated with chronic HBV infection in Chinese patients.
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Affiliation(s)
- Feng Lv
- Feng Lv, Yu-Feng Gao, Zhen-Huan Zhang, Ming-Fang Cui, Shu-Ling Xia, Xu Li, Hua-Fa Yin, Department of Infectious Diseases, the First Affiliated Hospital, Anhui Medical University, Hefei 230022, Anhui Province, China
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Howell JA, Visvanathan K. A novel role for human leukocyte antigen-DP in chronic hepatitis B infection: a genomewide association study. Hepatology 2009; 50:647-9. [PMID: 19642163 DOI: 10.1002/hep.23147] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Jessica A Howell
- Innate Immunity Laboratory, Department of Medicine, Monash University, Melbourne, Australia
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Kamatani Y, Wattanapokayakit S, Ochi H, Kawaguchi T, Takahashi A, Hosono N, Kubo M, Tsunoda T, Kamatani N, Kumada H, Puseenam A, Sura T, Daigo Y, Chayama K, Chantratita W, Nakamura Y, Matsuda K. A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians. Nat Genet 2009; 41:591-5. [PMID: 19349983 DOI: 10.1038/ng.348] [Citation(s) in RCA: 426] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2008] [Accepted: 01/16/2009] [Indexed: 12/12/2022]
Abstract
Chronic hepatitis B is a serious infectious liver disease that often progresses to liver cirrhosis and hepatocellular carcinoma; however, clinical outcomes after viral exposure vary enormously among individuals. Through a two-stage genome-wide association study using 786 Japanese chronic hepatitis B cases and 2,201 controls, we identified a significant association of chronic hepatitis B with 11 SNPs in a region including HLA-DPA1 and HLA-DPB1. We validated these associations by genotyping two SNPs from the region in three additional Japanese and Thai cohorts consisting of 1,300 cases and 2,100 controls (combined P = 6.34 x 10(-39) and 2.31 x 10(-38), OR = 0.57 and 0.56, respectively). Subsequent analyses revealed risk haplotypes (HLA-DPA1(*)0202-DPB1(*)0501 and HLA-DPA1(*)0202-DPB1(*)0301, OR = 1.45 and 2.31, respectively) and protective haplotypes (HLA-DPA1(*)0103-DPB1(*)0402 and HLA-DPA1(*)0103-DPB1(*)0401, OR = 0.52 and 0.57, respectively). Our findings show that genetic variants in the HLA-DP locus are strongly associated with risk of persistent infection with hepatitis B virus.
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Affiliation(s)
- Yoichiro Kamatani
- Human Genome Center, Institute of Medical Science, the University of Tokyo, Japan
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A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol 2008; 6:1315-41; quiz 1286. [PMID: 18845489 DOI: 10.1016/j.cgh.2008.08.021] [Citation(s) in RCA: 362] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/30/2008] [Revised: 08/18/2008] [Accepted: 08/20/2008] [Indexed: 02/07/2023]
Abstract
Chronic HBV infection is an important public health problem worldwide and in the United States. A treatment algorithm for the management of this disease, published previously by a panel of U.S. hepatologists, has been revised on the basis of new developments in the understanding of the disorder, the availability of more sensitive molecular diagnostic tests, and the licensure of new therapies. In addition, a better understanding of the advantages and disadvantages of new treatments has led to the development of strategies for reducing the rate of resistance associated with oral agents and optimizing treatment outcomes. This updated algorithm was based primarily on available evidence by using a systematic review of the literature. Where data were lacking, the panel relied on clinical experience and consensus expert opinion. The primary aim of antiviral therapy is durable suppression of serum HBV DNA to low or undetectable levels. Assays can now detect serum HBV DNA at levels as low as 10 IU/mL and should be used to establish a baseline level, monitor response to antiviral therapy, and survey for the development of drug resistance. Interferon alfa-2b, lamivudine, adefovir, entecavir, peginterferon alfa-2a, telbivudine, and tenofovir are approved as initial therapy for chronic hepatitis B and have certain advantages and disadvantages. Although all of these agents can be used in selected patients, the preferred first-line treatment choices are entecavir, peginterferon alfa-2a, and tenofovir. Issues for consideration for therapy include efficacy, safety, rate of resistance, method of administration, and cost.
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Cui JJ, Zeng Z, Tian GB, Tian D, Lu HY. Advance in genetic factors influencing hepatitis B virus infection. Shijie Huaren Xiaohua Zazhi 2007; 15:1246-1251. [DOI: 10.11569/wcjd.v15.i11.1246] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a major global health problem. A complex combination of environment and virus, especially host genetic factors, play a critical role in determining both susceptibility to HBV persistence and different clinical outcomes after HBV infection. In this review, we summarized the main relevant genes such as human leukocyte antigen (HLA), tumor necrosis factor (TNF), interleukins (ILs), interferons (IFNs), etc. However, in order to identify all the relevant polymorphisms that affect the outcome of HBV infection, alternative strategies such as genome-wide association studies with large sample sizes are required to define the majority of the related genes.
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Härtel C, Schultz C, Herting E, Göpel W. Genetic association studies in VLBW infants exemplifying susceptibility to sepsis--recent findings and implications for future research. Acta Paediatr 2007; 96:158-65. [PMID: 17429897 DOI: 10.1111/j.1651-2227.2007.00128.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
CONTEXT In recent years, tremendous effort has been carried out to study the genetic basis of susceptibility to development, progression and severity of complex diseases and response to therapy. The ultimate goal of these investigations is to find new tools for prevention and treatment of these complex diseases, such as sepsis in very-low-birth-weight (VLBW) infants. VLBW cohorts have a restricted clinical risk profile for the development of sepsis including immaturity of immune functions and antenatal/perinatal risk factors but also a significant event rate of sepsis within a short period of observational time. Therefore, prospective VLBW cohorts are advantageous for the investigation of candidate genetic risk factors of sepsis compared to adult cohorts. Furthermore, environmental factors are much better documented and highly controlled for VLBW infants in a standardized NICU setting compared to adult cohorts which are influenced by a variety of environmental risk factors, e.g. habits and comorbidities. OBJECTIVE The aim of this review is to discuss the value and limitations of genetic association studies in VLBW infant cohorts exemplifying recent findings for genetic susceptibility to neonatal sepsis. DATA SOURCE Published Medline articles reporting on studies of associations between genetic polymorphisms, neonatal sepsis and septic shock in VLBW infants. CONCLUSIONS Up-to-date, the classical approach to investigate the genetic component of susceptibility to sepsis in VLBW infants by means of twin and concordance studies has not been implemented yet. Regarding the interpretation of data from current genetic association studies, one should be aware of significant differences in cohort size, study design and definition of cases, controls and clinical end points. Furthermore, the contribution of genetic variants to susceptibility to sepsis may be specifically influenced by the immaturity of the immune response in VLBW infants, the selectivity of responsiveness to certain pathogens and the genotopyic/phenotypic variability of pathogens. We provide implications for the conduct and evaluation of future association studies with particular reference to methodological quality standards.
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Affiliation(s)
- Christoph Härtel
- Department of Pediatrics, University of Lübeck Children's Hospital, Ratzeburger Allee 160, 23538 Lübeck, Germany.
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Abstract
Genetic epidemiology researches such as twin studies, family-clustering of hepatitis B virus (HBV) infection studies and ethnic difference studies have provided the evidence that host genetic factors play an important role in determining the outcome of HBV infection. The opening questions include which human genes are important in infection and how to find them. Though a number of studies have sought genetic associations between HBV infection/persistence and gene polymorphisms, the candidate gene-based approach is clearly inadequate to fully explain the genetic basis of the disease. With the advent of new genetic markers and automated genotyping, genetic mapping can be conducted extremely rapid. This approach has been successful in some infectious diseases. Linkage analysis can find host genes susceptible to HBV and is of great clinical importance.
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Affiliation(s)
- Ying-Li He
- Department of Infectious Diseases, the First Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
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den Hartog JE, Morré SA, Land JA. Chlamydia trachomatis-associated tubal factor subfertility: Immunogenetic aspects and serological screening. Hum Reprod Update 2006; 12:719-30. [PMID: 16832042 DOI: 10.1093/humupd/dml030] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Chlamydia (C.) trachomatis female genital tract infections usually remain asymptomatic and untreated. Therefore, an adequate immune response, rather than antibiotic treatment, is essential to clear the pathogen. Most women will effectively clear C. trachomatis infections, but some will have persistent C. trachomatis infections, which may ascend to the upper genital tract and increase the risk of tubal factor subfertility. Pattern recognition receptors (PRRs) of the toll-like receptor (TLR) and nucleotide-binding oligomerization domain (NOD) families recognize C. trachomatis and initiate the immune response. Host immune factors are determinants of the course of C. trachomatis infections. Genetic variations in TLR and NOD genes may affect receptor function, leading to inadequate recognition of C. trachomatis, an inadequate immune response, and consequently an increased risk of persistence and late sequelae. For the risk assessment of tubal pathology in subfertile women, C. trachomatis immunoglobulin (Ig) G antibody testing (CAT) in serum is widely used. A positive CAT is indicative of a previous infection but not of a persistent infection. Measuring serological markers of persistence, of which C-reactive protein (CRP) seems promising, in CAT-positive women may identify a subgroup of subfertile women with persistent C. trachomatis infections and the highest risk of tubal pathology.
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Affiliation(s)
- J E den Hartog
- Research Institute Growth and Development (GROW) and Department of Obstetrics and Gynaecology, Academic Hospital Maastricht, Maastricht, the Netherlands.
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