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1
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Tong M, Zheng Q, Chen F, Zhu Y. Reply to Padhi et al. J Infect Dis 2021; 224:736. [PMID: 34192328 DOI: 10.1093/infdis/jiab280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 06/29/2021] [Indexed: 11/14/2022] Open
Affiliation(s)
- Ming Tong
- Department of Infectious Diseases, The First-affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, China.,Institute of Emergency Medicine, Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics, The First-affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, China
| | - Qing Zheng
- Department of Geriatrics, The First-affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, China
| | - Fang Chen
- Institute of Emergency Medicine, Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics, The First-affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, China
| | - Yimin Zhu
- Institute of Emergency Medicine, Hunan Provincial Key Laboratory of Emergency and Critical Care Metabonomics, The First-affiliated Hospital of Hunan Normal University (Hunan Provincial People's Hospital), Changsha, Hunan, China
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2
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ICAM1K469E Polymorphism Effect in Gastroschisis Patients. Int Surg 2018. [DOI: 10.9738/intsurg-d-17-00045.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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3
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Association of ICAM-1 K469E polymorphism with dengue infection in North Indian population. Microb Pathog 2016; 96:80-4. [DOI: 10.1016/j.micpath.2016.05.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Revised: 03/15/2016] [Accepted: 05/10/2016] [Indexed: 12/31/2022]
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4
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Habibi M, Naderi N, Farnood A, Balaii H, Dadaei T, Almasi S, Zojaji H, Asadzadeh Aghdae H, Zali MR. Association between two single base polymorphisms of intercellular adhesion molecule 1 gene and inflammatory bowel disease. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2016; 9:87-93. [PMID: 27099667 PMCID: PMC4833846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
AIM The present study evaluated the association between G241R and K469E polymorphisms of intercellular adhesion molecule 1 gene and inflammatory bowel disease in Iranian population. BACKGROUND Inflammatory bowel disease including ulcerative colitis and Crohn's disease, is a chronic idiopathic inflammatory disease of the gastrointestinal tract. There are two single base polymorphisms of intercellular adhesion molecule 1gene, G241R and K469E, reported to be associated with inflammatory disorders. PATIENTS AND METHODS In this case-control study, 156 inflammatory bowel disease patients (110 ulcerative colitis and 46 Crohn's disease patients) and 131 healthy controls were enrolled. Two polymorphisms of intercellular adhesion molecule 1 gene, including G241R and K469E, were assessed by polymerase chain reaction followed by restriction fragment length polymorphism. RESULTS The E469 allele of K469E polymorphism was significantly more frequent in Crohn's disease patients compared to controls (P< 0.05, OR= 1.83; 95% CI: 1.13 to 2.96). The mutant homozygote genotype of K469E polymorphism (E/E) was also significantly more frequent in Crohn's disease patients compared to controls (P< 0.05, OR= 4.23; 95% CI: 1.42 to 12.59). No difference was observed in the frequency of K469E polymorphism among ulcerative colitis patients compared to controls. There were no significant differences in genotype and allele frequencies of G241R polymorphism among ulcerative colitis and Crohn's disease patients compared to control subjects. CONCLUSION According to our findings, K469E polymorphism of intercellular adhesion molecule 1 gene may probably participate in the pathogenesis of Crohn's disease in Iran.
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Affiliation(s)
- Manijeh Habibi
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nosratllah Naderi
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alma Farnood
- Ayatollah Musavi Hospital, Zanjan University of Medical Sciences, Tehran, Iran
| | - Hedieh Balaii
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Tahereh Dadaei
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shohreh Almasi
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Homayoun Zojaji
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdae
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Song GG, Lee YH. The Polymorphisms K469E and G261R of Intercellular Adhesion Molecule-1 and Susceptibility to Inflammatory Bowel Disease: A Meta-Analysis. Immunol Invest 2015; 44:361-72. [DOI: 10.3109/08820139.2015.1010685] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Singh A, Singh AK, Singh SK, Paliwal VK, Gupta RK, Prasad KN. Association of ICAM-1 K469E polymorphism with neurocysticercosis. J Neuroimmunol 2014; 276:166-71. [PMID: 25128351 DOI: 10.1016/j.jneuroim.2014.07.018] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2014] [Revised: 05/29/2014] [Accepted: 07/24/2014] [Indexed: 10/24/2022]
Abstract
Neurocysticercosis (NCC), a central nervous system (CNS) disease is caused by the larval stage of Taenia solium. The disease is heterogeneous in clinical presentation; some infected individuals develop symptoms and others may remain symptom free. Impaired blood brain barrier allows recruitment of immune cells in the CNS during infection and soluble intercellular adhesion molecule-1 (sICAM-1) plays an important role in the recruitment of immune cells. We studied ICAM-1 K469E polymorphism among symptomatic and asymptomatic NCC patients. The study revealed that individuals with variant (EE) genotype were more susceptible to symptomatic NCC and also had an elevated level of sICAM-1.
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Affiliation(s)
- Amrita Singh
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India
| | - Aloukick K Singh
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India
| | - Satyendra K Singh
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India
| | - Vimal K Paliwal
- Department of Neurology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow,Uttar Pradesh 226014, India
| | - Rakesh K Gupta
- Department of Radiodiagnosis, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow,Uttar Pradesh 226014, India
| | - Kashi N Prasad
- Department of Microbiology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh 226014, India.
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7
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Characteristics of Japanese inflammatory bowel disease susceptibility loci. J Gastroenterol 2014; 49:1217-30. [PMID: 23942620 DOI: 10.1007/s00535-013-0866-2] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2013] [Accepted: 07/29/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND There are substantial differences in inflammatory bowel disease (IBD) genetics depending on the populations examined. We aimed to identify Japanese population-specific or true culprit susceptibility genes through a meta-analysis of past genetic studies of Japanese IBD. METHODS For this study, we reviewed 2,703 articles. The review process consisted of three screening stages: we initially searched for relevant studies and then relevant single nucleotide polymorphisms (SNPs). Finally, we adjusted them for the meta-analysis. To maximize our chances of analysis, we introduced proxy SNPs during the first stage. To minimize publication bias, no significant SNPs and solitary SNPs without pairs were combined to be reconsidered during the third stage. Additionally, two SNPs were newly genotyped. Finally, we conducted a meta-analysis of 37 published studies in 50 SNPs located at 22 loci corresponding to the total number of 4,853 Crohn's disease (CD), 5,612 ulcerative colitis (UC) patients, and 14,239 healthy controls. RESULTS We confirmed that the NKX2-3 polymorphism is associated with common susceptibility to IBD and that HLA-DRB1*0450 alleles increase susceptibility to CD but reduce risk for UC while HLA-DRB1*1502 alleles increase susceptibility to UC but reduce CD risk. Moreover, we found individual disease risk loci: TNFSF15 and TNFα to CD and HLA-B*5201, and NFKBIL1 to UC. The genetic risk of HLA was substantially high (odds ratios ranged from 1.54 to 2.69) while that of common susceptibility loci to IBD was modest (odds ratio ranged from 1.13 to 1.24). CONCLUSIONS Results indicate that Japanese IBD susceptibility loci identified by the meta-analysis are closely associated with the HLA regions.
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9
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Serum intercellular adhesion molecule 1 variations in young children with acute otitis media. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2010; 17:1909-16. [PMID: 20926702 DOI: 10.1128/cvi.00194-10] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Acute otitis media (AOM) is an inflammatory reaction in the middle ear, most often occurring in young children. Streptococcus pneumoniae, nontypeable Haemophilus influenzae, and Moraxella catarrhalis are the most common bacteria isolated. Intercellular adhesion molecule 1 (ICAM-1) is involved in the innate immune response to infection by microorganisms, in effective antigen presentation, and in subsequent T-cell activation. Here we prospectively studied levels of serum soluble ICAM-1 (sICAM-1) before, at the time of, and after antimicrobial treatment of AOM in a group of 138 children ages 6 to 30 months. Middle ear fluids were collected by tympanocentesis to identify otopathogens. We found that (i) serum levels of sICAM-1 were significantly higher in S. pneumoniae-, nontypeable H. influenzae-, and M. catarrhalis-infected children than in well children (P < 0.001), confirming that a systemic inflammatory response occurs during AOM; (ii) sICAM-1 levels varied from no elevation (110 ng/ml) to elevation to high levels (maximum, 1,470 ng/ml) among children with AOM; (iii) in paired samples, sICAM-1 levels increased 4- to 20-fold when children developed AOM compared to their sICAM-1 levels before infection; and (iv) the level of sICAM-1 returned to the pre-AOM level at the convalescent stage of AOM after successful antimicrobial therapy. We conclude that AOM often causes a systemic inflammatory reaction, as measured by elevation of the serum sICAM-1 level, and that a high variability in sICAM-1 responses occurs with the presence of otopathogens during AOM.
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Vainer B. Intercellular adhesion molecule-1 (ICAM-1) in ulcerative colitis: presence, visualization, and significance. APMIS 2010:1-43. [PMID: 20653648 DOI: 10.1111/j.1600-0463.2010.02647.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Affiliation(s)
- Ben Vainer
- Department of Pathology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
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11
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Ooi CJ, Fock KM, Makharia GK, Goh KL, Ling KL, Hilmi I, Lim WC, Kelvin T, Gibson PR, Gearry RB, Ouyang Q, Sollano J, Manatsathit S, Rerknimitr R, Wei SC, Leung WK, de Silva HJ, Leong RW. The Asia-Pacific consensus on ulcerative colitis. J Gastroenterol Hepatol 2010; 25:453-468. [PMID: 20370724 DOI: 10.1111/j.1440-1746.2010.06241.x] [Citation(s) in RCA: 122] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Inflammatory bowel disease (IBD) is increasing in many parts of the Asia-Pacific region. There is a need to improve the awareness of IBD and develop diagnostic and management recommendations relevant to the region. This evidence-based consensus focuses on the definition, epidemiology and management of ulcerative colitis (UC) in Asia. A multi-disciplinary group developed the consensus statements, reviewed the relevant literature, and voted on them anonymously using the Delphi method. The finalized statements were reviewed to determine the level of consensus, evidence quality and strength of recommendation. Infectious colitis must be excluded prior to diagnosing UC. Typical histology and macroscopic extent of the disease seen in the West is found in the Asia-Pacific region. Ulcerative colitis is increasing in many parts of Asia with gender distribution and age of diagnosis similar to the West. Extra-intestinal manifestations including primary sclerosing cholangitis are rarer than in the West. Clinical stratification of disease severity guides management. In Japan, leukocytapheresis is a treatment option. Access to biologic agents remains limited due to high cost and concern over opportunistic infections. The high endemic rates of hepatitis B virus infection require stringent screening before initiating immune-suppressive agents. Vaccination and prophylactic therapies should be initiated on a case-by-case basis and in accordance with local practice. Colorectal cancer complicates chronic colitis. A recent increase in UC is reported in the Asia-Pacific region. These consensus statements aim to improve the recognition of UC and assist clinicians in its management with particular relevance to the region.
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Affiliation(s)
- Choon Jin Ooi
- Department of Gastroenterology and Hepatology, Duke-NUS Graduate Medical School and Singapore General Hospital, Singapore.
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Ben Dhifallah I, Karray EF, Sassi F, Hamzaoui K. Intercellular adhesion molecule 1 K469E gene polymorphism is associated with presence of skin lesions in Tunisian Behçet's disease patients. ACTA ACUST UNITED AC 2010; 75:74-8. [DOI: 10.1111/j.1399-0039.2009.01395.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Burim RV, Teixeira SA, Colli BO, Peria FM, Tirapelli LF, Marie SKN, Malheiros SMF, Oba-Shinjo SM, Gabbai AA, Lotufo PA, Carlotti-Júnior CG. ICAM-1 (Lys469Glu) and PECAM-1 (Leu125Val) polymorphisms in diffuse astrocytomas. Clin Exp Med 2009; 9:157-63. [PMID: 19306055 DOI: 10.1007/s10238-009-0040-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2008] [Accepted: 08/24/2008] [Indexed: 12/12/2022]
Abstract
Cell adhesion molecules such as intercellular adhesion molecule-1 (ICAM-1) and platelet-endothelial cell adhesion molecule-1 (PECAM-1) play an important role in glioma invasion and angiogenesis. The aim of this study was to investigate whether specific genetic polymorphisms of ICAM-1 and PECAM-1 could be associated with glioma development and progression. Single-nucleotide polymorphism in codon 469 of ICAM-1 and codon 125 of PECAM-1 were examined in 158 patients with astrocytomas and 162 controls using polymerase chain reaction and restriction enzyme analysis. The distribution of PECAM-1 polymorphic genotypes in astrocytomas did not show any significant difference. However, a specific ICAM-1 genotype (G/G, corresponding to Lys469Glu) exhibited higher frequency in grade II astrocytomas compared to controls, grade III, and grade IV astrocytomas; suggesting that this polymorphism could be involved in the development of grade II astrocytomas.
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Affiliation(s)
- Regislaine Valéria Burim
- Department of Surgery and Anatomy, Faculty of Medicine of Ribeirão Preto, University of São Paulo (USP), Ribeirão Preto, SP 14040-903, Brazil.
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Polymorphism in ICAM-1, PECAM-1, E-selectin, and L-selectin genes in Tunisian patients with inflammatory bowel disease. Eur J Gastroenterol Hepatol 2009; 21:167-75. [PMID: 19212205 DOI: 10.1097/meg.0b013e32830e6fc8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND Ulcerative colitis (UC) and Crohn's disease (CD) are chronic intestinal disorders characterized by immune dysregulation and leukocytes recruitment into gastrointestinal tract. Cell adhesion molecules (CAM) mediate the extravasation of leukocytes and their accumulation in inflamed intestinal mucosa. Recently, CAM genes have been implicated in determining susceptibility to UC and CD. We investigate seven mutations in CAM: G241R and K469E in ICAM-1, V125L in PECAM-1, G98T, S128R, and L554F in E-selectin and F206L in L-selectin in 197 Tunisian patients (73 with UC and 124 with CD) and 194 controls. These polymorphisms were detected by polymerase chain reaction sequence-specific primers and restriction enzyme analysis. RESULTS A significant increase in allele frequencies of 206L of L-selectin and the associated genotype F/L was observed in both patients with UC and CD compared with controls. Subgroup analysis showed that the L206 allele and F/L206 genotype frequencies were significantly increased in UC patients with left-sided type; whereas, the F/L206 genotype was significant in CD patients with ileocolonic location and stricturing behavior compared with controls. No significant differences in allele or genotype frequencies were observed for ICAM-1 K469E, E-selectin, and PECAM-1 polymorphisms between UC patients, CD patients, and controls. CONCLUSION We found an association of inflammatory bowel disease with allele L206 of L-selectin gene, whereas genotype L/F was associated with a subgroup of UC (left-sided type) and CD patients with more extensive location of disease and stricturing behavior. However, further studies are needed to confirm our findings.
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Variations in host genes encoding adhesion molecules and susceptibility to falciparum malaria in India. Malar J 2008; 7:250. [PMID: 19055786 PMCID: PMC2612678 DOI: 10.1186/1475-2875-7-250] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2008] [Accepted: 12/04/2008] [Indexed: 01/28/2023] Open
Abstract
Background Host adhesion molecules play a significant role in the pathogenesis of Plasmodium falciparum malaria and changes in their structure or levels in individuals can influence the outcome of infection. The aim of this study was to investigate the association of SNPs of three adhesion molecule genes, ICAM1, PECAM1 and CD36, with severity of falciparum malaria in a malaria-endemic and a non-endemic region of India. Methods The frequency distribution of seven selected SNPs of ICAM1, PECAM1 and CD36 was determined in 552 individuals drawn from 24 populations across India. SNP-disease association was analysed in a case-control study format. Genotyping of the population panel was performed by Sequenom mass spectroscopy and patient/control samples were genotyped by SNaPshot method. Haplotypes and linkage disequilibrium (LD) plots were generated using PHASE and Haploview, respectively. Odds-ratio (OR) for risk assessment was estimated using EpiInfo™ version 3.4. Results Association of the ICAM1 rs5498 (exon 6) G allele and the CD36 exon 1a A allele with increased risk of severe malaria was observed (severe versus control, OR = 1.91 and 2.66, P = 0.02 and 0.0012, respectively). The CD36 rs1334512 (-53) T allele as well as the TT genotype associated with protection from severe disease (severe versus control, TT versus GG, OR = 0.37, P = 0.004). Interestingly, a SNP of the PECAM1 gene (rs668, exon 3, C/G) with low minor allele frequency in populations of the endemic region compared to the non-endemic region exhibited differential association with disease in these regions; the G allele was a risk factor for malaria in the endemic region, but exhibited significant association with protection from disease in the non-endemic region. Conclusion The data highlights the significance of variations in the ICAM1, PECAM1 and CD36 genes in the manifestation of falciparum malaria in India. The PECAM1 exon 3 SNP exhibits altered association with disease in the endemic and non-endemic region.
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Kwon HS, Sohn IS, Lee JY, Lee SJ, Kim SN, Kim BJ. Intercellular adhesion molecule-1 K469E polymorphism in Korean patients with spontaneous preterm delivery. Int J Gynaecol Obstet 2008; 104:37-9. [PMID: 18851856 DOI: 10.1016/j.ijgo.2008.08.020] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2008] [Revised: 08/14/2008] [Accepted: 08/14/2008] [Indexed: 10/21/2022]
Abstract
OBJECTIVES To investigate the association between intercellular adhesion molecule-1 (ICAM-1) gene K469E polymorphism and spontaneous preterm delivery in a Korean population. METHODS Genomic DNA was extracted from whole blood from 55 women experiencing preterm labor and 153 multiparous women (control group) with a history of at least 2 term deliveries. DNA samples were analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS The spontaneous preterm delivery (SPD) group carried the 469E allele significantly more frequently than those in the control group (odds ratio [OR], 1.62; 95% CI, 1.04-2.53). The EE genotype was significantly associated with increased risk of SPD (OR, 2.84; 95% CI, 1.17-6.89; P = 0.02). Allelic frequencies in women with abnormal C-reactive protein levels (K = 0.48; E = 0.52) were significantly different from frequencies in the controls (K = 0.68; E = 0.32) (P = 0.006). CONCLUSIONS ICAM-1 gene K469E polymorphism may be a candidate region and useful predictor of susceptibility to SPD in the Korean population.
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Affiliation(s)
- Han-Sung Kwon
- Department of Obstetrics and Gynecology, Konkuk University College of Medicine, Korea
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Dema B, Martínez A, Polanco I, Maluenda C, Fernández-Arquero M, de la Concha EG, Urcelay E, Núñez C. ICAM1 R241 is not associated with celiac disease in the Spanish population. Hum Immunol 2008; 69:675-8. [DOI: 10.1016/j.humimm.2008.07.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2008] [Revised: 07/02/2008] [Accepted: 07/16/2008] [Indexed: 11/24/2022]
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Li XX, Liu JP, Cheng JQ, Han SH, Geng YJ, Wei S, Gao ST, Huang DN, Nie SF. Intercellular adhesion molecule-1 gene K469E polymorphism and ischemic stroke: a case-control study in a Chinese population. Mol Biol Rep 2008; 36:1565-71. [PMID: 18791855 DOI: 10.1007/s11033-008-9351-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2008] [Accepted: 08/26/2008] [Indexed: 11/24/2022]
Abstract
BACKGROUND Intercellular adhesion molecule-1 (ICAM-1) was involved in the pathogenetic mechanisms responsible for ischemic stroke (IS). Population-based sample have revealed gene-gender interaction in blood pressure which is major risk for IS. We sought to evaluate whether ICAM-1 K469E polymorphism was involved in the causation of IS and whether it was different between female and male. METHODS A 1:1 case-control study was conducted. The K469E polymorphism of ICAM-1 gene were analyzed by polymerase chain reaction (PCR) and restriction enzyme analysis in Chinese patients with IS (n = 309) and elderly subjects without IS (n = 309). RESULTS ICAM-1 K469E polymorphism was significantly associated with IS. Interestingly, a further analysis stratified by sex found that there was significance between 469E genotypes and IS in female, but not in male. Multiple regression analysis revealed that ICAM-1 K469E polymorphism was still significantly associated with IS, compared with ICAM-1 KK genotype in all population (OR = 1.60, P = 0.030). Stratified by sex, EE combined EK was contributory factor to IS in female (OR = 3.03, P = 0.004), but not in male. After adjustment for confounding factors, the interaction between female and ICAM-1 EK/EE genotypes was found (OR = 3.54, P = 0.001). CONCLUSIONS It is suggested that the ICAM-1 469E allele may be important in the pathogenesis of ischemic stroke, especially in female but not in male.
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Affiliation(s)
- Xiao Xia Li
- Department of Epidemiology and Statistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, Hubei, 430030, China
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Paré G, Chasman DI, Kellogg M, Zee RYL, Rifai N, Badola S, Miletich JP, Ridker PM. Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women. PLoS Genet 2008; 4:e1000118. [PMID: 18604267 PMCID: PMC2432033 DOI: 10.1371/journal.pgen.1000118] [Citation(s) in RCA: 260] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2008] [Accepted: 06/04/2008] [Indexed: 01/01/2023] Open
Abstract
While circulating levels of soluble Intercellular Adhesion Molecule 1 (sICAM-1) have been associated with diverse conditions including myocardial infarction, stroke, malaria, and diabetes, comprehensive analysis of the common genetic determinants of sICAM-1 is not available. In a genome-wide association study conducted among 6,578 participants in the Women's Genome Health Study, we find that three SNPs at the ICAM1 (19p13.2) locus (rs1799969, rs5498 and rs281437) are non-redundantly associated with plasma sICAM-1 concentrations at a genome-wide significance level (P<5×10−8), thus extending prior results from linkage and candidate gene studies. We also find that a single SNP (rs507666, P = 5.1×10−29) at the ABO (9q34.2) locus is highly correlated with sICAM-1 concentrations. The novel association at the ABO locus provides evidence for a previously unknown regulatory role of histo-blood group antigens in inflammatory adhesion processes. Soluble Intercellular Adhesion Molecule 1 (sICAM-1) is an inflammatory marker that has been associated with several common diseases such as diabetes, heart disease, stroke, and malaria. While it is known that blood concentrations of sICAM-1 are at least partially genetically determined, our current knowledge of which genes mediate this effect is limited. Taking advantage of new technologies allowing us to interrogate genetic variation on a whole genome basis, we found that a variation in the ABO gene is an important determinant of sICAM-1 blood concentrations. Since the ABO gene is responsible for the ABO blood groups, this discovery sheds light on a new role for blood groups and offers novel mechanisms to explain the association between sICAM-1 blood concentrations and various common diseases.
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Affiliation(s)
- Guillaume Paré
- Center for Cardiovascular Disease Prevention, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
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Arandi N, Talei A, Erfani N, Ghaderi A. Intercellular adhesion molecule-1 genetic markers (+241G/A and +469A/G) in Iranian women with breast cancer. ACTA ACUST UNITED AC 2008; 183:9-13. [PMID: 18474291 DOI: 10.1016/j.cancergencyto.2008.01.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2007] [Revised: 01/22/2008] [Accepted: 01/24/2008] [Indexed: 01/08/2023]
Abstract
Breast cancer is the most common cancer among women, the second-most leading cause of women's death after lung cancer. ICAM-1 is a cell adhesion molecule that belongs to the Ig-superfamily, with a glycoprotein structure playing a key role in leukocyte recruitment into inflammatory sites, as well as in leukocyte activation and effector function. Proteolytic cleavage of ICAM-1 results in the formation of a soluble form, sICAM-1, which is present in low-serum levels in healthy individuals but becomes elevated in inflammatory and malignant conditions. The ICAM1 gene is located on chromosome 19 and contains two well-known single-nucleotide polymorphisms (SNP) of +241G/A (G241R) and +469A/G (K469E). In this study, the frequencies of the two polymorphisms were investigated in breast cancer patients and healthy individuals. For G241R, we selected 276 breast cancer patients and 235 healthy sex-matched controls, and for K469E, 264 patients and 200 healthy sex-matched controls were chosen. The results of this study show that the frequency of the GA genotype was significantly higher in breast cancer patients in comparison to the control group (P = 0.007). In addition, the frequency of the R allele was significantly higher in breast cancer patients compared to controls (P = 0.008). However, both the genotype and allele frequency of K469E did not differ significantly between patients and controls. A significant difference was observed in the frequency of genotype combination A/G (+241 G/A and +469 A/G, respectively) between patients and controls (6.2 vs. 2.2%; (*)P = 0.007). These findings indicate that individuals carrying the A allele of the ICAM1 gene as well as the A/G haplotype may have a higher risk of developing breast cancer.
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Affiliation(s)
- Nargess Arandi
- Department of Immunology, Shiraz University of Medical Sciences, Zand Street, PO Box 71345-7198, Shiraz, Iran
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Abstract
Crohn's disease (CD) and ulcerative colitis (UC) are complex polygenic disorders, characterized by several genes together with environmental factors contributing to the development of inflammatory bowel disease (IBD). Recent advances in research on genetic susceptibility have allowed the identification of diverse genes at different levels: (1) Innate immunity; (2) Antigen presentation molecules; (3) Epithelial integrity; (4) Drug transporter; (5) Cell adhesion. The application of genetic testing into clinical practice is close and all genetic markers may have several clinical implications: prediction of disease phenotype, molecular classification, prevention of complications, and prognosis.
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22
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Douglas IS, Dassopoulos T. Rheostat regulation of integrin-mediated leukocyte adhesion. J Clin Invest 2007; 117:2391-5. [PMID: 17786236 PMCID: PMC1952648 DOI: 10.1172/jci33376] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The homing of activated T lymphocytes to the gut in inflammatory bowel diseases is dependent on their coordinated, integrin-mediated adhesion and de-adhesion to substrates and blood vessel walls. In this issue of the JCI, Park and colleagues reveal a key modulatory role of a binding site within beta integrins, known as the ADMIDAS domain, in controlling integrin de-adhesion in mice (see the related article beginning on page 2526). These observations add to our growing understanding of how integrin adhesiveness is regulated and raise the notion of the existence of a biological rheostat for lymphocyte homing. Disturbed migratory rheostat tone could account for variations in interindividual immune responses observed in patients with inflammatory bowel disease or other lymphocyte-mediated inflammatory disorders. These findings will inform future strategies to design small molecules for the treatment of a spectrum of chronic inflammatory conditions.
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Affiliation(s)
- Ivor S Douglas
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado at Denver and Health Sciences Center, and Denver Health Medical Center, Denver, Colorado 80204, USA.
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Hong J, Leung E, Fraser AG, Merriman TR, Vishnu P, Krissansen GW. Polymorphisms in NFKBIA and ICAM-1 genes in New Zealand Caucasian Crohn's disease patients. J Gastroenterol Hepatol 2007; 22:1666-70. [PMID: 17593226 DOI: 10.1111/j.1440-1746.2007.05020.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Crohn's disease (CD) is a complex polygenetic inflammatory disease of the bowel. NFKBIA (IkappaBalpha) is a downstream regulator of NF-kappaB, which is an effector of the major Crohn's susceptibility gene CARD15/NOD2. ICAM-1 is an integrin ligand and vascular addressin, which contributes to the trafficking of pathogenic leukocytes into the inflamed bowel. Here we examined whether the NFKBIA 2758G/A and ICAM-1 K469E variants, recently shown to be CD susceptibility genes in Caucasian populations in Germany and the United Kingdom, are associated with CD in Caucasian patients in New Zealand. METHODS PCR-RFLP analysis was used to examine the frequency of gene polymorphisms in 182 CD patients and 188 ethnically matched controls. RESULTS There was no significant evidence of a difference in the allele frequency of either the 2758G/A polymorphism in NFKBIA (0.38 vs 0.35, P = 0.47) or the K469E polymorphism in ICAM-1 (0.43 vs 0.37, P = 0.10) between CD patients and controls. Nevertheless, the ICAM-1 469E allele significantly (P = 0.016, Pc = 0.047) influenced the age of diagnosis of CD. Meta-analysis with five other studies confirmed a lack of association of the K469E polymorphism with Crohn's disease (P = 0.33; OR = 0.93; 95% CI, 0.82-1.07). CONCLUSION The NFKBIA 2758G/A and ICAM-1 K469E polymorphisms are not significant risk factors for CD in New Zealand; however, there is evidence that the latter polymorphism influences the age of diagnosis.
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Affiliation(s)
- Jiwon Hong
- Department of Molecular Medicine & Pathology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
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24
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Sun J, Turner A, Xu J, Grönberg H, Isaacs W. Genetic variability in inflammation pathways and prostate cancer risk. Urol Oncol 2007; 25:250-9. [PMID: 17483024 DOI: 10.1016/j.urolonc.2006.10.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Genetic susceptibility to prostate cancer has been consistently observed by a large number of studies. Recently, several pieces of evidence obtained from epidemiological and pathological studies support that chronic inflammation in prostate tissues may play a role in prostate cancer development. Multiple genes that play critical roles in inflammatory pathways have been associated with prostate cancer risk. In this article we review the key genetic findings of the associated genes. This includes 2 genes identified through family studies, ribonuclease L (RNASEL) and macrophage scavenger receptor 1 (MSR1), as well as a number of genes suggested by case-control studies, such as macrophage inhibitory cytokine-1 (MIC-1), interleukins (IL-8, IL-10), vascular endothelial growth factor (VEGF), intercellular adhesion molecule (ICAM), and Toll-like receptors (TLR-4, TLR-1-6-10 gene cluster). Overall, recent studies seem to suggest multiple genes work together to increase prostate risk, and this is consistent with the reality that inflammation is a very complex process. Thus, future studies are expected to place an emphasis on the study of gene-gene interactions. Advances in high throughput genotyping, data mining, and algorithm development are needed in order to produce interpretable results.
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Affiliation(s)
- Jielin Sun
- Center for Human Genomics, Wake Forest University, Winston-Salem, NC 27157, USA
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25
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Ramakers JD, Mensink RP, Schaart G, Plat J. Arachidonic acid but not eicosapentaenoic acid (EPA) and oleic acid activates NF-kappaB and elevates ICAM-1 expression in Caco-2 cells. Lipids 2007; 42:687-98. [PMID: 17610002 PMCID: PMC2039812 DOI: 10.1007/s11745-007-3071-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2006] [Accepted: 04/28/2007] [Indexed: 01/27/2023]
Abstract
In patients with inflammatory bowel disease (IBD), intestinal activation of the transcription factor NF-κB as well as intercellular adhesion molecule (ICAM)-1 expression, which is involved in recruiting leukocytes to the side of inflammation is increased. Moreover, colonic arachidonic acid (ARA) proportions are increased and oleic acid (OA) proportions are decreased. Fish oils are protective in IBD patients however, a side-by-side comparison between effects of fish oils, ARA and OA has not been made. We therefore, compared effects of eicosapentaenoic acid (EPA) versus ARA and OA on ICAM-1 expression in Caco-2 enterocytes. To validate our model we showed that dexamethasone, sulfasalazine and PPARα (GW7647) or PPARγ (troglitazone) agonists significantly lowered ICAM-1 expression. ICAM-1 expression of non-stimulated and cytokine stimulated Caco-2 cells cultured for 22 days with ARA was significant higher as compared to EPA and OA. Furthermore, ARA increased NF-κB activation in a reporter cell-line as compared to EPA. Antibody array analysis of multiple inflammatory proteins particularly showed an increased monocyte chemotactic protein (MCP)-1 and angiogenin production and a decreased interleukin (IL)-6 and IL-10 production by ARA as compared to EPA. Our results showed that ARA but not EPA and OA activates NF-κB and elevates ICAM-1 expression in Caco-2 enterocytes. It suggests that replacement of ARA by EPA or OA in the colon mucosa might have beneficial effects for IBD patients. Finally, we suggest that the pro-inflammatory effects of ARA versus EPA and OA are not related to PPARγ activation and/or eicosanoid formation.
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Affiliation(s)
- Julian D Ramakers
- Department of Human Biology, Nutrition and Toxicology Research Institute Maastricht, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands.
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Wang S, Sun H, Chen HY, Zhao ZF, Yang Y, Zhao YJ, Cui B, Ning G. Intercellular adhesion molecule 1 gene polymorphisms do not contribute to Graves' disease in Chinese patients. Endocrine 2007; 31:114-8. [PMID: 17873320 DOI: 10.1007/s12020-007-0032-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2006] [Revised: 03/02/2007] [Accepted: 03/02/2007] [Indexed: 11/25/2022]
Abstract
OBJECTIVE In order to study the association of G241R polymorphism of ICAM-1 gene with an earlier onset of Graves' disease (GD) and the susceptibility of K469E polymorphism to Graves' ophthalmopathy (GO) in Chinese population. STUDY DESIGN A case-control and replication study was performed in 212 GD patients and 204 healthy subjects to analyze the genotypes. Furthermore the distribution of ICAM-1 genotypes was investigated in subgroups of patients with GD according to the onset age and the ophthalmopathy. RESULTS No G241R polymorphism of ICAM-1 gene was detected in Chinese. No significant differences of allele and genotype frequencies regarding K469E polymorphism were found between GD patients and healthy controls (chi2 = 0.092, P = 0.762; chi2 = 1.089, P = 0.580). In addition, the genotype-phenotype correlation was not identified either. CONCLUSIONS We found no association of G241R and K469E polymorphisms of the ICAM-1gene with the development of GD in a Chinese population. However, we could not rule out possible contributions of other polymorphisms of the ICAM-1gene to the pathogenesis of GD. Therefore, further studies are needed to elucidate the role of ICAM-1gene in Graves' disease in different population.
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Affiliation(s)
- Shu Wang
- Shanghai Clinical Center for Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai JiaoTong University School of Medicine, 197 Ruijin 2nd Road, Shanghai, 200025, PR China
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Goyette P, Labbé C, Trinh TT, Xavier RJ, Rioux JD. Molecular pathogenesis of inflammatory bowel disease: genotypes, phenotypes and personalized medicine. Ann Med 2007; 39:177-99. [PMID: 17457716 DOI: 10.1080/07853890701197615] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Crohn's disease (CD) and ulcerative colitis (UC), also known as inflammatory bowel diseases (IBD), are characterized by chronic inflammation of the gastrointestinal tract. IBD is among the few complex diseases for which several genomic regions and specific genes have been identified and confirmed in multiple replication studies. We will review the different loci implicated in disease risk in the context of three proposed mechanisms leading to chronic inflammation of the gut mucosa: 1) deregulation of the innate immune response to enteric microflora or pathogens; 2) increased permeability across the epithelial barrier; and 3) defective regulation of the adaptive immune system. As our knowledge of genetic variation, analytical approaches and technology improves, additional genetic risk factors are expected to be identified. With the identification of novel risk variants, additional pathophysiological mechanisms are likely to emerge. The resulting discoveries will further our molecular understanding of IBD, potentially leading to improved disease classification and rational drug design. Moreover, these approaches and tools can be applied in the context of variable drug response with the goal of providing more personalized clinical management of patients with IBD.
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Affiliation(s)
- Philippe Goyette
- Université de Montréal, Department of Medicine, Montréal, Québec, Canada
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28
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Kitawaki J, Kiyomizu M, Obayashi H, Ohta M, Ishihara H, Hasegawa G, Nakamura N, Yoshikawa T, Honjo H. Synergistic effect of interleukin-6 promoter (IL6 -634C/G) and intercellular adhesion molecule-1 (ICAM-1 469K/E) gene polymorphisms on the risk of endometriosis in Japanese women. ACTA ACUST UNITED AC 2006; 56:267-74. [PMID: 16938116 DOI: 10.1111/j.1600-0897.2006.00426.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
PROBLEM Endometriosis is an immune-related, chronic inflammatory disease with a polygenic predisposition. The aim of this study was to investigate whether the interleukin-6 (IL-6) gene promoter region polymorphism (-634C/G) and the intercellular adhesion molecule-1 (ICAM-1) gene 469K/E polymorphism are responsible in part for the genetic susceptibility to endometriosis. METHODS OF STUDY The IL-6 -634C/G and ICAM-1 469K/E genotypes were determined in 202 patients with endometriosis and 236 control women by polymerase chain reaction-restriction fragment length polymorphism. RESULTS There were no differences in the IL-6 -634C/G or the ICAM-1 469K/E genotypes and allele frequencies between control women and endometriosis patients collectively, or between control women and each clinical subgroup of endometriosis patients. Interestingly, the frequency of ICAM-1 EE homozygotes who concomitantly carried the IL-6 -634G allele was significantly higher in patients with endometriosis (chi(2) = 6.458, P = 0.0396, d.f. = 2). CONCLUSION Our results suggest that the IL-6 -634C/G and ICAM-1 469K/E polymorphisms synergistically affect the susceptibility for endometriosis in the Japanese population.
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Affiliation(s)
- Jo Kitawaki
- Department of Obstetrics and Gynecology, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566, Japan.
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29
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Bowlus CL, Karlsen TH, Broomé U, Thorsby E, Vatn M, Schrumpf E, Lie BA, Boberg KM. Analysis of MAdCAM-1 and ICAM-1 polymorphisms in 365 Scandinavian patients with primary sclerosing cholangitis. J Hepatol 2006; 45:704-10. [PMID: 16750586 DOI: 10.1016/j.jhep.2006.03.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2005] [Revised: 03/17/2006] [Accepted: 03/29/2006] [Indexed: 01/06/2023]
Abstract
BACKGROUND/AIMS Mucosal addressin cellular adhesion molecule-1 (MAdCAM-1) has been implicated in the aberrant homing of intestinal lymphocytes to the liver in primary sclerosing cholangitis (PSC). Intercellular adhesion molecule-1 (ICAM-1) has also been implicated in the pathogenesis of PSC and the E/E genotype of the K469E polymorphism has been reported to be associated with PSC susceptibility. The aims of this study were to determine if MAdCAM-1 polymorphisms or the K469E polymorphism of ICAM-1 are associated with PSC in Scandinavia. METHODS Seven single nucleotide polymorphisms (SNPs) in MAdCAM-1 and the G421R and K469E ICAM-1 SNPs were genotyped in 365 PSC patients from Norway and Sweden. 327 Norwegian ulcerative colitis (UC) patients and 368 Norwegian bone marrow donors served as controls. RESULTS No significant association with PSC was found for any of the MAdCAM-1 or ICAM-1 SNPs. Allele frequencies for these polymorphisms were not significantly different between PSC patients with UC, UC patients and healthy controls. CONCLUSIONS Polymorphisms in MAdCAM-1 are not likely to significantly affect PSC susceptibility. In addition, the E/E genotype of the K469E in ICAM-1 does not influence PSC susceptibility in Scandinavia.
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Affiliation(s)
- Christopher L Bowlus
- Division of Gastroenterology, University of California Davis Medical Center, 4150 V Street, PSSB3500, Sacramento, CA 95817, USA
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Theodoropoulos G, Papaconstantinou I, Felekouras E, Nikiteas N, Karakitsos P, Panoussopoulos D, Lazaris AC, Patsouris E, Bramis J, Gazouli M. Relation between common polymorphisms in genes related to inflammatory response and colorectal cancer. World J Gastroenterol 2006; 12:5037-5043. [PMID: 16937502 PMCID: PMC4087409 DOI: 10.3748/wjg.v12.i31.5037] [Citation(s) in RCA: 112] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2006] [Revised: 03/13/2006] [Accepted: 03/20/2006] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the association between common single nucleotide polymorphisms (SNPs) in inflammatory response-related genes such as interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNFalpha), peroxisome proliferators-activated receptor gamma (PPARgamma), intercellular adhesion molecule-1 (ICAM-1) and the risk of colorectal cancer (CRC) in a group of Greek patients. METHODS The study group consisted of 222 CRC patients and 200 healthy controls. Genotyping was performed using allele-specific PCR of PRC-RFLP and the results were confirmed by sequencing. We studied the association of SNPs in the IL-6 (-174G>C), IL-8 (-251T>A), TNFalpha (-308G>A), ICAM-1 (R241G and K469E), and PPARgamma (Pro12Ala) genes and the risk of CRC. RESULTS The IL-6 -174G, R241 and K469 alleles of ICAM-1 were associated with increased risk of CRC (OR = 1.77, 95% CI: 1.34-2.34; OR = 1.83, 95% CI: 1.23-2.72; and OR = 1.35, 95% CI: 1.03-1.77 respectively). The IL-8 and TNFalpha polymorphisms had no effect. Whereas the PPARgamma Pro12 genotype was associated with increased risk of disease (OR = 1.78, 95% CI: 1.25-2.49). CONCLUSION The association between common SNPs in immunologic response-related genes and CRC is reported in the present study. Apart from shedding light on the mechanisms of malignancy initiation and progression, SNPs may improve appropriate screening for sub-populations at risk.
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Affiliation(s)
- George Theodoropoulos
- 1st Propaideutic Surgical Department, Hippocration University Hospital, University of Athens, Greece
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Abel M, Cellier C, Kumar N, Cerf-Bensussan N, Schmitz J, Caillat-Zucman S. Adulthood-Onset Celiac Disease Is Associated with Intercellular Adhesion Molecule-1 (ICAM-1) Gene Polymorphism. Hum Immunol 2006; 67:612-7. [PMID: 16916657 DOI: 10.1016/j.humimm.2006.04.011] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2006] [Indexed: 11/25/2022]
Abstract
Celiac disease (CD) is a multifactorial T-cell-mediated autoimmune disease characterized by gluten-triggered villous atrophy and malabsorption. Although human leukocyte antigen (HLA) class II genes are strong susceptibility factors, non-HLA genes likely contribute to most of CD predisposition. The intercellular adhesion molecule-1 (ICAM-1) gene is a good candidate for CD predisposition because its encoded protein acts as an adhesion and costimulatory receptor. Two single-base polymorphisms (G/A in exon 4 encoding G241R, and A/G in exon 6 encoding K469E) were analyzed in 180 French Caucasian CD case patients (110 patients diagnosed before the age of 15 and 70 patients after the age of 18), and 212 French Caucasian healthy controls. The R241 allele frequency was increased in CD case patients compared with controls (14.2% vs. 5.4% respectively, p = 0.000015, odds ratio [OR] for the R241 allele = 2.9, 95% confidence intervals [CI] = 1.7-4.8). After stratifying for age of disease onset, the R241 variant mainly conferred predisposition to CD occurring during adulthood (OR = 4.2, 95% CI = 2.3-7.5, Pc = 0.000004 for adulthood-onset CD vs. R = 2.1, 95%, CI = 1.2-3.9, Pc = 0.0047 for childhood-onset CD). Position 241 of ICAM-1 maps to the binding site for the integrin Mac-1 and might modify the strength of interaction between endothelium and immune cells. If confirmed in independent datasets, these results may be of importance in at-risk individuals to distinguish rapid from delayed progression to clinical CD.
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Affiliation(s)
- Michal Abel
- INSERM U561 Equipe AVENIR, Hôpital St-Vincent de Paul, Paris, France
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Tello-Ruiz MK, Curley C, DelMonte T, Giallourakis C, Kirby A, Miller K, Wild G, Cohen A, Langelier D, Latiano A, Wedemeyer N, Lander E, Schreiber S, Annese V, Daly MJ, Rioux JD. Haplotype-based association analysis of 56 functional candidate genes in the IBD6 locus on chromosome 19. Eur J Hum Genet 2006; 14:780-790. [PMID: 16570073 DOI: 10.1038/sj.ejhg.5201612] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Evidence from four independent linkage studies and two meta-analyses of genome-wide data support the existence of a locus conferring susceptibility to inflammatory bowel diseases (IBD) in chromosomal region 19p. Identification of a susceptibility allele in this approximately 28.5 Mb region with over 600 genes is a formidable task. To tackle this problem, we undertook two approaches: (1) haplotype-based candidate-gene screen, and (2) evaluation of previously reported associations. For the former, we selected genes with potential implication in IBD pathogenesis based on published functional and expression data, typed SNPs, constructed haplotypes, screened for association in 180 IBD trios, and followed up preliminary associations in 343 IBD patients and 207 control individuals. Overall, we analyzed 465 SNPs, and 260 haplotypes distributed across 56 candidate genes. We found suggestive evidence of association (nominal P<0.01) with four genes (C3, FCER2, IL12RB1, and CRLF1) in a screening stage, but were unable to confirm these preliminary observations at follow-up. In the second approach, we typed four nonsynonymous polymorphisms in genes C3 (R102G and L314P) and ICAM1 (G241R and K469E) in four independent cohorts totaling 2178 IBD cases. We evaluated these data together with previously published reports for three of these variants (C3-Gly102, ICAM1-Arg241, and ICAM1-Glu469), in a meta-analysis. Our pooled meta-analysis provides compelling evidence against association of these variants with disease. Overall, we performed the most comprehensive candidate-gene association study for IBD to date. The information hereby generated constitutes a valuable resource to investigate other common genetic immune diseases, such as celiac disease.
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Ozen SC, Dagli U, Kiliç MY, Törüner M, Celik Y, Ozkan M, Soykan I, Cetinkaya H, Ulker A, Ozden A, Bozdayi AM. NOD2/CARD15, NOD1/CARD4, and ICAM-1 gene polymorphisms in Turkish patients with inflammatory bowel disease. J Gastroenterol 2006; 41:304-10. [PMID: 16741608 DOI: 10.1007/s00535-005-1780-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2005] [Accepted: 11/17/2005] [Indexed: 02/04/2023]
Abstract
PURPOSE The genetic susceptibility of people with certain NOD2/CARD15, NOD1/CARD4, and ICAM-1 gene variants to inflammatory bowel disease is still under investigation. The aim of this study was to investigate polymorphisms in the NOD2/CARD15 (R702W, G908R, and 3020insC), NOD1/CARD4 (E266K, D372N), and ICAM-1 (G241R, K469E) genes, which are known to be associated with inflammation, in Turkish patients with inflammatory bowel disease and healthy control groups. METHODS The genotypes of 70 patients with endoscopically and histopathologically diagnosed Crohn's disease (38 men, 32 women; mean age, 38.8 +/- 1.3), 120 patients with ulcerative colitis (67 men, 53 women; mean age, 41.7 +/- 1.3) and 106 healthy control subjects (37 men, 69 women; mean age, 35.7 +/- 1.4), who stated that they had never had any prior bowel disease history, were compared. A polymerase chain reaction-restriction fragment length polymorphism analysis was performed for two variants of the ICAM-1 gene, the three main variants of the NOD2/CARD15 gene, and the E266K variant of the NOD1/CARD4 gene, and DNA sequencing was used for the D372N polymorphism of the NOD1/CARD4 gene. RESULTS In this study, the three previously described Crohn's disease-predisposing variants of the NOD2/CARD15 gene and the polymorphisms examined in the NOD1/CARD4 and ICAM-1 genes were not found to be associated with ulcerative colitis or Crohn's disease. CONCLUSIONS These findings suggest that the polymorphisms observed in the NOD2/CARD15, NOD1/CARD4, and ICAM-1 genes are not genetic susceptibility factors for Crohn's disease or ulcerative colitis in Turkey.
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Lakatos PL, Fischer S, Lakatos L, Gal I, Papp J. Current concept on the pathogenesis of inflammatory bowel disease-crosstalk between genetic and microbial factors: pathogenic bacteria and altered bacterial sensing or changes in mucosal integrity take "toll" ? World J Gastroenterol 2006; 12:1829-1841. [PMID: 16609988 PMCID: PMC4087507 DOI: 10.3748/wjg.v12.i12.1829] [Citation(s) in RCA: 90] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2005] [Revised: 10/20/2005] [Accepted: 11/10/2005] [Indexed: 02/06/2023] Open
Abstract
The pathogenesis of inflammatory bowel disease (IBD) is only partially understood. Various environmental and host (e.g. genetic-, epithelial-, immune and non-immune) factors are involved. It is a multifactorial polygenic disease with probable genetic heterogeneity. Some genes are associated with IBD itself, while others increase the risk of ulcerative colitis (UC) or Crohn's disease (CD) or are associated with disease location and/or behaviour. This review addresses recent advances in the genetics of IBD. The article discusses the current information on the crosstalk between microbial and genetic factors (e.g. NOD2/CARD15, SLC22A46A5 and DLG5). The genetic data acquired in recent years help in understanding the pathogenesis of IBD and can identify a number of potential targets for therapeutic intervention. In the future, genetics may help more accurately diagnose and predict disease course in IBD.
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Affiliation(s)
- Peter Laszlo Lakatos
- 1st Department of Medicine, Semmelweis University, Koranyi str. 2/A, H-1083 Budapest, Hungary.
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Yamashita M, Yoshida S, Kennedy S, Ohara N, Motoyama S, Maruo T. Association study of endometriosis and intercellular adhesion molecule-1 (ICAM-1) gene polymorphisms in a Japanese population. ACTA ACUST UNITED AC 2006; 12:267-71. [PMID: 15866119 DOI: 10.1016/j.jsgi.2005.03.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
OBJECTIVE Endometriosis is an immune-related, chronic inflammatory disease with polygenic predisposition. Cell adhesion molecules are expressed in endometriotic lesions, and in cells and tissues that are involved in the development and progression of the disease. In this study, we investigated the possible association between endometriosis and the G241R and K469E polymorphisms in the intercellular adhesion molecule-1 (ICAM-1) gene in a Japanese population. METHODS We compared the distribution of the G241R and K469E polymorphisms in the ICAM-1 gene in 126 endometriosis patients and 172 controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in a Japanese population. RESULTS There were no significant differences between the cases and controls in the allele frequencies or genotype distributions of either the G241R or K469E polymorphisms in the ICAM-1 gene. The endometriosis patients were divided into a subgroup of women with severe disease only. However, no significant differences were observed in the allele frequencies and genotype distributions of the ICAM-1 K469E polymorphisms between this subgroup and the controls. In contrast, only one in 169 controls was heterozygous (G/A genotype), and the A allele in the G241R polymorphism was not found in any of the 126 endometriosis patients. CONCLUSION Our findings suggest that the G241R and K469E polymorphisms in the ICAM-1 gene are unlikely to be associated with an increased risk of endometriosis in the Japanese population.
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Affiliation(s)
- Masako Yamashita
- Department of Obstetrics and Gynecology, Kobe University Graduate School of Medicine, Kobe, Japan
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Miklossy J, Doudet DD, Schwab C, Yu S, McGeer EG, McGeer PL. Role of ICAM-1 in persisting inflammation in Parkinson disease and MPTP monkeys. Exp Neurol 2006; 197:275-83. [PMID: 16336966 DOI: 10.1016/j.expneurol.2005.10.034] [Citation(s) in RCA: 171] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2005] [Revised: 08/25/2005] [Accepted: 10/17/2005] [Indexed: 11/22/2022]
Abstract
It has been established that neuroinflammation is present in the substantia nigra (SN) of Parkinson disease (PD) cases but the factors responsible are as yet unknown. One contributing protein may be the intercellular adhesion molecule-1 (ICAM-1, CD54). ICAM-1 with its counter receptor, the lymphocyte function-associated antigen 1 (LFA-1) is known to play a key role in inflammatory processes and in T-cell mediated host defense mechanisms. We detected large numbers of ICAM-1-positive reactive astrocytes in the SN of a series of 14 patients with neuropathologically confirmed PD, including 3 of familial origin, compared with 11 age-matched controls. In PD SN, these ICAM-1-positive reactive astrocytes were particularly concentrated around many residual neurons in areas of heavy neuronal loss and extracellular melanin accumulation. LFA-1-positive reactive microglia gathered in areas of intense ICAM-1 expression, and LFA-1-positive leukocytes were identified infiltrating the tissue. Double immunostaining for ICAM-1 and LFA-1 revealed aggregates of reactive microglia embedded in areas of diffuse ICAM-1. Leukocyte counts were 5 fold higher in PD SN compared to controls (P < 0.001). Similar over-expression of ICAM-1 was found in monkeys that had been exposed to MPTP from 5.5 to 14 years previously compared with control monkeys. The presence of ICAM-1-positive reactive astrocytes in Parkinson disease and MPTP-treated monkeys is indicative of a sustained inflammatory process and suggests that antiinflammatory agents may have a place in PD therapy.
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Affiliation(s)
- J Miklossy
- Kinsmen Laboratory of Neurological Research, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T1Z3
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Gordon MA, Gil J, Lu B, Zhang W, Yang D, Yun J, Schneider S, Groshen S, Iqbal S, Press OA, Rhodes K, Lenz HJ. Genomic profiling associated with recurrence in patients with rectal cancer treated with chemoradiation. Pharmacogenomics 2006; 7:67-88. [PMID: 16354126 DOI: 10.2217/14622416.7.1.67] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Purpose: Stage II and III adenocarcinoma of the rectum has an overall 5-year survival rate of approximately 50%, and tumor recurrence remains a major problem despite an improvement in local control through chemotherapy and radiation. The efficacy of chemoradiation therapy may be significantly compromised as a result of interindividual variations in clinical response and host toxicity. Therefore, it is imperative to identify those patients who will benefit from chemoradiation therapy and those who will develop recurrent disease. In this study, we tested whether a specific pattern of 21 polymorphisms in 18 genes involved in the critical pathways of cancer progression (i.e., drug metabolism, tumor microenvironment, cell cycle regulation, and DNA repair) will predict the risk of tumor recurrence in rectal cancer patients treated with chemoradiation. Patients and methods: A total of 90 patients with Stage II or III rectal cancer treated with chemoradiation were genotyped using polymerase chain reaction (PCR)-based techniques for 21 polymorphisms. Results: A polymorphism in interleukin (IL)-8 was individually associated with risk of recurrence. Classification and regression tree analysis of all polymorphisms and clinical variables developed a risk tree including the following variables: node status, IL-8, intracellular adhesion molecule-1, transforming growth factor-β, and fibroblast growth factor receptor 4. Conclusion: Genomic profiling may help to identify patients who are at high risk for developing tumor recurrence, and those who are more likely to benefit from chemoradiation therapy. A larger prospective study is needed to validate these preliminary data using germline polymorphisms on tumor recurrences in rectal cancer patients treated with chemoradiation.
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Affiliation(s)
- Michael A Gordon
- University of Southern California/Norris Comprehensive Cancer Center, Division of Medical Oncology, Keck School of Medicine, 1441 Eastlake Avenue, Suite 3456, Los Angeles, CA 90033, USA
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Vejchapipat P, Jirapanakorn N, Thawornsuk N, Theamboonlers A, Chongsrisawat V, Chittmittrapap S, Poovorawan Y. There is no association between K469E ICAM-1 gene polymorphism and biliary atresia. World J Gastroenterol 2005; 11:4886-4890. [PMID: 16097065 PMCID: PMC4398743 DOI: 10.3748/wjg.v11.i31.4886] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2005] [Revised: 01/23/2005] [Accepted: 01/26/2005] [Indexed: 02/06/2023] Open
Abstract
AIM To determine whether there was an association between inter-cellular adhesion molecule-1 (ICAM-1) gene polymorphism and biliary atresia (BA), and to investigate the relationship between serum soluble ICAM-1 (sICAM-1) and clinical outcome in BA patients after surgical treatment. METHODS Eighty-three BA patients and 115 normal controls were genotyped. K469E ICAM-1 polymorphism was analyzed using PCR assay. Serum sICAM-1 was determined using ELISA method from 72 BA patients. In order to evaluate the association between these variables and their clinical outcome, the patients were categorized into two groups: patients without jaundice and those with persistent jaundice. RESULTS There were no significant differences between BA patients and controls in terms of gender, K469E ICAM-1 genotypes, and alleles. The proportion of patients having serum sICAM-1 >=3 500 ng/mL in persistent jaundice group was significantly higher than that in the other group. In addition, there was no association between K469E ICAM-1 polymorphism and the status of jaundice in BA patients after Kasai operation. CONCLUSION ICAM-1 possibly plays an important and active role in the disease progression. However, the process is not associated with genetic variation of K469E ICAM-1 polymorphism.
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Affiliation(s)
- Paisarn Vejchapipat
- Pediatric Surgery Unit, Department of Surgery, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
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Yacyshyn BR, Schievella A, Sewell KL, Tami JA. Gene polymorphisms and serological markers of patients with active Crohn's disease in a clinical trial of antisense to ICAM-1. Clin Exp Immunol 2005; 141:141-7. [PMID: 15958080 PMCID: PMC1809420 DOI: 10.1111/j.1365-2249.2005.02830.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Serological profiles for anti-Saccharomyces cerevisiae antibodies (ASCA)/ perinuclear antineutrophil cytoplasmic antibodies (pANCA) and gene polymorphisms in tumour necrosis factor (TNF)-alpha and intercellular adhesion molecule-1 (ICAM-1) are associated with occurrence and/or outcome in Crohn's disease. The aim of the study was to characterize the ASCA/pANCA profile, soluble ICAM-1 expression and single nucleotide gene polymorphisms (SNPs) in TNF-alpha and ICAM-1 genes. Crohn's patients with moderate disease activity were enrolled in a clinical trial of Alicaforsen (ISIS 2302). Peripheral blood samples were collected prospectively for serum studies and for potential analysis of gene polymorphisms. A multivariate analysis was performed to compare treatment effect with the biomarkers studied. Serological testing for ASCA/pANCA was obtained for 257 patients at baseline: 37% were ASCA(+)/pANCA(-) (Crohn's pattern), 9% had both markers, 15% were ASCA(-)/pANCA(+) and 39% had neither marker. When the data were analysed by multiple regression analysis, a trend was found within the Alicaforsen-treated groups for greater rates of remission in the ASCA(+)/pANCA(-) subgroup versus all other serological profiles (25 versus 14%, P = 0.068), but not versus the placebo remission rate (18.8%). Gene polymorphisms were assessed in 64 patients, 21 from the placebo group. ICAM-1 assessment revealed no over-representation. However, three unique TNF-alpha SNPs were identified that correlated significantly with remission; sites 290 (P = 0.0253), -2735 (P = 0.0317) and -3090 (P = 0.0067). Although the overall clinical trial was negative, we have identified a trend towards clinical remission with Alicaforsen therapy in a subgroup of patients with Crohn's disease expressing ASCA(+)/pANCA(-). Furthermore, we have identified three TNF-alpha SNPs that may also predict a positive therapeutic outcome.
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Affiliation(s)
- B R Yacyshyn
- Case Western Reserve University Hospital and Louis Stokes VAMC, Cleveland, OH, USA.
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Yokoyama H, Tahara H, Emoto M, Fujiwara S, Araki T, Shinohara K, Hatsuda S, Maeno T, Shoji T, Koyama H, Shoji T, Nishizawa Y. The K469E polymorphism of the intercellular adhesion molecule-1 gene is associated with plasma fibrinogen level in type 2 diabetes. Metabolism 2005; 54:381-6. [PMID: 15736117 DOI: 10.1016/j.metabol.2004.10.002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Intercellular adhesion molecule-1 (ICAM-1) is involved in inflammation and development of atherosclerotic change of vascular endothelium. The aim of the present study is to investigate whether K469E polymorphism of the ICAM-1 gene is associated with various clinical factors including plasma fibrinogen in patients with type 2 diabetes. ICAM-1 gene polymorphism was examined using polymerase chain reaction and restriction enzyme analysis in 360 type 2 diabetic patients. Plasma fibrinogen levels and other clinical variables were measured as well as circulating soluble ICAM-1 (sICAM-1) levels by enzyme-linked immunosorbent assay. The distribution of ICAM-1 genotypes, EE, EK, and KK, was not significantly different between type 2 diabetes and 152 healthy control subjects. Among 3 groups according to ICAM-1 genotypes in type 2 diabetes, no difference was found in adiposity, glycemic control, lipid profile, insulin sensitivity evaluated by homeostasis model assessment, or sICAM-1. Regarding fibrinogen, the patients with E allele showed significantly lower plasma fibrinogen levels in a dose-dependent manner (P = .033). Spearman rank correlation analyses revealed that ICAM-1 genotype showed significant correlation with plasma fibrinogen level (P < .001). In multiple regression analysis, ICAM-1 genotype was independent contribution factor of plasma fibrinogen level as well as high-density lipoprotein-cholesterol and urinary albumin excretion (R2 = 0.148, P < .001). In conclusion, K469E polymorphism of the ICAM-1 gene had impact on plasma fibrinogen level independently of other clinical factors in 360 type 2 diabetic patients, suggesting that fibrinogen is a candidate which links the ICAM-1 gene polymorphism to atherosclerosis.
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Affiliation(s)
- Hisayo Yokoyama
- Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, Osaka, Japan
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Kammerer S, Roth RB, Reneland R, Marnellos G, Hoyal CR, Markward NJ, Ebner F, Kiechle M, Schwarz-Boeger U, Griffiths LR, Ulbrich C, Chrobok K, Forster G, Praetorius GM, Meyer P, Rehbock J, Cantor CR, Nelson MR, Braun A. Large-scale association study identifies ICAM gene region as breast and prostate cancer susceptibility locus. Cancer Res 2005; 64:8906-10. [PMID: 15604251 DOI: 10.1158/0008-5472.can-04-1788] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
We conducted a large-scale association study to identify genes that influence nonfamilial breast cancer risk using a collection of German cases and matched controls and >25,000 single nucleotide polymorphisms located within 16,000 genes. One of the candidate loci identified was located on chromosome 19p13.2 [odds ratio (OR) = 1.5, P = 0.001]. The effect was substantially stronger in the subset of cases with reported family history of breast cancer (OR = 3.4, P = 0.001). The finding was subsequently replicated in two independent collections (combined OR = 1.4, P < 0.001) and was also associated with predisposition to prostate cancer in an independent sample set of prostate cancer cases and matched controls (OR = 1.4, P = 0.002). High-density single nucleotide polymorphism mapping showed that the extent of association spans 20 kb and includes the intercellular adhesion molecule genes ICAM1, ICAM4, and ICAM5. Although genetic variants in ICAM5 showed the strongest association with disease status, ICAM1 is expressed at highest levels in normal and tumor breast tissue. A variant in ICAM5 was also associated with disease progression and prognosis. Because ICAMs are suitable targets for antibodies and small molecules, these findings may not only provide diagnostic and prognostic markers but also new therapeutic opportunities in breast and prostate cancer.
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Abstract
The genetic revolution has been with us for over a decade now. We have yet to see this impacting the care of patients except in a few rare examples. However, progress has been made in the field of inflammatory bowel disease (IBD) that could soon be translated to the bedside, both in terms of predicting the disease course as well as in the response to therapy. IBD traditionally has been classified as ulcerative colitis and Crohn's disease, with 10% of patients classified as having indeterminate colitis on the basis of clinical, radiologic, endoscopic, and histologic findings. However, this traditional view is now being challenged. Developments in genetics and serological markers, as well as an appreciation of the disease course, have led to an understanding that IBD is a heterogeneous group of diseases with some common genetic and environmental factors but different clinical manifestations in terms of disease behavior, location, and response to treatment. Data are now emerging that may allow us to more objectively select the correct therapy for the correct patient, rather than the current approach, which is based on clinical experience backed up by a less-than-perfect evidence base. In this article, we will review the evidence for this.
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Affiliation(s)
- J R Fraser Cummings
- Gastroenterology Unit, University of Oxford, Gibson Laboratories Radcliffe Infirmary, Oxford, UK.
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Lee EB, Kim JY, Kim EH, Nam JH, Park KS, Song YW. Intercellular adhesion molecule-1 polymorphisms in Korean patients with rheumatoid arthritis. ACTA ACUST UNITED AC 2004; 64:473-7. [PMID: 15361125 DOI: 10.1111/j.1399-0039.2004.00285.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Rheumatoid arthritis (RA) is characterized by synovial proliferation and the accumulation of inflammatory cells in the affected joints. Intercellular adhesion molecule-1 (ICAM-1) is readily detected in RA synovial tissues and helps recruit inflammatory cells to the joint. ICAM-1 shows genetic polymorphisms at codons 241 (R241G) and 469 (K469E). In order to investigate the association between ICAM-1 gene polymorphisms and RA, we genotyped ICAM-1 R241G and ICAM-1 K469E polymorphisms in 143 Korean patients with RA, and in 138 healthy controls, by using the polymerase chain reaction-restriction fragment length polymorphism method. No polymorphism of R241G was found in Korean subjects. However, the frequency of the K469 allele was found to be significantly lower in RA patients than in healthy controls. Allele frequency of K469 was lower in RA patient group, compared to that in healthy controls, regardless of the shared epitope status. Distribution of K469E allele frequencies was not different whether the patient had rheumatoid factor, radiographic erosion or extra-articular complications. In conclusion, this study shows lower frequency of the ICAM-1 K469E allele in Korean patients with RA than that in healthy controls.
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Affiliation(s)
- E B Lee
- Department of Internal Medicine, Seoul National University College of Medicine, Yungon-dong, Chongno-gu, Seoul, South Korea
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Papa A, Pola R, Flex A, Danese S, Armuzzi A, Gaetani E, Guidi L, De Vitis I, Urgesi R, Grillo A, Serricchio M, Proia AS, Fedeli G, Gasbarrini G, Pola P, Gasbarrini A. Prevalence of the K469E polymorphism of intercellular adhesion molecule 1 gene in Italian patients with inflammatory bowel disease. Dig Liver Dis 2004; 36:528-32. [PMID: 15334773 DOI: 10.1016/j.dld.2004.03.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Intercellular adhesion molecule 1 plays an important role in the recruitment of leucocytes at sites of inflammation and is up-regulated in intestinal mucosa of inflammatory bowel disease. Intercellular adhesion molecule 1 gene lies on chromosome 19p13, implicated in determining susceptibility to inflammatory bowel disease. Recently, the polymorphism K469E of intercellular adhesion molecule 1 gene has been identified. AIM To assess the potential association of this polymorphism with inflammatory bowel disease. PATIENTS A total of 165 inflammatory bowel disease patients, 75 with Crohn's disease and 90 with ulcerative colitis, and 187 controls were studied. METHODS The K469E polymorphism was detected by polymerase chain reaction and restriction enzyme analysis. Statistical analysis was performed by chi2-test. RESULTS In inflammatory bowel disease, the distribution of intercellular adhesion molecule 1 genotypes was 24.9% E/E, 44.2% E/K and 30.9% K/K. In controls, 11.8% showed E/E genotype, 55.6% E/K and 32.6% K/K. The frequency of the E/E genotype was significantly higher in inflammatory bowel disease (Crohn's disease and ulcerative colitis) patients than in controls. Subgroup analysis showed that the frequency of the E469 allele was significantly increased only in Crohn's disease patients with ileocolonic location of disease and penetrating behaviour compared with controls. CONCLUSIONS We found an association of inflammatory bowel disease with the E/E genotype of intercellular adhesion molecule 1 gene, while allele E469 was associated with a subgroup of Crohn's disease patients with more extensive location of disease and penetrating behaviour. However, further studies are needed to confirm our findings.
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Affiliation(s)
- A Papa
- Department of Internal Medicine, Gastroenterology Unit, Catholic University of Rome, A. Gemelli University Hospital, Largo A. Gemelli 8, 00168 Rome, Italy.
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Abstract
PURPOSE OF REVIEW During the last few years, significant advances have been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD). By gaining new insights, paradigms that seemed to be a safe basis of our knowledge on IBD pathogenesis have recently become doubtful. This review discusses and summarizes the most recent developments. RECENT FINDINGS Important new insights have been gained into the function of caspase-activating and recruitment domain-15 (CARD15)/NOD2, the first cloned susceptibility gene for Crohn disease (CD). New data on CARD15/NOD2 function and nuclear factor-kappaB activation indicate that an inflammatory reaction of the intestinal mucosa as a response of the innate immune system may be necessary for the maintenance of gut homeostasis. CD may therefore be seen as a defective immune response, no longer only as hyperresponsiveness of the mucosal immune system. Data on CARD15/NOD2 expression suggest that macrophages and epithelial cells could be the site of a primary pathophysiologic defect, and T-cell activation might just be a secondary effect inducing chronification of the inflammation, perhaps as a backup mechanism to a defective innate immunity. In addition to CARD15/NOD2, there are additional "innate" pathways by which commensal and pathogenic bacteria can directly interact with cells of the intestinal mucosa (eg, toll-like receptors). The "germ concept" and the "genetic concept" of IBD pathophysiology are converging. SUMMARY New findings are changing our concepts of the pathogenesis of IBD. The innate immune system, early responses to bacterial products, and the modulation of T-cell responses are important aspects that are reviewed.
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Affiliation(s)
- Gerhard Rogler
- Department of Internal Medicine I, University of Regensburg, Germany.
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Agius LM. A primary dysregulation in the immunoregulatory role of the intestinal mucosal epithelial cell in inflammatory bowel disease pathogenesis? Biology of inflammatory response as tissue pattern entities in Crohn's versus ulcerative colitis. J Theor Biol 2004; 227:219-28. [PMID: 14990386 DOI: 10.1016/j.jtbi.2003.11.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2003] [Revised: 10/28/2003] [Accepted: 11/05/2003] [Indexed: 12/14/2022]
Abstract
Within a framework of dual involvement of mucosa and submucosa on the one hand, and of the muscularis propria of the bowel wall on the other, it might be valid to consider involvement of the vascular supply as the essential means in itself of not only causing the morphologic lesions in inflammatory bowel disease, but also especially in accounting for persisting patterns of inflammatory response both in ulcerative colitis and in Crohn's disease. Inflammatory bowel disease as a group constitutes a spectrum of biologic and pathobiologic manifestations in terms not only of inflammatory involvement of the bowel wall but also in terms of how the bowel in its turn deals with inflammation as a pathologic lesion in its own right. Parameters of inflammatory bowel activity transcend simple concepts of etiology and pathogenesis as applicable to category disorders such as infections or bowel ischemia. Indeed, the strictly characterized initiation of the inflammatory bowel response as a function of defective regulation of the antigenicity of the luminal contents on the one hand, and on interactions between nitric oxide and free oxygen radicals on the other, might help determine a persistence of tissue damage in inflammatory bowel disease that is either relapsing/remitting or chronic in progression. In a final analysis, perhaps, there might be involved a single central form of pathway induction of dysregulated immune reactivity arising from an early disturbance in activation patterns as induced by the onset of luminal antigenicity at an early or specific-stage, further characterized perhaps by specific forms of intestinal epithelial defects of the bowel mucosa in patients subsequently developing inflammatory bowel disease. Specific genetic markers for disease susceptibility and for therapeutic responsiveness are particularly of interest. The Nucleotide binding oligomerization Domain 2 (NOD2) would recognize microbial lipopolysaccharide or else mark systemic responses to pathogens that are pathogenic to evolving inflammatory bowel disease.
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Affiliation(s)
- Lawrence M Agius
- Department of Pathology, St. Luke's Hospital, Medical School, University of Malta, Gwardamangia, Msida, Malta, UK.
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Low JH, Williams FA, Yang X, Cullen S, Colley J, Ling KL, Armuzzi A, Ahmad T, Neville MJ, Dechairo BM, Walton R, Lench NJ, Jewell DP. Inflammatory bowel disease is linked to 19p13 and associated with ICAM-1. Inflamm Bowel Dis 2004; 10:173-81. [PMID: 15290909 DOI: 10.1097/00054725-200405000-00001] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Genome-wide scans have implicated several susceptibility loci, but linkage of 19p13 (IBD6) to Crohn's disease (CD) has not been fully replicated. We report a replication study of IBD6 in a UK Caucasian population. Two hundred eighty-four affected sibling pairs from 234 families were used for the linkage study. Linkage between IBD6 linkage and CD was replicated (LOD score = 1.59). Two candidate genes (DDXL and ICAM-1) within the IBD6 locus were examined in a case/control study with a total of 228 CD and 243 ulcerative colitis (UC) patients and 407 healthy controls. No association to either UC or CD was found in three novel intronic single nucleotide polymorphisms (SNPs) in DDXL. For ICAM-1, a significant association was found between K469 homozygosity and CD overall (39.9% vs 29.4%; Pc = 0.0096) and between E469 and fistulating disease (21.8% vs 10.0%, Pc = 0.030). In the UC group, limited disease extent was associated with homozygosity of the G241 allele (82.7% vs 64.7%, Pc = 0.0040). These data support linkage for CD at 19p13 and suggest that the amino acid polymorphisms in ICAM-1 may be associated with IBD.
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Affiliation(s)
- Jin Hong Low
- Gastroenterology Unit, Gibson Laboratories, Radcliffe Infirmary, University of Oxford, Oxford, UK
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