Genetic variation in CLDN1 and susceptibility to hepatitis C virus infection.
Claudin-1 is a recently discovered co-receptor for hepatitis C virus (HCV) that is required for late-stage binding of the virus. Because variants in the gene that encodes claudin-1 (CLDN1) could play a role in HCV infection, we conducted a 'whole gene association study' among injection drug users (IDUs) to examine whether CLDN1 genetic variants were associated with the risk of HCV infection or with viral clearance. In a cross sectional study, we examined genotype results for 50 single nucleotide polymorphisms (SNPs) across the CLDN1 gene region, comparing genotypes among participants with chronic HCV (n = 658) to those in IDUs who had cleared HCV (n = 199) or remained HCV-uninfected (n = 68). Analyses were controlled for racial ancestry (African-American or European-American) by stratification and logistic regression modeling. We found that participants who remained uninfected more often carried CLDN1 promoter region SNPs -15312C [odds ratio (OR), 1.72; 95% confidence interval (CI) 1.00-2.94; P = 0.048], -7153A (OR, 2.13; 95% CI, 1.25-3.62; P = 0.006) and -5414C (OR, 1.78; 95% CI, 1.06-3.00; P = 0.03). HCV-uninfected participants less often carried CLDN1 IVS1-2983C (OR, 0.55; 95% CI, 0.31-0.97; P = 0.04), which lies in intron 1. CLDN1 -15312C, -7153A and -5414C formed a haplotype in both the African-American and European-American participants and a haplotype analysis supported the association of CLDN1 -7153A in the HCV-uninfected participants. The analyses of HCV clearance revealed no associations with any SNP. These results indicate that genetic variants in regulatory regions of CLDN1 may alter susceptibility to HCV infection.
Bekker
V
V
Section on Genomic Variation, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Chanock
S J
SJ
Yeager
M
M
Hutchinson
A A
AA
von Hahn
T
T
Chen
S
S
Xiao
N
N
Dotrang
M
M
Brown
M
M
Busch
M P
MP
Edlin
B R
BR
Rice
C M
CM
O'Brien
T R
TR
D000328:Adult; D062445:Claudin-1; D003430:Cross-Sectional Studies; D055030:Drug Users; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006526:Hepatitis C / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D015819:Substance Abuse, Intravenous
C568108:CLDN1 protein, human; D062445:Claudin-1; D008565:Membrane Proteins
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