Genetic variation in toll-like receptors and retinoic acid-inducible gene I and outcome of hepatitis C virus infection: a candidate gene association study.
We evaluated the effects of genetic variation in toll-like receptors (TLR), retinoic acid-inducible gene I (RIG-I) and their signalling pathways on spontaneous hepatitis C virus (HCV) resolution. We screened 95 single-nucleotide polymorphisms (SNPs) in 22 genes. SNPs significantly associated with resolution in the discovery cohort were genotyped in a validation cohort. Multivariate logistic regression adjusted for sex, hepatitis B surface antigen, HIV infection and the interleukin-28B rs12979860 SNP was performed in the combined cohort. Haplotype reconstruction and linkage disequilibrium analysis were performed. srs2233437, rs730775 and rs28362857 in Inhibitor of NF-kB ε (IkBε) and rs352140 in TLR9 were associated with spontaneous HCV resolution (P ≤ 0.05) in the discovery cohort (n = 308). In the validation cohort (n = 216), we replicated a significant association with HCV resolution for two SNPs in the IkBε, rs2233437 and rs730775. Presence of one or two of the variant allele in rs2233437 had more than twofold higher odds of resolution in adjusted logistic regression (adjusted odds ratio (aOR), 2.6; (95% CI, 1.4, 4.8) P = 0.002). We identified polymorphisms in the IkBε gene associated with spontaneous HCV resolution in two independent cohorts.
Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Denmark; Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark; Copenhagen Hepatitis C Program (CO-HEP), Department of Infectious Diseases and Clinical Research Centre, Copenhagen University Hospital, Hvidovre, Denmark; Department of International Health, Immunology and Microbiology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.
L N
LN
Clausen
S
S
Ladelund
N
N
Weis
J
J
Bukh
T
T
Benfield
D000328:Adult; D015331:Cohort Studies; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases / Q000235:genetics*; D060467:Disease Resistance; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D006239:Haplotypes; D006526:Hepatitis C / Q000235:genetics* / Q000276:immunology*; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics*; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011971:Receptors, Immunologic; D015398:Signal Transduction / Q000235:genetics*; D051193:Toll-Like Receptors / Q000235:genetics*
D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D051550:I-kappa B Kinase; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases
IkBε haplotypes; host genetics; prediction of spontaneous HCV resolution