The absence of seroconversion after exposition to hepatitis C virus is not related to KIR-HLA genotype combinations (GEHEP-012 study).

BACKGROUND & AIMS: It has been reported that specific killer-cell immunoglobulin-like receptors (KIRs) and HLA genotype combinations, such as KIR2DS4/HLA-C1 with presence of KIRDL2 or KIRDL3, homozygous KIRDL3/HLA-C1 and KIR3DL1/≥2HLA-Bw4, are strongly associated with the lack of active infection and seroconversion after exposition to hepatitis C virus (HCV). OBJECTIVE: To determine whether these KIR-HLA combinations are relevant factors involved in that phenotype. PATIENTS AND METHODS: In this retrospective case-control study, genotype data from a genome-wide association study previously performed on low susceptibility to HCV-infection carried out on 27 high-risk HCV-seronegative (HRSN) individuals and 743 chronically infected (CI) subjects were used. HLA alleles were imputed using R package HIBAG v1.2223 and KIR genotypes were imputed using the online resource KIR*IMP v1.2.0. RESULTS: It was possible to successfully impute at least one KIR-HLA genotype combination previously associated with the lack of infection and seroconversion after exposition to HCV in a total of 23 (85.2%) HRSN individuals and in 650 (87.5%) CI subjects. No KIR-HLA genotype combination analyzed was related to the HRSN condition. CONCLUSIONS: Our results suggest that those KIR-HLA genotype combinations are not relevant factors involved in the lack of infection and seroconversion after exposition to HCV. More studies will be needed to completely understand this phenotype.

A genome-wide association study on low susceptibility to hepatitis C virus infection (GEHEP012 study).

BACKGROUND: A low proportion of individuals repeatedly exposed to the hepatitis C virus (HCV) remain uninfected. This condition could have a genetic basis but it is not known whether or not it is mainly driven by a high-penetrance common allele. OBJECTIVE: To explore whether low susceptibility to HCV infection is mainly driven by a high-penetrance common allele. METHODS: In this genome-wide association study (GWAS), a total of 804 HCV-seropositive individuals and 27 high-risk HCV-seronegative (HRSN) subjects were included. Plink and Magma software were used to carry out single nucleotide polymorphism (SNP)-based and gene-based association analyses respectively. RESULTS: No SNP nor any gene was associated with low susceptibility to HCV infection after multiple testing correction. However, SNPs previously associated with this trait and allocated within the LDLR gene, rs5925 and rs688, were also associated with this condition in our study under a dominant model (24 out of 27 [88.9%] rs5925-C carriers in the HRSN group vs 560 of 804 [69.6%] rs5925-C carriers in the HCV-seropositive group, P = 0.031, odds ratio [OR] = 3.48; 95% confidence interval [CI] = 1.04-11.58; and 24 out of 27 [88.9%] rs688-T carriers in the HRSN group vs 556 of 804 [69.1%] rs688-T carriers in the HCV-seropositive group, P = 0.028, OR = 3.57, 95% CI = 1.65-11.96). CONCLUSIONS: Low susceptibility to HCV infection does not seem to be mainly driven by a high-penetrant common allele. By contrast, it seems a multifactorial trait where genes such as LDLR could be involved.