IFNL4 genotype is associated with hepatitis A virus infection findings from a focused phenotype study in the UK Biobank Cohort.

The IFNL4-ΔG/TT (rs368234815) polymorphism controls production of the IFN-λ4 protein; the IFNL4-ΔG allele generates IFN-λ4, IFNL4-TT disrupts IFN-λ4 production. Individuals who carry IFNL4-ΔG have impaired clearance of hepatitis C virus (HCV), but less hepatic inflammation in the face of chronic hepatitis C. To conduct a focused phenotype association study to identify additional manifestations of IFNL4-ΔG/TT. In the UK Biobank Cohort, we analyzed inpatient data from 401,239 White participants with a directly assayed IFNL4-ΔG/TT genotype, of whom 176,555 also provided primary care (outpatient) data. We selected 266 phenotypes with potential biological relevance to IFN-λ4 and created logistic regression models to estimate odds ratios (ORs) for associations between IFNL4-ΔG/TT genotype and these phenotypes in inpatients and outpatients. Three phenotypes yielded consistent findings (P < 0.05) in both databases. For hepatitis A virus (HAV) infection, we found a novel protective association for IFNL4-ΔG carriers (outpatient: OR = 0.77, P = 0.0005; inpatient: OR = 0.62, P = 0.015). IFNL4-ΔG was also associated with increased risk for HCV infection (outpatient: OR = 1.51, P = 0.025; inpatient: OR = 1.24, P = 0.036) and protectively associated with giant cell arteritis (GCA; outpatient: OR = 0.79, P = 0.038; inpatient: OR = 0.88, P = 0.047). Based on calculations that combined inpatient and outpatient data and corrected for multiple comparisons, the association between IFNL4-ΔG and HAV was statistically significant (P = 0.00004), while those for HCV and GCA were not. We report a novel protective association between the IFNL4-ΔG allele, which generates IFN-λ4 protein, and HAV infection. Future studies might examine the mechanism for this association and the therapeutic potential of IFN-λ4 for treating infection with HAV.