Additive effects of HLA alleles and innate immune genes determine viral outcome in HCV infection

Background Chronic HCV infection is a leading cause of liver-related morbidity globally. The innate and adaptive immune responses are thought to be important in determining viral outcomes. Polymorphisms associated with the IFNL3 (IL28B) gene are strongly associated with spontaneous clearance and treatment outcomes. Objective This study investigates the importance of HLA genes in the context of genetic variation associated with the innate immune genes IFNL3 and KIR2DS3. Design We assess the collective influence of HLA and innate immune genes on viral outcomes in an Irish cohort of women (n= 319) who had been infected from a single source as well as a more heterogeneous cohort (Swiss Cohort, n= 461). In the Irish cohort, a number of HLA alleles are associated with different outcomes, and the impact of IFNL3-linked polymorphisms is profound. Results Logistic regression was performed on data from the Irish cohort, and indicates that the HLA-A*03 (OR 0.36 (0.15 to 0.89), p= 0.027) -B*27 (OR 0.12 (0.03 to 0.45), p=< 0.001), -DRB1*01: 01 (OR 0.2 (0.07 to 0.61), p= 0.005), -DRB1*04: 01 (OR 0.31 (0.12 to 0.85, p= 0.02) and the CC IFNL3 rs12979860 genotypes (OR 0.1 (0.04 to 0.23), p< 0.001) are significantly associated with viral clearance. Furthermore, DQB1*02: 01 (OR 4.2 (2.04 to 8.66), p= 0.008), KIR2DS3 (OR 4.36 (1.62 to 11.74), p= 0.004) and the rs12979860 IFNL3 'T' allele are associated with chronic infection. This study finds no interactive effect between IFNL3 and these Class I and II alleles in relation to viral clearance. There is a clear additive effect, however. Data from the Swiss cohort also confirms independent and additive effects of HLA Class I, II and IFNL3 genes in their prediction of viral outcome. Conclusions This data supports a critical role for the adaptive immune response in the control of HCV in concert with the innate immune response.