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.
['Fitzmaurice|Karen|K|', 'Hurst|Jacob|J|', 'Dring|Megan|M|', 'Rauch|Andri|A|', 'McLaren|Paul J|PJ|', 'Günthard|Huldrych F|HF|', 'Gardiner|Clair|C|', 'Klenerman|Paul|P|', '|||', '|||']
D056704:Adaptive Immunity D000293:Adolescent D000328:Adult D000368:Aged D000483:Alleles D015331:Cohort Studies D005260:Female D005805:Genes, MHC Class I D005802:Genes, MHC Class II D005838:Genotype D015791:HLA-A3 Antigen D015796:HLA-B27 Antigen D015236:HLA-C Antigens D019698:Hepatitis C, Chronic D006801:Humans D007113:Immunity, Innate D007372:Interferons D007378:Interleukins D008297:Male D008875:Middle Aged D011379:Prognosis D054340:Receptors, KIR D019562:Viral Load D055815:Young Adult
HLA Hepatitis C Immunogenetics Immunology in Hepatology T Lymphocytes