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.