Genetic variations in toll-like receptors 7 and 8 modulate natural hepatitis C outcomes and liver disease progression.

Abstract

The natural outcomes of hepatitis C virus (HCV) as well as the progression of the liver disease are highly variable and depend primarily on an efficient immune response. As toll-like receptors seven (TLR7) and eight (TLR8) are important effectors of the innate immunity, this study aims to evaluate the association between TLR7 and TLR8 polymorphisms and the HCV infection outcomes in Moroccan subjects. In this case-control study, 643 subjects including 293 mild chronic hepatitis patients, 119 with advanced liver disease (AdLD), 93 with HCV spontaneous clearance and 138 healthy controls were genotyped using TaqMan SNPs assays. Patients carrying TLR7 rs179008-A allele were more likely to clear the virus spontaneously (P=.0001 for women, and P<.001 for men). Besides, carriage of TLR7 rs179009-A allele was associated with a twofold increase in spontaneous viral clearance in female patients (P=.0002), but not in men. In addition, we observed that TLR7 rs179008-T and rs179009-G alleles increased the risk of disease progression in both sexes (P<.05). TLR8 rs3764880-G allele was associated with spontaneous HCV clearance in both sexes (P<.0001) albeit with an apparently stronger association in males (OR=6.02 for men vs 2.2 for women). In males, TLR8 rs3764879-C and TLR8 rs3764880-A alleles were significantly associated with AdLD status (P<.05). Our results suggest that variations in TLR7 and TLR8 genes modulate the clearance and progression of HCV infection with different magnitudes between sexes. Our results refine, therefore, our understanding of the sex-specific differences observed regarding the susceptibility to chronic hepatitis.