No significant interactions between age and genetic associations of ABCB1 rs1045642 or XRCC1 rs1799782 were found (P = 0.08 and 0.34, respectively). A weak check details interaction was detected with TGFB1 rs1800469 (P = 0.02), but the trend of the odds of infection prevalence was not increased with age as expected (Supporting Table 4). Therefore, age appears to be an independent determinant of HAV infection. This is the first study assessing associations between human genetic variants and HAV infection among a nationally representative sample of the three major race/ethnicities in the United States. Variants in ABCB1, TGFB1, and XRCC1 were significantly

associated with the prevalence of HAV infection in Mexican Americans. We observed that individuals carrying the functional T allele of TGFB1 rs1800469 are more prone to have been infected with HAV. TGFB1 is a multifunctional cytokine that regulates proliferation and differentiation of a wide variety of cell types. It plays a crucial role in the pathogenesis of liver injury during acute hepatitis A infection.34 The TT genotype of TGFB1 rs1800469 (C-509T), located at nucleotide −509 in the TGFB1 promoter, is associated with higher plasma levels of TGFB1, which have been shown to be under genetic control (heritability estimate, 0.54), with C-509T responsible for 8.2% of additive genetic variance

in a twin study.35 The T allele of C-509T alters

TGFB1 transcription NVP-BEZ235 molecular weight activity by influencing affinity of transcription factor Yin Yang 1 for its promoter.36 Excessive release of TGFB1 in serum during acute hepatitis A infection can markedly inhibit antigen-specific T cell activation and proliferation as well as humoral response.37 This may explain why carriers of the TGFB1 rs1800469 T allele (the high TGFB1 producers) are more susceptible to HAV infection. We found that Mexican American carriers of the T allele of XRCC1 rs1799782 have a higher prevalence of HAV infection. XRCC1 is a major DNA repair gene involved in efficient repairs of single-strand DNA breaks and base excision to correct DNA damage caused 上海皓元医药股份有限公司 by oxidative stress and inflammation.38 Genetic variants in DNA repair genes can be associated with differences in the ability to repair DNA damage, which may be a requisite for risk of many diseases, including HIV and HBV-related hepatocellular carcinoma.39, 40 HAV induces oxidative stress that alters base excision repair pathways and increases apoptotic response in acute hepatitis A.23, 41 The Arg194Trp variant (rs1799782) of XRCC1 resides in a microRNA-binding site and alters microRNA-target interaction to affect gene and protein expression, in turn influencing the risk of certain human diseases. The rs1799782 T allele is associated with increased binding with microRNA-138.