Genetic variants underlying vitamin D metabolism and VDR–TGFβ-1–SMAD3 interaction may impact on HCV progression: a study based on dbGaP data from the HALT-C study

Vitamin d deficiency is prevalent in liver disease and vitamin d has been shown to decrease hepatic fibrosis through an anti-tgfβ-1/smad3 effect mediated by the vitamin d receptor. thus, we hypothesized that genetic variants involved in vitamin d metabolism and/or vdr/tgfβ-1/smad3 interaction could impact on the progression of chronic hcv. we obtained or imputed genotypes for 40 single nucleotide polymorphisms (snps) located in genes implicated in vitamin d metabolism from the halt-c cohort via dbgap. the halt-c study followed 692 chronic hcv patients over 4 years, evaluating clinical outcomes including worsening of fibrosis, hepatic decompensation (gastric/esophageal bleeding, ctp>7, ascites, spontaneous bacterial peritonitis and encephalopathy), development of hepatocellular carcinoma, and liver death. we tested the selected snps for association with these outcomes in 681 halt-c subjects. eleven snps presented tendency towards significance (p<0.05): four snps in dhcr7 related to with hepatic decompensation (rs4944957, rs12800438, rs3829251 and rs4945008); two in gc to worsening of fibrosis and liver death (rs7041 and rs222020); two in cyp2r1 to ascites and hepatocellular carcinoma (rs7116978 and rs1562902); two in vdr to gastric/esophageal bleeding and hepatocellular carcinoma (rs4516035 and rs2239186); and one in smad3 to worsening of fibrosis and encephalopathy (rs2118610). only rs1800469 in tgfb1 was statistically associated with hepatic decompensation after bonferroni’s correction (p<0.00125). in conclusion, rs1800469 in tgfb1 was associated to hepatic decompensation in chronic hepatitis c, while the other 11 described polymorphisms must be evaluated in a larger cohort to determine the possible role of vitamin d in hepatitis c.