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

J Hum Genet. 2017 Nov;62(11):969-977. doi: 10.1038/jhg.2017.75. Epub 2017 Jul 13.

Abstract

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.

MeSH terms

  • Adult
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / virology
  • Disease Progression
  • Female
  • Genetic Association Studies*
  • Genotype
  • Hepacivirus / pathogenicity
  • Hepatitis C, Chronic / genetics*
  • Hepatitis C, Chronic / pathology
  • Hepatitis C, Chronic / virology
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Liver Neoplasms / virology
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Receptors, Calcitriol / genetics
  • Signal Transduction / genetics
  • Smad3 Protein / genetics
  • Transforming Growth Factor beta1 / genetics*
  • Vitamin D / genetics
  • Vitamin D / metabolism*

Substances

  • Receptors, Calcitriol
  • SMAD3 protein, human
  • Smad3 Protein
  • TGFB1 protein, human
  • Transforming Growth Factor beta1
  • VDR protein, human
  • Vitamin D