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.

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.

• Authors: Laura A de Azevedo, Ursula Matte, Themis R da Silveira, Mário R Álvares-da-Silva
• Journal: Journal of human genetics (J Hum Genet) Vol. 62 Issue 11 Pg. 969-977 (Nov 2017) ISSN: 1435-232X [Electronic] England
• PMID: 28703134 (Publication Type: Journal Article)

Chemical References

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

Topics

• Adult
• Carcinoma, Hepatocellular (genetics, pathology, virology)
• Disease Progression
• Female
• Genetic Association Studies
• Genotype
• Hepacivirus (pathogenicity)
• Hepatitis C, Chronic (genetics, pathology, virology)
• Humans
• Liver Neoplasms (genetics, pathology, 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, metabolism)