Genetic control of vitamin d levels and liver fibrosis by variants in genes regulating vitamin D homoeostasis in a cohort of patients with chronic liver disease

Abstract

BackgroundP Recently, genome wide studies identified a number of genetic variants that affect on vitamin D levels in healthy populations (rs12785878, near dehydrocholesterol reductase, DHCR7; rs10741657, near CYP2R1; and rs7041, near vitamin D binding protein GC; Wang et al. Lancet 2010). Since vitamin D deficiency is associated with advanced liver disease, we hypothesized that these variants are associated with vitamin D levels and fibrosis in patients with chronic liver disease.P Patients and methodsP 834 patients with chronic liver diseases were included. Liver stiffness was measured using transient elastography (TE). Liver fibrosis stage was determined by histological staging according to Desmet and Scheuer in a subgroup of patients (n=249). Serum levels of 25(OH)-vitamin D3 (VD3) were correlated with TE and liver histology. Genotypes were determined using Taqman assays and tested for association with levels of 25(OH)-vitamin D3 and fibrosis assessed by TE. Furthermore, we correlated 25(OH)-vitamin D3 levels with sunshine hours at the time interval of inclusion. ResultsP Most patients suffered from chronic viral hepatitis C (58.9%), alcoholic (10.6%) and autoimmune (AIH, PBC, PSC) liver diseases (8.1%). Mean VD3 levels were 28.4 +/- 15.8 ng/ml. Patients with advanced fibrosis (> 7.0 kPa) had significantly lower VD3 levels as compared to patients with < 7.0 kPa (21.7 vs. 29.7 ng/ml; p<0.001). VD3 levels were inversely correlated with liver stiffness and histology (p<0.001). We detected an association with fibrosis and variant rs12785878, near DHCR7. Interestingly, this SNP was not associated with liver fibrosis in the overall cohort. However after exclusion of patients with advanced fibrosis (> 7.0 kPa), the rare allele was significantly associated with increased liver stiffness (genotypes TT & TG vs. GG: 5.1 +/- 1.0 kPa vs. 5.4 +/- 1.0 kPa; p < 0.05). We observed a highly significant correlation of VD3 levels with sunshine hours at time of inclusion (r= 0.61; p = 0.001) with an effect size exceeding all significant allele effects.P ConclusionsP A common SNP in linked to the DHCR7 gene, which encodes a reductase of the vitamin D precursor dehydrocholesterol, is associated with VD3 serum concentrations in patients with chronic liver disease. Interestingly, the association of this SNP with liver fibrosis is restricted to patients with no or mild fibrosis, suggesting that the modifier effect of vitamin D might only be discernible during fibrosis initiation and/or early fibrosis stages. However, environmental factors such as sunshine exposure may outperform genetic effects on fibrosis progression.