Serum 25‐hydroxyvitamin D, vitamin D‐related variants, and risk of chronic liver disease

Abstract The associations of serum 25‐hydroxyvitamin D (25(OH)D) with cirrhosis and liver cancer have not been well examined. It remained unclear whether functional vitamin D‐related variants modify these associations. During follow‐up of 401,551 UK Biobank participants with valid 25(OH)D data, we documented 4404 incident non‐alcoholic fatty liver disease (NAFLD), 1989 incident cirrhosis, and 480 incident liver cancer. The binding affinity values of 25(OH)D to vitamin D binding protein (VDBP) were estimated based on combinations of VDBP variants rs4588 and rs7041. Vitamin D receptor (VDR) activity was calculated by summing the number of related alleles for rs11568820, rs2228570, and rs1544410. Hazard ratio (95% confidence intervals) for serum 25(OH)D of ≥50 nmol/L (vs. <25 nmol/L) were 0.70 (0.63–0.77) for NAFLD (ptrend = 1.37 × 10−14), 0.43 (0.38–0.49) for cirrhosis (ptrend = 8.66 × 10−29) and 0.65 (0.48–0.87) for liver cancer (ptrend = .010). We observed differential associations of 25(OH)D with hepatic fibrosis and cirrhosis (pinteraction = .024), and portal hypertension (pinteraction = .019) by VDR activity, with a stronger inverse association among participants with low VDR activity (ptrend = 1.28 × 10−9 for hepatic fibrosis and cirrhosis and ptrend = 1.52 × 10−14 for portal hypertension). The association of 25(OH)D with liver cancer differed by GC isoforms (pinteraction = .033), with a stronger inverse association among participants with low affinity isoforms (ptrend = .001). Serum 25(OH)D appears to prevent NAFLD, cirrhosis, and liver cancer, especially for participants with low VDR activity/low affinity GC isoforms.