Association Between Vitamin D Protein Gene Polymorphisms and Non-Alcoholic Fatty Liver Disease Risk

Abstract

Background
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, affecting approximately one-quarter of the global population, and is strongly influenced by genetic predisposition. Vitamin D contributes to hepatic steatosis, fibrosis, and insulin resistance, and low vitamin D levels have been linked to an increased risk of NAFLD. Vitamin D receptor protein (VDR) is a key nuclear receptor that binds to vitamin D, so polymorphisms in its gene may influence vitamin D availability and, in turn, NAFLD risk and severity. Data on the relationship between VDR single-nucleotide polymorphisms (SNPs) and NAFLD remain limited. In this study, we aim to investigate the association between the VDR gene polymorphisms rs7975232 and rs2228570 and the risk and severity of NAFLD.
Methods
This cross-sectional study enrolled 100 participants (50 with NAFLD, diagnosed by abdominal ultrasound and transient elastography, and 50 controls) over 12 months, all attending the Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Benha University. Serum 25(OH)D was measured by enzyme-linked immunosorbent assay (ELIZA) method according to manufacture instructions and regarding to rs7975232 and rs2228570 were genotyped by TaqMan allelic-discrimination real-time PCR.
Results
Serum vitamin D was significantly lower in the NAFLD group than in controls (17.07±5.64 vs 28.38±3.04 ng/mL, p<0.001). Among NAFLD patients, the rs7975232 AA genotype was associated with lower vitamin D (12.57±1.71 vs 19.86±7.89 ng/mL, p=0.002) and a higher steatosis grade (269.92±11.77 vs 252.00±11.19, p<0.001) than the CC genotype. Similarly, the rs2228570 TT genotype was associated with lower vitamin D (14.25±4.50 vs 19.25±5.88 ng/mL, p=0.013) and a higher steatosis grade (266.95±11.42 vs 247.33±3.12, p<0.001) than the CC genotype. Within the NAFLD group, both rs7975232 and rs2228570 dosage correlated positively with cholesterol (r=0.369 and r=0.309, respectively; p<0.001 and p=0.002, respectively) and triglycerides level (r=0.440 and r=0.409, respectively; both p<0.001) In addition, both rs7975232 and rs2228570 dosage correlated positively with steatosis grade (r=0.539 and r=0.654, respectively; both p<0.001) and steatosis grade (r=0.412 and r=0.490, respectively; both p<0.001), and rs2228570 dosage also correlated with the FIB-4 index (r=0.437, p<0.001). A combined model of vitamin D and both SNPs achieved the best discrimination for NAFLD (AUC 0.961, 95% CI 0.910–0.996).
Conclusion
The rs2228570 and rs7975232 VDR variants are associated with lower vitamin D levels and greater hepatic steatosis, and genotype information modestly improves the diagnostic performance of vitamin D for NAFLD. Because the study is cross-sectional, these findings cannot establish causality or disease progression; longitudinal and mechanistic studies are needed.