BackgroundIt has been demonstrated that vitamin D receptor (VDR), a key gene in the metabolism of vitamin D (VD), may affect the development of Non-alcoholic fatty liver disease (NAFLD) by regulating VD level and its biological effects.ObjectivesTo investigate the effects of serum VD level, VDR variation, and a combination of VDR SNP and environmental behavior factor on the risk of NAFLD.MethodsA total of 3023 subjects from a community in Nanjing were enrolled, including 1120 NAFLD cases and 1903 controls. Serum 25(OH)D3 levels were measured and eight single nucleotide polymorphisms (SNPs) in VDR gene were genotyped.ResultsLogistic regression analyses indicated that VD sufficiency and VD insufficiency were significantly associated with a low risk of NAFLD (all P<0.05; all Ptrend<0.05, in a locus-dosage manner). After adjusting for gender and age, VDR rs2228570-A and rs11168287-A alleles were all reduced the risk of NAFLD (all PFDR=0.136, in dominant model; Ptrend =0.039, combined effects in a locus-dosage manner). The protective effects of two favorable alleles were more evident among subjects ≤40 years, non-hypertension, non-hyperglycemia and non-low high density lipoprotein-cholesterol (all P<0.05). The area under the receiver operating curve of the combination of VDR SNP and exercise time for assessing NAFLD risk was slightly higher than that of only including exercise time or neither (all P<0.05).ConclusionHigh serum VD levels and VDR variants (rs2228570-A and rs11168287-A) might contribute to a low risk of NAFLD in Chinese Han population. The inclusion of VDR SNP and exercise time could improve the efficiency in assessment of NAFLD risk, which might provide a novel perspective for early screening and preventing NAFLD.

BackgroundPrevious studies have highlighted the important role of vitamin D and calcium pathway genes in immune modulation, cell differentiation and proliferation, and inflammation regulation, all closely implicated in the pathogenesis of non-alcoholic fatty liver disease (NAFLD).ObjectiveThis study aims to investigate whether 11 candidate single nucleotide polymorphisms (SNPs) in vitamin D and calcium pathway genes (CYP2R1, CYP24A1, and CYP27B1) are associated with the risk of NAFLD.MethodsIn this case-control study, a total of 3,023 subjects were enrolled, including 1,114 NAFLD cases and 1,909 controls. Eleven genetic variants in CYP2R1, CYP24A1, and CYP27B1 genes were genotyped. Logistic regression analysis was used to assess the effects of these variants on NAFLD risk. The functional annotations of positive SNPs were further evaluated by bioinformatics analysis.ResultsAfter adjusting for age, gender, and metabolic measures, we identified that CYP24A1 rs2296241 variant genotypes (recessive model: OR, 1.316; 95% CI, 1.048–1.653; p = 0.018), rs2248359 variant genotypes (recessive model: OR, 1.315; 95% CI, 1.033–1.674; p = 0.026), and CYP27B1 rs4646536 variant genotypes (additive model: OR, 1.147; 95% CI, 1.005–1.310; p = 0.042) were associated with an elevated risk of NAFLD. In combined effects analysis, we found that NAFLD risk significantly increased among patients carrying more rs2296241-A, rs2248359-T, and rs4646536-T alleles (ptrend = 0.049). Multivariate stepwise analysis indicated that age, visceral obesity, ALT, γ-GT, hypertriglyceridemia, hypertension, low HDL-C, hyperglycemia, and unfavorable alleles were independent predictors of NAFLD (all p < 0.05). The area under the receiver operating characteristic curve was 0.789 for all the above factors.ConclusionThe polymorphisms of vitamin family genes CYP24A1 (rs2296241, CYP24A1, and rs2248359) and CYP27B1 (rs4646536) were associated with NAFLD risk in Chinese Han population, which might provide new insight into NAFLD pathogenesis and tools for screening high-risk population.

Introduction: Vitamin D binding protein (VDBP) is correlated with non-alcoholic fatty liver disease (NAFLD) through the biological functions of regulating plasma vitamin D (VD) level and the inflammatory process. Objective: This study aims to investigate the effects of VD level and VDBP gene polymorphisms on the risk of NAFLD in a Chinese population. Methods: Plasma 25-hydroxyvitamin D3 [25(OH)D3] levels were measured and seven VDBP candidate genetic variants (rs222020, rs2282679, rs4588, rs1155563, rs7041, rs16847024, rs3733359) were genotyped among participants in this case-control study. The control group was frequency-matched to NAFLD case group by age and gender. Correlation analysis and multiple linear regression were used to screen determinants of 25(OH)D3 levels. Multivariable unconditional logistic regression was performed to estimate odds ratio (OR) and 95% confidence interval (95% CI). The prediction capability of models containing independent factors was estimated by the area under the receiver operating characteristic curve (AUROC) and Hosmer-Lemeshow test. Results: Age, BMI and TG were independent factors influencing VD levels. Participants with low VD levels had significantly higher prevalence of NAFLD compared to subjects with normal VD levels (P < 0.001). A low VD level contributed to increased risk of NAFLD, independent of metabolic factors known to affect VD levels (adjusted OR = 2.282, 95% CI = 1.422-3.661, P = 0.001). Logistic regression analysis showed that individuals carrying rs7041-G allele had a significantly decreased risk of NAFLD occurrence compared to T allele (additive model: adjusted OR = 0.814, 95% CI = 0.713-0.929, P = 0.002; codominant model: adjusted OR = 0.623, 95% CI = 0.449-0.866, P = 0.005), after adjusting for age, gender, and overweight. Stratification by multiple metabolic disorders did not alter this relationship. Moreover, we developed a simple model including age, gender, metabolic disorders and VDBP SNP to assess NAFLD risk, an AUC of which being 0.817, significantly higher than the model not included VDBP SNP, with Hosmer-Lemeshow test fitting well (P = 0.182). Conclusions: Low plasma VD levels may increase susceptibility to NAFLD, while rs7041-G allele in VDBP contributed to a decreased NAFLD risk among Chinese population. The VDBP variant significantly improved the capability for NAFLD risk assessment, which could be used for early screening and management of NAFLD.

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