Genetic Polymorphism of Vitamin D Family Genes CYP2R1, CYP24A1, and CYP27B1 Are Associated With a High Risk of Non-alcoholic Fatty Liver Disease: A Case-Control Study

Abstract

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.

Association of Vitamin-D Receptor (Vdr), Gc-globulin and Cyp2r1 Polymorphism With Progression of Hbv Related Liver Disease Along With an Exclusive Svm Based Disease Prediction Model

“…Absence of A allele is associated with insu ciency of Vitamin-D [27,28]. However, until date no association has been reported between CYP2R1 rs10741657 polymorphism and acute to chronic transition of HBV infection neither its association with NAFLD risk [29]. In this study, no any signi cant association was found between CYP2R1 polymorphism and clinical outcomes of HBV infection both in terms of pathophysiological parameter and in terms of disease progression.…”

The Interplay of Vitamin D Deficiency and Cellular Senescence in The Pathogenesis of Obesity-Related Co-Morbidities

“…Genome-wide studies have emphasized the role of vitamin D pathway genes in many processes that are strongly linked to NAFLD, such as immunological alteration, cellular differentiation, and inflammatory processes [133,134]. Various genetic studies have revealed frequent single nucleotide polymorphisms (SNPs) in vitamin D pathway genes and highlighted their association with low serum vitamin D levels both in healthy subjects and those with hepatitis, such as the genes for CYP2R1 and CYP27B1 [133], while mutations in the CYP24A1 gene, responsible to vitamin D degradation [135], causes calcitriol elevation [136].…”

“…Various genetic studies have revealed frequent single nucleotide polymorphisms (SNPs) in vitamin D pathway genes and highlighted their association with low serum vitamin D levels both in healthy subjects and those with hepatitis, such as the genes for CYP2R1 and CYP27B1 [133], while mutations in the CYP24A1 gene, responsible to vitamin D degradation [135], causes calcitriol elevation [136]. A case-control study that investigated the effect of vitamin D gene SNPs has shown that alleles CYP24A1 rs2296241-A, rs2248359-T, and CYP27B1 rs4646536-T were all considered a risk factor for NAFLD when combined with other clinical factors [134]. Additionally, these alleles were found to co-exist in some NAFLD patients [134].…”

“…A case-control study that investigated the effect of vitamin D gene SNPs has shown that alleles CYP24A1 rs2296241-A, rs2248359-T, and CYP27B1 rs4646536-T were all considered a risk factor for NAFLD when combined with other clinical factors [134]. Additionally, these alleles were found to co-exist in some NAFLD patients [134]. Another study that determined SNPs of the VDR gene in NAFLD-proven subjects with liver biopsy has shown VDR rs1544410 genotype CC to be independently correlated with advanced liver fibrosis [133].…”

Genetic polymorphisms related to the vitamin D pathway in patients with cirrhosis with or without hepatocellular carcinoma (HCC)

“…Additionally, the increased expression of CYP24A1 , a regulator of vitamin D, and the activity of the respective 24-hydroxylase enzyme are associated with the degradation of 25(OH)D 3 into 24.25(OH) 2 D 3 [ 13 ]. CYP24A1 induces low serum levels of 25(OH)D 3 , which has been shown with liver disease severity in studies with non-alcoholic fatty liver disease (NAFLD) [ 14 ] and patients with hepatitis C (HCV) [ 15 ]. Furthermore, some studies suggest that CYP24A1 single nucleotide polymorphisms (SNPs) contributes to a chronic HCV infection, progressing to more defined conditions [ 16 ], such as the risk for liver cancer [ 17 ].…”