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.

Minxian Wang,Zongzhe Tang,Liuxin Zhang,Wei Zhang,Hongliang Wang,Jie Wang,Ru Zhang,Yue Chen,Yajie Ding,Min Wang

doi:10.3389/fgene.2021.717533

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.

Highlights

Non-alcoholic fatty liver disease (NAFLD) has emerged as a major chronic liver disease, afflicting more than one-quarter of adults worldwide (Younossi et al, 2016)
Previous studies have shown that NAFLD cannot only cause liver-related complications, such as non-alcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma (HCC) (Lindenmeyer and McCullough, 2018) and increase the risk of other extrahepatic diseases, such as cardiovascular disease (CVD) (Targher et al, 2010), type 2 diabetes mellitus (T2DM) (Tilg et al, 2017), and chronic kidney disease (Byrne and Targher, 2020)
After adjusting for gender, age, AST, ALT, γ-GT, TG, total cholesterol (TC), and high-density lipoprotein cholesterol (HDL-C), logistic regression analyses showed that CYP24A1-rs2296241-A allele (AA vs. GG: adjusted odds ratio (OR) = 1.337, 95% CI = 1.035–1.726, p = 0.026; recessive model: adjusted OR = 1.316, 95% CI = 1.048–1.653, p = 0.018; additive model: adjusted OR = 1.135, 95% CI = 1.002–1.287, p = 0.047), CYP24A1-rs2248359-T allele

Summary

Introduction

Non-alcoholic fatty liver disease (NAFLD) has emerged as a major chronic liver disease, afflicting more than one-quarter of adults worldwide (Younossi et al, 2016). Previous studies have shown that NAFLD cannot only cause liver-related complications, such as non-alcoholic steatohepatitis (NASH), cirrhosis, hepatocellular carcinoma (HCC) (Lindenmeyer and McCullough, 2018) and increase the risk of other extrahepatic diseases, such as cardiovascular disease (CVD) (Targher et al, 2010), type 2 diabetes mellitus (T2DM) (Tilg et al, 2017), and chronic kidney disease (Byrne and Targher, 2020). Previous studies have indicated that NAFLD is a multi-factorial disease associated with a high frequency of metabolic comorbidities (Italian Association for the Study of the Liver (Aisf), 2017). Previous 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)

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