Elsevier

Gene

Volume 678, 15 December 2018, Pages 361-369
Gene

Review
Effects of CYP2R1 gene variants on vitamin D levels and status: A systematic review and meta-analysis

https://doi.org/10.1016/j.gene.2018.08.056Get rights and content

Highlights

  • The meta-analysis showed that the risk-allele G of rs10741657 was associated with an increased risk of vitamin D deficiency.

  • GG genotype of rs10741657 was associated with a clear descending trend of 25(OH)D levels when compared with the AA genotype.

  • Rs12794714 and rs10766197 polymorphisms were not associated with 25(OH)D levels.

  • No publication bias was detected in this meta-analysis.

Abstract

Background and objective

CYP2R1 is a key gene in the vitamin D metabolic pathway. It has been suggested that CYP2R1 gene variants in European populations are associated with concentrations of 25(OH)D, a biomarker of vitamin D levels and status in peripheral blood. However, a comprehensive meta-analysis of this effect including different ethnicities has never been conducted. The objective of this meta-analysis was to evaluate the association between CYP2R1 gene variants and 25(OH)D levels and vitamin D status.

Methods

PubMed, EMBASE, Web of Science, CNKI and Wanfang databases were systematically searched up to May 2018. Reporting followed PRISMA guidelines. The quality of the evidence was assessed using the STREGA system. Random or fixed effects model combined estimates and sub-group tested for ethnic differences. The I2 statistic quantified between-study variation due to heterogeneity.

Results

Sixteen articles with a total of 52,417 participants met the inclusion criteria and were included in the meta-analysis. For rs10741657, GG genotype was associated with a clear descending trend of 25(OH)D levels when compared with the AA genotype [SMD = −2.32, 95% CI (−4.42, −0.20); SMD = −3.46, 95% CI (−6.60, −0.33) and SMD = −0.24, 95% CI (−0.51, −0.03) for total, Caucasian and Asian groups, respectively] with the following heterogeneities I2 = 37.9%, 69.2% and 24.5%, respectively. However, under the AG/AA genetic model, significant changes in 25(OH)D levels [SMD and 95% CI: −1.27(−2.32, −0.23)] were only evident in the Caucasian population. The meta-analysis on vitamin D deficiency showed that the risk-allele G was associated with an increased risk of vitamin D deficiency (OR = 1.09; 95% CI = 1.03–1.15, P = 0.002). The association between rs10741657 and increased risk of vitamin D deficiency was significant (OR = 1.42; 95% CI = 1.11–1.83, P = 0.006) under the dominant model (GG + AG/AA), but not under the recessive model (GG/AG + AA), (OR = 1.28; 95% CI = 0.89–1.84, P = 0.181). There was no evidence of publication bias.

Conclusion

Published articles provide evidence supporting a major role for the rs10741657 polymorphism of the CYP2R1 gene in determining 25(OH)D levels and the presence of vitamin D deficiency.

Introduction

Vitamin D is a fat-soluble vitamin and steroid pro-hormone that is involved in the regulation of various biological processes, such as immunoregulation and insulin resistance and also has anti-inflammatory and anti-cancer effects (Mccullough and Mayo, 2009; Sharma et al., 2017; Tabatabaeizadeh et al., 2017; Abudawood et al., 2018). Accumulating evidence supports the notion that low vitamin D concentrations are strongly associated with various adverse outcomes, such as asthma, diabetes, cardiovascular disease and some forms of cancer (Mccullough and Mayo, 2009; Abudawood et al., 2018; Parr et al., 2018). Factors which influence the concentrations of 25-hydroxyvitamin D [25(OH)D], a vitamin D biomarker that can be measured in blood, include sun exposure, latitude, race, age, gender and dietary supplements. (Fohner et al., 2016). However, these environmental factors appear to only contribute to 13% of the individual heterogeneity in vitamin D levels (Burgaz et al., 2007). Accumulating evidence indicates that differences in vitamin D levels, including vitamin D deficiency, are under strong genetic control. Several twin and family studies have reported that 23% to 80% of the heterogeneity in vitamin D levels was attributable to genetic factors (Bahrami et al., 2017). Attention has now turned to the gene effects that could have an impact on vitamin D metabolism.

The production of 1,25(OH)2D, an active form of vitamin D, relies on a series of enzymatic processes. Sun light (UVB at 270 nm–290 nm), acting on 7-dehydrocholesterol (7-DHC) in the epidermis of the skin, generates pre-vitamin D. Pre-vitamin D is an inactive precursor, requiring 25-hydroxylase (encoded by the cytochrome P450 CYP2R1 gene in the liver) to yield the 25(OH)D. Subsequently, 1α-hydroxylase in the kidney (encoded by the CYP27B1 gene) catalyzes the conversion of 25(OH)D to 1,25(OH)2D. (Fig. 1). The human CYP2R1 gene contains 5 exons and spans about 15.5 kb. It is located on chromosome 11p15.2 (gene ID: 120227), and contains 501 amino acids (Cheng et al., 2003). It encodes a microsomal vitamin D 25-hydroxylase which is considered to be the most important enzyme in the metabolism of vitamin D. In mice, the combined knockout of both Cyp2r1 and Cyp27b1, only reduced levels of 25(OH)D by 50%, did not affect circulating 1,25(OH)2D (Burgaz et al., 2007). In humans, Cheng et al. first identified a missense mutation in exon 2 of the CYP2R1 gene that could result in vitamin D deficiency (Cheng et al., 2004). Subsquently, several genome-wide association studies (GWAS) performed in European populations (Ahn et al., 2010; Wang et al., 2010; Anderson et al., 2014; O'Brien et al., 2018; Xia et al., 2018), identified >25 SNPs of the CYP2R1 gene associated with vitamin D levels or vitamin D deficiency. Numerous replication studies were conducted in other ethnic/racial populations (Wen, 2012; Robien et al., 2013; Xu et al., 2015; Yu, 2016; Mao, 2017). However, the results of these studies did not seem to support the conclusions observed in the European populations.

Here, we conducted a meta-analysis including a large scale and unrelated population with general health condition to evaluate more precisely the association between CYP2R1 gene polymorphisma and 25(OH)D levels and vitamin D status.

Section snippets

Data sources and search strategies

This study was performed following a predefined protocol and under the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Table S1) (Moher et al., 2009).

The searches were conducted by LZ.D and YW from Jan 2010 to May 2018 using PubMed, EMBASE, Web of Science, CNKI and WanFang databases with the following search terms: (“CYP2R1” or “25-hydroxylase” or “cytochrome P450 2R1”) and (“SNP” or “polymorphism” or “variants” or “mutation”) and (“vitamin D" or

Results of the search strategy

A systematic search of the literature led to the identification of 311 possibly relevant articles. One hundred and fifty-nine duplicate studies were removed using the “Find Duplicates” tool in EndNote X7. An initial examination identified 46 articles by screening the titles and abstracts. After manual examination and detailed consideration, 16 articles with a total of 52,417 participants were included in the present meta-analysis. Of these, 7 articles investigated rs10741657 and vitamin D

Disscusion

To our knowledge, this is the first comprehensive meta-analysis evaluating the association between CYP2R1 SNPs and 25(OH)D levels and vitamin D status. The meta-analysis of 25(OH)D levels and vitamin D status in European and Asian populations identified rs10741657 variants that showed a large effect and strong association with 25(OH)D levels and vitamin D deficiency.

The gene of CYP2R1 encodes 25-hydroxylase which can convert vitamin D into 25(OH)D (Cheng et al., 2003). Growing evidence suggests

Conclusion

The present meta-analysis confirmed that a statistically significant association exists between the rs10741657 polymorphism and 25(OH)D levels and vitamin D deficiency in Caucasian and Asian populations. However, these results may not be generalizable to all races, because our meta-analysis did not included African populations. Therefore, in the future we plan to conduct a well-designed, more comprehensive study with a larger sample size study to validate our conclusions.

Acknowledgments

We thank all the investigators in this study.

Funding sources

No funding supports this work.

Disclosure

We declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.

Authors contributions

The authors' responsibilities were as follows: YW: conceived and designed the study; LZD, ZGX and HWJ: performed literature search and Data collection; LZD: analyzed data and wrote the manuscript; YW and DDZ: modified the language of the manuscript. All authors read and provided critical comment on the manuscript.

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