ReviewEffects of CYP2R1 gene variants on vitamin D levels and status: A systematic review and meta-analysis
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.
References (43)
- et al.
Assessment of gender-related differences in vitamin D levels and cardiovascular risk factors in Saudi patients with type 2 diabetes mellitus
Saudi J. Biol. Sci.
(2018) - et al.
Associations of diet, supplement use, and ultraviolet B radiation exposure with vitamin D status in Swedish women during winter
Am. J. Clin. Nutr.
(2007) - et al.
De-orphanization of cytochrome P450 2R1 a microsomal vitamin D 25-hydroxylase
J. Biol. Chem.
(2003) - et al.
Genetics, diet, and season are associated with serum 25-hydroxycholecalciferol concentration in a Yup'ik study population from southwestern Alaska
J. Nutr.
(2016) - et al.
Environmental and genetic determinants of vitamin D status among older adults in London, UK
J. Steroid Biochem. Mol. Biol.
(2016) - et al.
Low-frequency synonymous coding variation in CYP2R1 has large effects on vitamin D levels and risk of multiple sclerosis
Am. J. Hum. Genet.
(2017) - et al.
Meta-analysis of genetic association studies
Trends Genet.
(2004) - et al.
Vitamin a and D intake in pregnancy, infant supplementation, and asthma development: the Norwegian mother and child cohort
Am. J. Clin. Nutr.
(2018) - et al.
Common genetic determinants of vitamin D insufficiency: a genome-wide association study
Lancet
(2010) - et al.
Association between circulating 25-hydroxyvitamin D and incident type 2 diabetes: a mendelian randomisation study
Lancet Diabetes Endocrinol.
(2015)
Genome-wide association study of circulating vitamin D levels
Hum. Mol. Genet.
Genome-wide association study of vitamin D levels in children: replication in the western Australian pregnancy cohort (Raine) study
Genes Immun.
CYP2R1 polymorphisms are important modulators of circulating 25-hydroxyvitamin D levels in elderly females with vitamin insufficiency, but not of the response to vitamin D supplementation
Osteoporos. Int.
Genetic and epigenetic factors influencing vitamin D status
J. Cell. Physiol.
Comprehensive association analysis of nine candidate genes with serum 25-hydroxy vitamin D levels among healthy Caucasian subjects
Hum. Genet.
Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase
Proc. Natl. Acad. Sci. U. S. A.
Genetic variant in vitamin D binding protein is associated with serum 25-hydroxyvitamin D and vitamin D insufficiency in southern Chinese
J. Hum. Genet.
Genetic polymorphisms in vitamin D metabolism and signaling genes and risk of breast cancer: a nested case-control study
PLoS One
Vitamin D insufficiency in Arabs and south Asians positively associates with polymorphisms in GC and CYP2R1 genes
PLoS One
Triangular relationship between single nucleotide polymorphisms in the CYP2R1 gene (rs10741657 and rs12794714), 25-hydroxyvitamin d levels, and coronary artery disease incidence
Biomarkers
Association of rs7041 and rs4588 polymorphisms of the vitamin D binding protein and the rs10741657 polymorphism of CYP2R1 with vitamin D status among Jordanian patients
Genet. Test. Mol. Biomarkers
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