Single nucleotide polymorphisms in the vitamin D pathway associating with circulating concentrations of vitamin D metabolites and non-skeletal health outcomes: Review of genetic association studies

doi:10.1016/j.jsbmb.2015.12.007

The Journal of Steroid Biochemistry and Molecular Biology

Volume 164, November 2016, Pages 18-29

https://doi.org/10.1016/j.jsbmb.2015.12.007 Get rights and content

Highlights

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We review a total of 120 genetic association studies on vitamin D pathway SNP.
•
Significant associations reported for a total of 55 SNP in 11 vitamin D pathway genes.
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44 studies report 114 findings of SNP which determine metabolite concentration.
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76 studies report 105 findings of SNP which affect non-skeletal health outcomes.
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Infectious and auto-immune related disease were most frequent to associate with SNP.
•
Limited overlap of SNP predicting vitamin D status and SNP affecting disease outcomes.

Abstract

Polymorphisms in genes encoding proteins involved in vitamin D metabolism and transport are recognised to influence vitamin D status. Syntheses of genetic association studies linking these variants to non-skeletal health outcomes are lacking. We therefore conducted a literature review to identify reports of statistically significant associations between single nucleotide polymorphisms (SNP) in 11 vitamin D pathway genes (DHCR7, CYP2R1, CYP3A4, CYP27A1, DBP, LRP2, CUB, CYP27B1, CYP24A1, VDR and RXRA) and non-bone health outcomes and circulating levels of 25-hydroxyvitamin D (25[OH]D and 1,25-dihydroxyvitamin D (1,25[OH]₂D). A total of 120 genetic association studies reported positive associations, of which 44 investigated determinants of circulating 25(OH)D and/or 1,25(OH)₂D concentrations, and 76 investigated determinants of non-skeletal health outcomes. Statistically significant associations were reported for a total of 55 SNP in the 11 genes investigated. There was limited overlap between genetic determinants of vitamin D status and those associated with non-skeletal health outcomes: polymorphisms in DBP, CYP2R1 and DHCR7 were the most frequent to be reported to associate with circulating concentrations of 25(OH)D, while polymorphisms in VDR were most commonly reported to associate with non-skeletal health outcomes, among which infectious and autoimmune diseases were the most represented.

Introduction

Genetic variation in the vitamin D pathway was first reported to influence human health more than 20 years ago, when Morrison and colleagues found associations between allelic variants in the gene encoding the vitamin D receptor (VDR) and bone density [1], [2]. Since then the scope of genetic association studies in the vitamin D field has widened to investigate the effects of variation in other genes in the vitamin D pathway on both skeletal and non-skeletal health outcomes. Several systematic reviews of the literature linking VDR polymorphisms to various disease outcomes have been performed to date [3], [4], [5], [6], [7]. Reviews of studies investigating the influence of variation in other vitamin D pathway genes on bone health have also been performed [8]. However, reviews of studies that have investigated associations with non-skeletal health and variants in vitamin D pathway genes other than VDR are lacking. This is a significant omission, because genome-wide association studies have reported that polymorphisms in the genes encoding enzymes responsible for both synthesis and catabolism of 25-hydroxyvitamin D influence vitamin D status [9], [10]. Such variants might therefore be expected to influence non-skeletal health outcomes in their own right, or to modify the effects of vitamin D supplementation on risk of extra-skeletal disease—a hypothesis that we have addressed in clinical trials [11], [12].

We therefore conducted a literature review to identify genetic association studies reporting positive associations between risks of non-skeletal disease outcomes and single nucleotide polymorphisms (SNP) in the following genes encoding key players in the vitamin D pathway: DHCR7, CYP2R1, CYP3A4, CYP27A1, DBP, LRP2, CUBN, CYP27B1, CYP24A1, VDR and RXRA. The role for each of these genes in the vitamin D metabolic, transport and signaling pathways is illustrated in Fig. 1.

Section snippets

Search method

To identify eligible studies we searched the Pubmed database using the following terms: ‘DHCR7’; ‘CYP2R1’; ‘CYP3A4’; ‘CYP27A1’; ‘DBP’; ‘LRP2’; ‘Megalin’; ‘CUBN’; ‘Cubilin’; ‘CYP27B1’; ‘CYP24A1’; ‘VDR’; ‘RXRA’. Our initial search was conducted in April of 2012 and captured manuscripts published from 2000 to 2012; we then conducted the same search in June of 2015 to capture manuscripts published from 2012 to 2015. Abstracts and titles were reviewed to select studies on the basis of inclusion /

Identification and selection of studies

Fig. 2 depicts the study selection process. Our initial search identified 3828 publications of which 120, containing a total of 55 individual SNP, met eligibility criteria.

Study characteristics

Of the 120 studies selected for inclusion, 44 studies reported a combined 114 findings of significant association between the concentration of 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D and genotype of 35 vitamin D pathway SNP. Of these 35 SNP, 13 were in DBP; 7 in CYP2R1; 7 in DHCR7; 4 in CYP27B1; 2 in CYP24A1; 1 in RXRA

Discussion

To our knowledge, this is the first review to synthesise the literature reporting positive associations between genetic variation in the vitamin D pathway as a whole and biochemical and non-skeletal health outcomes. As might be expected, mutations in DBP, which encodes the binding protein that maintains serum concentration of 25(OH)D, is the most widely investigated source of variation in circulating concentrations of vitamin D metabolites. Mutations in CYP2R1 and DHCR7, Table 3 which encode

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This study randomly selected 459 postmenopausal women (aged ≥50 years) of multiple ethnicities in Jeddah, Saudi Arabia. Blood samples were collected from all participating women for DNA extraction and for assessment of serum levels of total 25(OH)D, directly measured free 25(OH)D and other biochemical parameters. SNPs in selected vitD related genes (rs4588 in GC, c.1364G > T with transcript ID: NM_001204307.1 and rs7041 in GC, c.1353A > C with transcript ID NM_001204307.1 and rs12794714 in CYP2R1, c.177G > A with transcript ID NM_024514.4) were determined in DNA samples using Sanger DNA sequencing.
Minor allele frequency for rs4588, rs7041 and rs12794714 were 0.25, 0.44 and 0.42 respectively. Genotypes of rs7041 showed significant difference in total 25(OH)D level but not in free 25(O)D level (P = 0.023). In comparison, genotypes of rs4588 and rs12794714 did not show any significant difference neither in total nor in free 25(OH)D level. Post hoc test revealed that total 25(OH)D was lower in the rs7041 TT allele compared to the GG allele (P = 0.022). Chi-square test showed that vitD status was associated with rs7041 genotypes (P = 0.035). In addition, rs7041 minor alleles were found to have an association with vitD deficiency with a statistical significant odds ratio (>1) of 2.24 and 3.51 with P = 0.006 and P = 0.007 for TG and GG genotypes respectively.
The rs7041 SNP in GC was associated with total 25(OH)D level in postmenopausal women in Saudi Arabia, while rs4588 in GC and rs12794714 in CYP2R1 did not show association with total 25(OH)D. Further studies exploring additional variants in vitD related genes are needed to understand genetic factors underlying vitD deficiency in Saudi population.

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ReviewSingle nucleotide polymorphisms in the vitamin D pathway associating with circulating concentrations of vitamin D metabolites and non-skeletal health outcomes: Review of genetic association studies

Highlights

Abstract

Introduction

Section snippets

Search method

Identification and selection of studies

Study characteristics

Discussion

Lancet

Lancet

J. Steroid Biochem. Mol. Biol.

Clin. Biochem.

Am. J. Clin. Nutr.

J. Steroid Biochem. Mol. Biol.

Lancet Diabetes Endocrinol.

J. Hepatol.

Am. J. Clin. Nutr.

J. Steroid Biochem. Mol. Biol.

Lancet

Arch. Med. Res.

Infect. Genet. Evol.

Egypt. J. Chest Dis. Tuberculosis

Maturitas

Clin. Immunol.

Clin. Microbiol. Infect.

Gene

J. Neurol. Sci

J. Am. Coll. Surg.

Transl. oncol.

Hum. Immunol.

Gene

Contribution of trans-acting factor alleles to normal physiological variability: vitamin D receptor gene polymorphism and circulating osteocalcin

Proc. Natl. Acad. Sci. U. S. A.

Prediction of bone density from vitamin D receptor alleles

Nature

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Lung

Vitamin D-related genes, serum vitamin D concentrations and prostate cancer risk

Carcinogenesis

Vitamin D receptor genetic polymorphisms and tuberculosis: updated systematic review and meta-analysis

Int. J. Tuberculosis Lung Dis.

Association between vitamin D receptor polymorphisms and multiple sclerosis: systematic review and meta-analysis of case–control studies

Cell. Mol. Immunol.

Association between vitamin D receptor gene polymorphisms (Fok1 and Bsm1) and osteoporosis: a systematic review

J. Diabetes Metab. Disorders

Vitamin D binding protein and bone health

Int. J. Endocrinol.

Genome-wide association study of circulating vitamin D levels

Hum. Mol. Genet.

Double-blind randomised placebo-controlled trial of bolus-dose vitamin D3 supplementation in adults with asthma (ViDiAs)

Thorax

Genetic and environmental determinants of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in Hispanic and African Americans

J. Clin. Endocrinol. Metab.

Low 25(OH) vitamin D3 levels are associated with adverse outcome in newly diagnosed, intensively treated adult acute myeloid leukemia

Cancer

Plasma concentrations of 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D are related to the phenotype of Gc (vitamin D-binding protein): a cross-sectional study on 595 early postmenopausal women

Calcified Tissue Int.

Vitamin D-binding protein (DBP) gene polymorphism is associated with Graves’ disease and the vitamin D status in a polish population study

Exp. Clin. Endocrinol. Diabetes

The Gc2 allele of the vitamin D binding protein is associated with a decreased postmenopausal breast cancer risk, independent of the vitamin D status

Cancer Epidemiol. Biomarkers Prev.

Vitamin D binding protein genotype and osteoporosis

Calcified Tissue Int.

Vitamin D deficiency is highly prevalent in COPD and correlates with variants in the vitamin D-binding gene

Thorax

Genetic and environmental predictors of serum 25-hydroxyvitamin D concentrations among middle-aged and elderly Chinese in Singapore

Br. J. Nutr.

Polymorphic variation in the GC and CASR genes and associations with vitamin D metabolite concentration and metachronous colorectal neoplasia

Cancer Epidemiol. Biomarkers Prev.

Associations between common variants in GC and DHCR7/NADSYN1 and vitamin D concentration in Chinese Hans

Hum. Genet.

An analysis of the association between the vitamin D pathway and serum 25-hydroxyvitamin D levels in a healthy Chinese population

J. Bone Miner. Res.

Genetic variations in the vitamin D binding protein and season-specific levels of vitamin D among older adults

Epidemiology

Vitamin D insufficiency in Arabs and South Asians positively associates with polymorphisms in GC and CYP2R1 genes

PLoS One

Genome-wide association study of vitamin D levels in children: replication in the Western Australian pregnancy cohort (Raine) study

Genes Immun.

Review
Single nucleotide polymorphisms in the vitamin D pathway associating with circulating concentrations of vitamin D metabolites and non-skeletal health outcomes: Review of genetic association studies

Double-blind randomised placebo-controlled trial of bolus-dose vitamin D₃ supplementation in adults with asthma (ViDiAs)

Low 25(OH) vitamin D₃ levels are associated with adverse outcome in newly diagnosed, intensively treated adult acute myeloid leukemia