Genome-Wide Association Study of Serum 25-Hydroxyvitamin D in US Women

Abstract

Genetic factors likely influence individuals' concentrations of 25-hydroxyvitamin D [25(OH)D], a biomarker of vitamin D exposure previously linked to reduced risk of several chronic diseases. We conducted a genome-wide association study of serum 25(OH)D (assessed using liquid chromatography-tandem mass spectrometry) and 386,449 single nucleotide polymorphisms (SNPs). Our sample consisted of 1,829 participants randomly selected from the Sister Study, a cohort of women who had a sister with breast cancer but had never had breast cancer themselves. 19,741 SNPs were associated with 25(OH)D (p < 0.05). We re-assessed these hits in an independent sample of 1,534 participants who later developed breast cancer. After pooling, 32 SNPs had genome-wide significant associations (p < 5 × 10−8). These were located in or near GC, the vitamin D binding protein, or CYP2R1, a cytochrome P450 enzyme that hydroxylates vitamin D to form 25(OH)D. The top hit was rs4588, a missense GC polymorphism associated with a 3.5 ng/mL decrease in 25(OH)D per copy of the minor allele (95% confidence interval [CI]: −4.1, −3.0; p = 4.5 × 10−38). The strongest SNP near CYP2R1 was rs12794714, a synonymous variant (p = 3.8 × 10−12; β = 1.8 ng/mL decrease in 25(OH)D per minor allele [CI: −2.2, −1.3]). Serum 25(OH)D concentrations from samples collected from some participants 3–10 years after baseline (811 cases, 780 non-cases) were also strongly associated with both loci. These findings augment our understanding of genetic influences on 25(OH)D and the possible role of vitamin D binding proteins and cytochrome P450 enzymes in determining measured levels. These results may help to identify individuals genetically predisposed to vitamin D insufficiency.

Association of SNPs in GC and CYP2R1 with total and directly measured free 25-hydroxyvitamin D in multi-ethnic postmenopausal women in Saudi Arabia

“…Although there are several forms of cytochrome p -450, CYP2R1 has the greatest specificity and affinity to vitD ( Schuster, 2011 ) with a missense mutation in CYP2R1 reported to cause vitD deficiency ( Cheng et al, 2004 ). In addition, a number of genome-wide association studies in cohorts from European descent detected more than 25 SNPs in CYP2R1 linked with vitD status ( Ahn et al, 2010 , Anderson et al, 2014 , Jiang et al, 2018 , O'Brien et al, 2018 , Wang et al, 2010 ). However, several studies performed in populations from non-European cohorts have been unable to replicate these results ( Duan et al, 2018 , Lu et al, 2012 , Robien et al, 2013 , Xu et al, 2015 ).…”

Genetic Association between Serum 25-Hydroxyvitamin D Levels and Lung Function in Korean Men and Women: Data from KNHANES 2011–2012

“…We selected five genetic variants for genotyping ( DHCR7 rs12785878, GC rs2282679, CYP2R1 rs10741657 and rs12794714, and CYP24A1 rs6013897) based on a previous GWAS available at the time of preparation of the manuscript related to vitamin D deficiency ( p = 2.1 × 10 −27 , 1.9 × 10 −109 , 3.3 × 10 −20 , and 1.8 × 10 −9 , and 6.0 × 10 −10 , respectively) [ 14 ] and its use in various Mendelian randomization studies [ 29 , 30 , 31 ]. These SNPs were reported to be associated with 25(OH)D in recent GWAS performed in Whites [ 32 , 33 ]. The associations and effect size of these genetic variants in Koreans and other races are discussed in detail elsewhere [ 34 ].…”

The CYP2R1 Enzyme: Structure, Function, Enzymatic Properties and Genetic Polymorphism

“…Subsequent to the discovery of CYP2R1*2, over 20 SNPs of the CYP2R1 gene associated with alteration in vitamin D levels have been identified in a number of genome-wide association studies (GWAS) carried out in European populations [54][55][56][57]. Numerous replication studies have also been conducted in populations of other ethnicity [58,59].…”