Journal
HUMAN MOLECULAR GENETICS
Volume 19, Issue 13, Pages 2739-2745Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddq155
Keywords
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Funding
- National Cancer Institute, NIH [N01-CO-12400]
- US Public Health Service [N01-CN-45165, N01-RC45035, N01-RC-37004]
- National Cancer Institute, NIH, DHHS [HHSN261201000006C]
- Division of Cancer Epidemiology and Genetics
- Division of Cancer Prevention
- National Cancer Institute (NCI)
- US National Institutes of Health (NIH)
- Department of Health and Human Services (DHHS)
- NIH [P01CA087969, 5U01HG004399-2, P01CA055075]
- NIH Kirschstein-NRSA [T32 ES016645-01]
- [U01 CA098710]
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The primary circulating form of vitamin D, 25-hydroxy-vitamin D [25(OH)D], is associated with multiple medical outcomes, including rickets, osteoporosis, multiple sclerosis and cancer. In a genome-wide association study (GWAS) of 4501 persons of European ancestry drawn from five cohorts, we identified single-nucleotide polymorphisms (SNPs) in the gene encoding group-specific component (vitamin D binding) protein, GC, on chromosome 4q12-13 that were associated with 25(OH) D concentrations: rs2282679 (P = 2.0 x 10(-30)), in linkage disequilibrium (LD) with rs7041, a non-synonymous SNP (D432E; P = 4.1 x 10(-22)) and rs1155563 (P = 3.8 x 10(-25)). Suggestive signals for association with 25(OH) D were also observed for SNPs in or near three other genes involved in vitamin D synthesis or activation: rs3829251 on chromosome 11q13.4 in NADSYN1 [encoding nicotinamide adenine dinucleotide (NAD) synthetase; P = 8.8 x 10(-7)], which was in high LD with rs1790349, located in DHCR7, the gene encoding 7-dehydrocholesterol reductase that synthesizes cholesterol from 7-dehydrocholesterol; rs6599638 in the region harboring the open-reading frame 88 (C10orf88) on chromosome 10q26.13 in the vicinity of ACADSB (acyl-Coenzyme A dehydrogenase), involved in cholesterol and vitamin D synthesis (P = 3.3 x 10(-7)); and rs2060793 on chromosome 11p15.2 in CYP2R1 (cytochrome P450, family 2, subfamily R, polypeptide 1, encoding a key C-25 hydroxylase that converts vitamin D-3 to an active vitamin D receptor ligand; P = 1.4 x 10(-5)). We genotyped SNPs in these four regions in 2221 additional samples and confirmed strong genome-wide significant associations with 25(OH) D through meta-analysis with the GWAS data for GC (P = 1.8 x 10(-49)), NADSYN1/DHCR7 (P = 3.4 x 10(-9)) and CYP2R1 (P = 2.9 x 10(-17)), but not C10orf88 (P = 2.4 x 10(-5)).
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