Common genetic determinants of vitamin D insufficiency: a genome-wide association study

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• 作者：Thomas J Wang ; Feng Zhang ; J Brent Richards ; Bryan Kestenbaum ; Joyce B van Meurs ; Diane Berry ; Douglas P Kiel ; Elizabeth A Streeten ; Claes Ohlsson ; Daniel L Koller ; Leena Peltonen ; Jason D Cooper ; Pau
• 刊名：The Lancet
• 出版年：2010
• 出版时间：17 July 2010-23 July 2010
• 年：2010
• 卷：376
• 期：9736
• 页码：180-188
• 全文大小：242 K

文摘

Summary

Background

Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.

Methods

We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.

Findings

Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1·9×10⁻¹⁰⁹ for rs2282679, in GC); 11q12 (p=2·1×10⁻²⁷ for rs12785878, near DHCR7); and 11p15 (p=3·3×10⁻²⁰ for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6·0×10⁻¹⁰ for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2·47, 95 % CI 2·20–2·78, p=2·3×10⁻⁴⁸) or lower than 50 nmol/L (1·92, 1·70–2·16, p=1·0×10⁻²⁶) compared with those in the lowest quartile.

Interpretation

Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.

Funding

Full funding sources listed at end of paper (see Acknowledgments).