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

被引：1254

作者：

Wang, Thomas J. ^{[1
,5
,6
]}

Zhang, Feng ^{[7
]}

Richards, J. Brent ^{[8
,10
,11
,12
]}

Kestenbaum, Bryan ^{[13
]}

van Meurs, Joyce B. ^{[18
,21
]}

Berry, Diane ^{[22
,23
]}

Kiel, Douglas P. ^{[4
,6
]}

Streeten, Elizabeth A. ^{[24
]}

Ohlsson, Claes ^{[25
]}

Koller, Daniel L. ^{[27
]}

Peltonen, Leena ^{[28
,29
,30
]}

Cooper, Jason D. ^{[31
]}

O'Reilly, Paul F. ^{[32
]}

Houston, Denise K. ^{[33
]}

Glazer, Nicole L. ^{[14
,15
]}

Vandenput, Liesbeth ^{[25
]}

Peacock, Munro ^{[27
]}

Shi, Julia ^{[24
]}

Rivadeneira, Fernando ^{[18
,21
]}

McCarthy, Mark I. ^{[35
,36
,38
]}

Anneli, Pouta ^{[39
]}

de Boer, Ian H. ^{[13
]}

Mangino, Massimo ^{[7
]}

Kato, Bernet ^{[7
]}

Smyth, Deborah J. ^{[31
]}

Booth, Sarah L. ^{[40
]}

Jacques, Paul F. ^{[40
]}

Burke, Greg L. ^{[34
]}

Goodarzi, Mark ^{[41
]}

Cheung, Ching-Lung ^{[4
,43
]}

Wolf, Myles ^{[42
]}

Rice, Kenneth ^{[14
,15
]}

Goltzman, David ^{[9
,10
]}

Hidiroglou, Nick ^{[44
]}

Ladouceur, Martin ^{[8
,10
,11
,12
]}

Wareham, Nicholas J. ^{[45
]}

Hocking, Lynne J. ^{[46
]}

Hart, Deborah ^{[7
]}

Arden, Nigel K. ^{[37
,47
]}

Cooper, Cyrus ^{[37
,47
]}

Malik, Suneil ^{[48
]}

Fraser, William D. ^{[49
]}

Hartikainen, Anna-Liisa ^{[50
]}

Zhai, Guangju ^{[7
]}

Macdonald, Helen M. ^{[46
]}

Forouhi, Nita G. ^{[45
]}

Loos, Ruth J. F. ^{[45
]}

Reid, David M. ^{[46
]}

Hakim, Alan ^{[53
]}

Dennison, Elaine ^{[47
]}

机构：

[1] Massachusetts Gen Hosp, Dept Med, Div Cardiol, Boston, MA 02114 USA

[2] Massachusetts Gen Hosp, Diabet Res Ctr, Diabet Unit, Boston, MA 02114 USA

[3] Massachusetts Gen Hosp, Ctr Human Genet Res, Boston, MA 02114 USA

[4] Hebrew SeniorLife, Inst Aging Res, Genet Epidemiol Program, Boston, MA USA

[5] Harvard Univ, Sch Med, Boston, MA USA

[6] Framingham Heart Dis Epidemiol Study, Framingham, MA USA

[7] Kings Coll London, Dept Twin Res & Genet Epidemiol, London SE1 7EH, England

[8] McGill Univ, Jewish Gen Hosp, Montreal, PQ H3T 1E2, Canada

[9] McGill Univ, Ctr Hlth, Montreal, PQ H3T 1E2, Canada

[10] McGill Univ, Dept Med, Montreal, PQ H3T 1E2, Canada

[11] McGill Univ, Dept Human Genet, Montreal, PQ H3T 1E2, Canada

[12] McGill Univ, Dept Epidemiol & Biostat, Montreal, PQ H3T 1E2, Canada

[13] Univ Washington, Harborview Med Ctr, Kidney Res Inst, Div Nephrol, Seattle, WA 98104 USA

[14] Univ Washington, Dept Med, Seattle, WA 98104 USA

[15] Univ Washington, Cardiovasc Hlth Res Unit, Seattle, WA 98104 USA

[16] Univ Washington, Dept Epidemiol, Seattle, WA 98104 USA

[17] Univ Washington, Dept Hlth Serv, Seattle, WA 98104 USA

[18] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[19] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[20] Erasmus MC, Dept Klin Genet, Rotterdam, Netherlands

[21] NGI, Sponsored NCHA, Rotterdam, Netherlands

[22] UCL, Inst Child Hlth, MRC Ctr Epidemiol Child Hlth, London, England

[23] Ctr Paediat Epidemiol & Biostat, London, England

[24] Univ Maryland, Sch Med, Div Endocrinol, Baltimore, MD 21201 USA

[25] Univ Gothenburg, Inst Med, Dept Internal Med, Sahlgrenska Acad, Gothenburg, Sweden

[26] Univ Gothenburg, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Physiol, Gothenburg, Sweden

[27] Indiana Univ, Sch Med, Indianapolis, IN USA

[28] Wellcome Trust Sanger Inst, Hinxton, England

[29] Univ Helsinki, Helsinki, Finland

[30] Inst Mol Med Finland, Natl Inst Hlth & Welf, Helsinki, Finland

[31] Univ Cambridge, JDRF WT Diabet & Inflammat Lab, Cambridge, England

[32] Univ London Imperial Coll Sci Technol & Med, Dept Epidemiol & Publ Hlth, Fac Med, London, England

[33] Wake Forest Univ, Sch Med, Sticht Ctr Aging, Winston Salem, NC 27109 USA

[34] Wake Forest Univ, Sch Med, Div Publ Hlth Sci, Winston Salem, NC 27109 USA

[35] Univ Oxford, OCDEM, Oxford, England

[36] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[37] Univ Oxford, NIHR Musculoskeletal Biomed Res Unit, Oxford, England

[38] Churchill Hosp, Oxford NIHR Biomed Res Ctr, Oxford OX3 7LJ, England

[39] Natl Inst Hlth & Welf, Oulu, Finland

[40] Tufts Univ, Human Nutr Res Ctr Aging, Jean Mayer USDA, Boston, MA 02111 USA

[41] Cedars Sinai Med Ctr, Dept Med, Los Angeles, CA 90048 USA

[42] Univ Miami, Miller Sch Med, Div Nephrol & Hypertens, Miami, FL 33136 USA

[43] ASTAR, Genome Inst Singapore Computat & Math Biol, Singapore, Singapore

[44] Hlth Canada, Ottawa, ON K1A 0L2, Canada

[45] Addenbrookes Hosp, MRC Epidemiol Unit, Inst Metab Sci, Cambridge, England

[46] Univ Aberdeen, Div Appl Med, Bone & Musculoskeletal Res Programme, Aberdeen, Scotland

[47] Univ Southampton, MRC Epidemiol Resource Ctr, Southampton, Hants, England

[48] Publ Hlth Agcy Canada, Off Biotechnol Genom & Populat Hlth, Toronto, ON, Canada

[49] Univ Liverpool, Unit Clin Chem, Sch Clin Sci, Liverpool L69 3BX, Merseyside, England

[50] Univ Oulu, Dept Obstet & Gynaecol, Oulu, Finland

来源：

LANCET | 2010年 / 376卷 / 9736期

基金：

英国惠康基金; 英国生物技术与生命科学研究理事会;

关键词：

D-BINDING PROTEIN; PLASMA-CONCENTRATIONS; D SUPPLEMENTATION; D DEFICIENCY; RISK; 25-HYDROXYVITAMIN-D; CALCIUM; CANCER; METAANALYSIS; REPLICATION;

D O I：

10.1016/S0140-6736(10)60588-0

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-22) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-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=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2-16, p=1.0x10(-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.

引用

页码：180 / 188

页数：9

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