Common genetic determinants of vitamin D insufficiency: a genome-wide association study.
Common genetic determinants of vitamin D insufficiency: a genome-wide association study.
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DOI：
10.1016/s0140-6736(10)60588-0
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发表时间：
2010-07-17
期刊：
影响因子：
168.9
通讯作者：
Spector, Timothy D.
中科院分区：
文献类型：
--
作者：
Wang, Thomas J.;Zhang, Feng;Richards, J. Brent;Kestenbaum, Bryan;van Meurs, Joyce B.;Berry, Diane;Kiel, Douglas P.;Streeten, Elizabeth A.;Ohlsson, Claes;Koller, Daniel L.;Peltonen, Leena;Cooper, Jason D.;O'Reilly, Paul F.;Houston, Denise K.;Glazer, Nicole L.;Vandenput, Liesbeth;Peacock, Munro;Shi, Julia;Rivadeneira, Fernando;McCarthy, Mark I.;Anneli, Pouta;de Boer, Ian H.;Mangino, Massimo;Kato, Bernet;Smyth, Deborah J.;Booth, Sarah L.;Jacques, Paul F.;Burke, Greg L.;Goodarzi, Mark;Cheung, Ching-Lung;Wolf, Myles;Rice, Kenneth;Goltzman, David;Hidiroglou, Nick;Ladouceur, Martin;Wareham, Nicholas J.;Hocking, Lynne J.;Hart, Deborah;Arden, Nigel K.;Cooper, Cyrus;Malik, Suneil;Fraser, William D.;Hartikainen, Anna-Liisa;Zhai, Guangju;Macdonald, Helen M.;Forouhi, Nita G.;Loos, Ruth J. F.;Reid, David M.;Hakim, Alan;Dennison, Elaine;Liu, Yongmei;Power, Chris;Stevens, Helen E.;Jaana, Laitinen;Vasan, Ramachandran S.;Soranzo, Nicole;Bojunga, Joerg;Psaty, Bruce M.;Lorentzon, Mattias;Foroud, Tatiana;Harris, Tamara B.;Hofman, Albert;Jonsson, John-Olov;Cauley, Jane A.;Uitterlinden, Andre G.;Gibson, Quince;Jarvelin, Marjo-Riitta;Karasik, David;Siscovick, David S.;Econs, Michael J.;Kritchevsky, Stephen B.;Florez, Jose C.;Todd, John A.;Dupuis, Josee;Hyppoenen, Elina;Spector, Timothy D.
维生素D对维持肌肉骨骼健康至关重要。最近，维生素D不足与许多骨骼外疾病有关，包括糖尿病、癌症和心血管疾病。循环25-羟基维生素D （25-OH D）的决定因素包括阳光照射和饮食摄入，但其高遗传性表明遗传决定因素也可能起作用。我们在来自15个队列的约30,000名欧洲血统个体中进行了25-OH D全基因组关联研究。5个队列被指定为发现队列（n=16,125）， 5个队列被指定为计算机复制队列（n=9,366）， 5个队列被指定为从头复制队列（n=8,378）。关联结果采用z分数加权meta分析合并。维生素D不足定义为25-OH D <75 nmol/L或<50 nmol/L。三个位点的变异在发现队列中达到全基因组显著性，并在复制队列中得到证实：4p12（在GC中，rs2282679的总体P=1.9 × 10-109）；11q12 (rs12785878的P=2.1 × 10-27，接近DHCR7)；rs10741657的P=3.3 × 10-20，靠近CYP2R1)。另外一个位点（20q13, CYP24A1）的变异在合并样本中具有全基因组显著性（rs6013897的P=6.0 × 10-10）。使用三个确认的变异构建基因型评分。基因型得分最高的四分之一组维生素D不足的几率高出2 ~ 2.5倍（P≤1 × 10-26）。与胆固醇合成（DHCR7）、羟化（CYP2R1、CYP24A1）和维生素D转运（GC）相关的基因附近的变异影响维生素D的状态。这些基因座的遗传变异表明，欧洲血统的人维生素D缺乏的风险显著增加。
Vitamin D is crucial for maintaining musculoskeletal health. Recently, vitamin D insufficiency has been linked to a number of extraskeletal disorders, including diabetes, cancer, and cardiovascular disease. Determinants of circulating 25-hydroxyvitamin D (25-OH D) include sun exposure and dietary intake, but its high heritability suggests that genetic determinants may also play a role. We performed a genome-wide association study of 25-OH D among ∼30,000 individuals of European descent from 15 cohorts. Five cohorts were designated as discovery cohorts (n=16,125), five as in silico replication cohorts (n=9,366), and five as de novo replication cohorts (n=8,378). Association results were combined using z-score-weighted meta-analysis. Vitamin D insufficiency was defined as 25-OH D <75 nmol/L or <50 nmol/L. Variants at three loci reached genome-wide significance in the discovery cohorts, and were confirmed in the replication cohorts: 4p12 (overall P=1.9 × 10-109 for rs2282679, in GC); 11q12 (P=2.1 × 10-27 for rs12785878, near DHCR7); 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). A genotype score was constructed using the three confirmed variants. Those in the top quartile of genotype scores had 2- to 2.5-fold elevated odds of vitamin D insufficiency (P≤1 × 10-26). Variants near genes involved in cholesterol synthesis (DHCR7), hydroxylation (CYP2R1, CYP24A1), and vitamin D transport (GC) influence vitamin D status. Genetic variation at these loci identifies individuals of European descent who have substantially elevated risk of vitamin D insufficiency.