Multiple genetic loci for bone mineral density and fractures
Multiple genetic loci for bone mineral density and fractures
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DOI：
10.1056/nejmoa0801197
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发表时间：
2008-05-29
影响因子：
158.5
通讯作者：
Stefansson, Kari
中科院分区：
文献类型：
--
作者：
Styrkarsdottir, Unnur;Halldorsson, Bjarni V.;Stefansson, Kari
背景：骨矿物质密度影响老年骨质疏松症的风险，并有助于评估骨折的风险。我们的目的是确定与骨矿物质密度和fraction.Methods相关的序列变异：我们进行了一个定量性状分析的数据从5861冰岛主题（发现集），测试301,019单核苷酸多态性（SNP）和髋关节和腰椎骨矿物质密度之间的关联。然后，我们测试了74个SNP之间的关联，（其中大部分与发现集有关）在冰岛、丹麦和澳大利亚受试者的复制集中的32个基因座上（分别为4165、2269和1491名受试者）。发现组中5个基因组区域的序列变异与骨密度显著相关，并在重复组中得到证实（组合P值，1.2 x 10 - 7至2.0 x 10- 21）。三个区域接近或位于先前显示对骨生物学特性重要的基因内：核因子-（κ）B配体基因（RANKL）的受体激活剂（染色体位置，13 q14）、骨保护素基因（OPG）（8 q24）和雌激素受体1基因（ESR 1）（6 q25）。另外两个区域靠近含锌指和BTB结构域的40基因（ZBTB 40）（1 p36）和主要组织相容性复合体区域（6p 21）。1 p36、8 q24和6 p21基因座也与骨质疏松性骨折相关，靠近核因子-kappa B基因受体激活剂（RANK）的18 q21基因座以及2 p16和11 p11基因座也与骨质疏松性骨折相关。结论：我们发现了共同的序列变异，这些变异与三个欧洲血统人群的骨矿物质密度和低创伤骨折一致相关。虽然这些变异单独在临床上对预测个体的风险并不有用，但它们提供了对骨质疏松症潜在生化途径的深入了解。
Background: Bone mineral density influences the risk of osteoporosis later in life and is useful in the evaluation of the risk of fracture. We aimed to identify sequence variants associated with bone mineral density and fracture.Methods: We performed a quantitative trait analysis of data from 5861 Icelandic subjects (the discovery set), testing for an association between 301,019 single-nucleotide polymorphisms (SNPs) and bone mineral density of the hip and lumbar spine. We then tested for an association between 74 SNPs (most of which were implicated in the discovery set) at 32 loci in replication sets of Icelandic, Danish, and Australian subjects (4165, 2269, and 1491 subjects, respectively).Results: Sequence variants in five genomic regions were significantly associated with bone mineral density in the discovery set and were confirmed in the replication sets (combined P values, 1.2 x 10(-7) to 2.0 x 10-(21)). Three regions are close to or within genes previously shown to be important to the biologic characteristics of bone: the receptor activator of nuclear factor-(kappa)B ligand gene (RANKL) (chromosomal location, 13q14), the osteoprotegerin gene (OPG) (8q24), and the estrogen receptor 1 gene (ESR1) (6q25). The two other regions are close to the zinc finger and BTB domain containing 40 gene (ZBTB40) (1p36) and the major histocompatibility complex region (6p21). The 1p36, 8q24, and 6p21 loci were also associated with osteoporotic fractures, as were loci at 18q21, close to the receptor activator of the nuclear factor-kappa B gene (RANK), and loci at 2p16 and 11p11.Conclusions: We have discovered common sequence variants that are consistently associated with bone mineral density and with low-trauma fractures in three populations of European descent. Although these variants alone are not clinically useful in the prediction of risk to the individual person, they provide insight into the biochemical pathways underlying osteoporosis.