Styrkarsdottir Unnur, Halldorsson Bjarni V, Gretarsdottir Solveig, Gudbjartsson Daniel F, Walters G Bragi, Ingvarsson Thorvaldur, Jonsdottir Thorbjorg, Saemundsdottir Jona, Center Jacqueline R, Nguyen Tuan V, Bagger Yu, Gulcher Jeffrey R, Eisman John A, Christiansen Claus, Sigurdsson Gunnar, Kong Augustine, Thorsteinsdottir Unnur, Stefansson Kari
deCODE Genetics, Reykjavik, Iceland.
N Engl J Med. 2008 May 29;358(22):2355-65. doi: 10.1056/NEJMoa0801197. Epub 2008 Apr 29.
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.
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).
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, 1.2x10(-7) to 2.0x10(-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-kappaB 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-kappaB gene (RANK), and loci at 2p16 and 11p11.
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.
骨矿物质密度会影响晚年患骨质疏松症的风险，并且对评估骨折风险很有用。我们旨在识别与骨矿物质密度和骨折相关的序列变异。
我们对来自5861名冰岛受试者的数据（发现集）进行了数量性状分析，检测301,019个单核苷酸多态性（SNP）与髋部和腰椎骨矿物质密度之间的关联。然后，我们在冰岛、丹麦和澳大利亚受试者的复制集中（分别为4165名、2269名和1491名受试者）检测了32个位点的74个SNP（其中大多数在发现集中有牵连）之间的关联。
发现集中五个基因组区域的序列变异与骨矿物质密度显著相关，并在复制集中得到证实（合并P值为1.2×10^(-7)至2.0×10^(-21)）。三个区域靠近或位于先前已证明对骨生物学特性很重要的基因内：核因子κB受体激活剂配体基因（RANKL）（染色体位置，13q14）、骨保护素基因（OPG）（8q24）和雌激素受体1基因（ESR1）（6q25）。另外两个区域靠近含锌指和BTB结构域的40基因（ZBTB40）（1p36）和主要组织相容性复合体区域（6p21）。1p36、8q24和6p21位点也与骨质疏松性骨折相关，18q21上靠近核因子κB受体激活剂基因（RANK）的位点以及2p16和11p11上的位点也与骨质疏松性骨折相关。
我们发现了常见的序列变异，这些变异在三个欧洲裔人群中始终与骨矿物质密度和低创伤性骨折相关。尽管这些变异单独在预测个体风险方面对临床没有用处，但它们为骨质疏松症潜在的生化途径提供了见解。
