Department of Osteoporosis and Bone Diseases, Metabolic Bone Disease and Genetics Research Unit, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
J Bone Miner Res. 2012 Dec;27(12):2582-91. doi: 10.1002/jbmr.1711.
To identify the susceptibility genes for osteoporotic fracture in postmenopausal Chinese women, a two-stage case-control association study using joint analysis was conducted in 1046 patients with nontraumatic vertebra, hip, or distal radius fractures and 2303 healthy controls. First, 113 single-nucleotide polymorphisms (SNPs) in 16 potential osteoporosis candidate genes reported in recent genomewide association studies, meta-analyses studies, large-scale association studies, and functional studies were genotyped in a small-sample-size subgroup consisting of 541 patients with osteoporotic fractures and 554 healthy controls. Variants and haplotypes in SPTBN1, TNFRSF11B, CNR2, LRP4, and ESR1 that have been identified as being associated with osteoporotic fractures were further reanalyzed in the entire case-control group. We identified one SNP in TNFRSF11B (rs3102734), three SNPs in ESR1 (rs9397448, rs2234693, and rs1643821), two SNPs in LRP4 (rs17790156 and rs898604), and four SNPs in SPTBN1 (rs2971886, rs2941583, rs2941584, and rs12475342) were associated with all of the broadly defined osteoporotic fractures. The most significant polymorphism was rs3102734, with increased risk of osteoporotic fractures (odds ratio, 1.35; 95% confidence interval [CI], 1.17-1.55, Bonferroni p = 2.6 × 10(-4) ). Furthermore, rs3102734, rs2941584, rs12475342, rs9397448, rs2234693, and rs898604 exhibited significant allelic, genotypic, and/or haplotypic associations with vertebral fractures. SNPs rs12475342, rs9397448, and rs2234693 showed significant genotypic associations with hip fractures, whereas rs3102734, rs2073617, rs1643821, rs12475342, and rs2971886 exhibited significant genotypic and/or haplotypic associations with distal radius fractures. Accordingly, we suggest that in addition to the clinical risk factors, the variants in TNFRSF11B, SPTBN1, ESR1, and LRP4 are susceptibility genetic loci for osteoporotic fracture in postmenopausal Chinese women.
为了鉴定绝经后中国女性骨质疏松性骨折的易感基因，我们采用两阶段病例对照关联研究，联合分析了 1046 例非创伤性椎体、髋部或桡骨远端骨折患者和 2303 例健康对照者。首先，在由 541 例骨质疏松性骨折患者和 554 例健康对照者组成的小样本亚组中，对最近全基因组关联研究、荟萃分析研究、大型关联研究和功能研究中报道的 16 个潜在骨质疏松候选基因中的 113 个单核苷酸多态性（SNP）进行了基因分型。在整个病例对照组中，进一步重新分析了已确定与骨质疏松性骨折相关的 SPTBN1、TNFRSF11B、CNR2、LRP4 和 ESR1 中的变异和单倍型。我们鉴定出 TNFRSF11B 中的一个 SNP（rs3102734）、ESR1 中的三个 SNP（rs9397448、rs2234693 和 rs1643821）、LRP4 中的两个 SNP（rs17790156 和 rs898604）和 SPTBN1 中的四个 SNP（rs2971886、rs2941583、rs2941584 和 rs12475342）与所有广义定义的骨质疏松性骨折均相关。最显著的多态性是 rs3102734，其增加了骨质疏松性骨折的风险（比值比，1.35；95%置信区间[CI]，1.17-1.55，Bonferroni p = 2.6×10(-4)）。此外，rs3102734、rs2941584、rs12475342、rs9397448、rs2234693 和 rs898604 与椎体骨折的等位基因、基因型和/或单倍型均存在显著关联。rs12475342、rs9397448 和 rs2234693 与髋部骨折的基因型显著相关，而 rs3102734、rs2073617、rs1643821、rs12475342 和 rs2971886 与桡骨远端骨折的基因型和/或单倍型显著相关。因此，我们建议，除了临床危险因素外，TNFRSF11B、SPTBN1、ESR1 和 LRP4 中的变异也可能是绝经后中国女性骨质疏松性骨折的易感遗传位点。
