Department of Medicine, Research Centre of Heart, Brain, Hormone & Healthy Aging, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Am J Hum Genet. 2010 Feb 12;86(2):229-39. doi: 10.1016/j.ajhg.2009.12.014. Epub 2010 Jan 21.
Bone mineral density (BMD), a diagnostic parameter for osteoporosis and a clinical predictor of fracture, is a polygenic trait with high heritability. To identify genetic variants that influence BMD in different ethnic groups, we performed a genome-wide association study (GWAS) on 800 unrelated Southern Chinese women with extreme BMD and carried out follow-up replication studies in six independent study populations of European descent and Asian populations including 18,098 subjects. In the meta-analysis, rs2273061 of the Jagged1 (JAG1) gene was associated with high BMD (p = 5.27 x 10(-8) for lumbar spine [LS] and p = 4.15 x 10(-5) for femoral neck [FN], n = 18,898). This SNP was further found to be associated with the low risk of osteoporotic fracture (p = 0.009, OR = 0.7, 95% CI 0.57-0.93, n = 1881). Region-wide and haplotype analysis showed that the strongest association evidence was from the linkage disequilibrium block 5, which included rs2273061 of the JAG1 gene (p = 8.52 x 10(-9) for LS and 3.47 x 10(-5) at FN). To assess the function of identified variants, an electrophoretic mobility shift assay demonstrated the binding of c-Myc to the "G" but not "A" allele of rs2273061. A mRNA expression study in both human bone-derived cells and peripheral blood mononuclear cells confirmed association of the high BMD-related allele G of rs2273061 with higher JAG1 expression. Our results identify the JAG1 gene as a candidate for BMD regulation in different ethnic groups, and it is a potential key factor for fracture pathogenesis.
骨密度（BMD）是骨质疏松症的诊断参数，也是骨折的临床预测指标，是一种具有高度遗传性的多基因特征。为了鉴定不同种族群体中影响 BMD 的遗传变异，我们对 800 名无亲缘关系的南方汉族女性进行了全基因组关联研究（GWAS），并对包括欧洲血统和亚洲血统的六个独立研究人群的 18098 名受试者进行了后续的复制研究。在荟萃分析中，Jagged1（JAG1）基因的 rs2273061 与高 BMD 相关（腰椎 [LS] 的 p = 5.27 x 10(-8)，股骨颈 [FN] 的 p = 4.15 x 10(-5)，n = 18898）。该 SNP 进一步被发现与骨质疏松性骨折的低风险相关（p = 0.009，OR = 0.7，95%CI 0.57-0.93，n = 1881）。全区域和单倍型分析表明，最强的关联证据来自包含 JAG1 基因的 rs2273061 的连锁不平衡块 5（LS 的 p = 8.52 x 10(-9)，FN 的 p = 3.47 x 10(-5)）。为了评估鉴定出的变异体的功能，电泳迁移率变动分析显示 c-Myc 与 rs2273061 的“G”而不是“A”等位基因结合。在人源性骨源性细胞和外周血单核细胞中的 mRNA 表达研究证实，与高 BMD 相关的 rs2273061 的 G 等位基因与更高的 JAG1 表达相关。我们的研究结果将 JAG1 基因确定为不同种族群体中 BMD 调节的候选基因，是骨折发病机制的一个潜在关键因素。
