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Am J Hum Genet. 2010 Feb 12;86(2):229-39. doi: 10.1016/j.ajhg.2009.12.014. Epub 2010 Jan 21.

Association of JAG1 with bone mineral density and osteoporotic fractures: a genome-wide association study and follow-up replication studies.

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  • 1Department of Medicine, Research Centre of Heart, Brain, Hormone & Healthy Aging, Faculty of Medicine, The University of Hong Kong, Hong Kong, China. awckung@hkucc.hku.hk

Abstract

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.

Copyright (c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

PMID:
20096396
[PubMed - indexed for MEDLINE]
PMCID:
PMC2820171
Free PMC Article

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