Hegarty Kevin G, Drummond Frances J, Daly Mary, Shanahan Fergus, Molloy Michael G
Department of Medicine, University College Cork, Cork, Ireland.
Department of Epidemiology and Public Health, University College Cork, Cork, Ireland.
J Bone Miner Metab. 2018 Mar;36(2):189-199. doi: 10.1007/s00774-017-0823-x. Epub 2017 Mar 14.
Gaining an understanding of factors contributing to bone quality is key to the development of effective preventative treatments for osteoporosis and reduction in osteoporotic fractures. Oestrogen is a strong regulator of bone remodelling which maintains skeletal structural integrity. The growth regulation by oestrogen in breast cancer 1 (GREB1) gene, with an as yet undefined function, is an early response gene in the oestrogen-regulated pathway. Suggestive evidence of linkage with bone mineral density (BMD) variation has been reported with D2S168, located telomeric of GREB1. The aim of this study was to determine if genetic variation within GREB1 was associated with BMD variation at two sites with high fracture rates-the lumbar spine (LS) and the femoral neck (FN). Informative GREB1 single-nucleotide polymorphisms (SNPs) (n = 12) were selected for genotyping and tested for association in a family-based dataset (n = 508 individuals from 229 families). Significantly associated SNPs were tested further in a postmenopausal dataset from the same geographic region (n = 477 individuals). One intronic SNP, rs5020877, was significantly associated with LS and FN BMD in the family-based dataset (P ≤ 0.005). The association was not observed in the postmenopausal dataset (P > 0.017); however, rs10929757 was significantly associated with FN BMD (P = 0.006). Markers, rs5020877 and rs10929757, were constituent SNPs in one GREB1 linkage disequilibrium block, although not historically correlated (r = 0.07). Our findings suggest that GREB1 is a novel gene target for osteoporosis genetics and needs to be investigated further.
了解影响骨质量的因素是开发有效的骨质疏松症预防治疗方法和减少骨质疏松性骨折的关键。雌激素是维持骨骼结构完整性的骨重塑的强调节剂。雌激素调节的乳腺癌1（GREB1）基因的生长调节功能尚未明确，是雌激素调节途径中的早期反应基因。据报道，位于GREB1端粒的D2S168与骨密度（BMD）变化存在关联的暗示性证据。本研究的目的是确定GREB1基因内的遗传变异是否与两个骨折率高的部位——腰椎（LS）和股骨颈（FN）的BMD变化相关。选择了12个信息丰富的GREB1单核苷酸多态性（SNP）进行基因分型，并在一个基于家系的数据集（来自229个家庭的508名个体）中测试其关联性。在来自同一地理区域的绝经后数据集（477名个体）中对显著相关的SNP进行了进一步测试。一个内含子SNP，rs5020877，在基于家系的数据集与LS和FN的BMD显著相关（P≤0.005）。在绝经后数据集中未观察到这种关联（P>0.017）；然而，rs10929757与FN的BMD显著相关（P = 0.006）。标记rs5020877和rs10929757是一个GREB1连锁不平衡区域的组成SNP，尽管历史上不相关（r = 0.07）。我们的研究结果表明，GREB1是骨质疏松症遗传学的一个新的基因靶点，需要进一步研究。
