Alam Imranul, Padgett Leah R, Ichikawa Shoji, Alkhouli Mohammed, Koller Daniel L, Lai Dongbing, Peacock Munro, Xuei Xiaoling, Foroud Tatiana, Edenberg Howard J, Econs Michael J
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.
Bone. 2014 Jul;64:166-72. doi: 10.1016/j.bone.2014.04.013. Epub 2014 Apr 18.
Osteoporosis is a common complex disorder with reduced bone mineral density (BMD) and increased susceptibility to fracture. Peak BMD is one of the primary determinants of osteoporotic fracture risk, and is under substantial genetic control. Extracellular matrix, a major component of the bone, influences BMD by regulating mineral deposition and maintaining cellular activity. It contains several SIBLING family proteins, null mutations of which cause mineralization defects in humans. In this study, we tested 59 single-nucleotide polymorphisms (SNPs) located in the 5 SIBLING family genes (DSPP, DMP1, IBSP, MEPE and SPP1) for association with normal variation in peak BMD in healthy men and women. We measured femoral neck (FN) and lumbar spine (LS) areal BMD by dual energy x-ray absorptiometry (DXA) in 1692 premenopausal European-American women, 512 premenopausal African-American women and 715 European-American men. SNPs were tested for association with FN and LS-BMD in the 3 subsamples. In the European-American women, we observed association (p≤0.005) with LS-BMD for SNPs in DSPP, IBSP and MEPE, and for FN-BMD with SNPs in DMP1 and IBSP. Allele-specific regulation of gene expression (ASE) is an important mechanism in which an allele giving rise to modest influence in transcript abundance might result in a predisposition to disease. To identify whether there was ASE of SIBLING family genes at these SNPs, we examined 52 human bone samples obtained from the femoral neck during surgical hip replacement (27 female, 25 male; 44 European-American and 8 African-American). We observed unidirectional ASE for the IBSP gene, with lower expression of the G allele compared to the A allele for SNP rs17013181. Our data suggest that SNPs within the SIBLING genes may contribute to normal variation of peak BMD. Further studies are necessary to identify the functional variants and to determine the mechanisms underlying the differences in ASE and how these differences relate to the pathophysiology of osteoporosis.
骨质疏松症是一种常见的复杂疾病，其骨矿物质密度（BMD）降低，骨折易感性增加。峰值骨密度是骨质疏松性骨折风险的主要决定因素之一，且受大量基因控制。细胞外基质是骨骼的主要成分之一，通过调节矿物质沉积和维持细胞活性来影响骨密度。它包含几种SIBLING家族蛋白，其无效突变会导致人类矿化缺陷。在本研究中，我们检测了位于5个SIBLING家族基因（DSPP、DMP1、IBSP、MEPE和SPP1）中的59个单核苷酸多态性（SNP）与健康男性和女性峰值骨密度正常变异的关联性。我们通过双能X线吸收法（DXA）测量了1692名绝经前欧美女性、512名绝经前非裔美国女性和715名欧美男性的股骨颈（FN）和腰椎（LS）面积骨密度。对这3个亚组中的SNP与FN和LS-骨密度的关联性进行了检测。在欧美女性中，我们观察到DSPP、IBSP和MEPE中的SNP与LS-骨密度存在关联（p≤0.005），DMP1和IBSP中的SNP与FN-骨密度存在关联。等位基因特异性基因表达调控（ASE）是一种重要机制，其中一个对转录本丰度有适度影响的等位基因可能导致疾病易感性。为了确定这些SNP处SIBLING家族基因是否存在ASE，我们检查了52份在髋关节置换手术期间从股骨颈获取的人类骨样本（27名女性，25名男性；44名欧美人和8名非裔美国人）。我们观察到IBSP基因存在单向ASE，对于SNP rs17013181，G等位基因的表达低于A等位基因。我们的数据表明，SIBLING基因内的SNP可能促成峰值骨密度的正常变异。有必要进行进一步研究以确定功能变异体，并确定ASE差异的潜在机制以及这些差异与骨质疏松症病理生理学的关系。
