Williams F M K, Spector T D
Twin Research and Genetic Epidemiology Unit, St Thomas' Hospital, London, UK.
J Musculoskelet Neuronal Interact. 2006 Jan-Mar;6(1):27-35.
It has been known for over 20 years that osteoporosis is highly influenced by genetic factors. Bone mineral density (BMD) has also been shown to be highly heritable. Other known risk factors for osteoporotic fractures such as reduced bone quality, femoral neck geometry and bone turnover are now also known to be heritable. Susceptibility to osteoporosis is mediated, in all likelihood, by multiple genes each having small effect. Different approaches are being used currently to identify the many genes responsible. These include linkage studies in man and experimental animals as well as candidate gene studies and alterations in gene expression. Linkage studies have identified multiple quantitative trait loci (QTL) for regulation of BMD and, with twin studies, have indicated that the effects of these loci are partly site-dependent and sex-specific. On the whole, the genes responsible for BMD regulation at these QTL have not yet been isolated. Most studies have used the candidate gene approach. The vitamin D receptor gene (VDR), the collagen type I alpha 1 gene (COLIA1) and estrogen receptor gene (ER) alpha have been most widely investigated and found to play a role in regulating BMD, but the effects are modest and together probably account for less than 5% of the heritable contribution to BMD. Genes may vary in their influence of particular intermediate phenotypes, and we now know that not all genes influencing BMD will be important in fracture. In addition, the study of other diseases such as osteoarthritis and metabolic bone syndromes may prove fruitful in highlighting genes which overlap to osteoporosis as well. As large scale genetic testing becomes more cost-effective, recent findings have illustrated the potential of novel approaches. These include combining large multi-national populations for candidate gene analysis, meta-analyses, DNA pooling studies and gene expression studies.
二十多年来，人们已经知道骨质疏松症受遗传因素的影响很大。骨矿物质密度（BMD）也已被证明具有高度遗传性。现在还知道，骨质疏松性骨折的其他已知风险因素，如骨质下降、股骨颈几何形状和骨转换，也是可遗传的。骨质疏松症的易感性很可能是由多个效应较小的基因介导的。目前正在采用不同的方法来识别众多相关基因。这些方法包括在人类和实验动物中进行连锁研究，以及候选基因研究和基因表达改变研究。连锁研究已经确定了多个调节骨矿物质密度的数量性状位点（QTL），并且通过双胞胎研究表明，这些位点的作用部分取决于部位和性别。总体而言，在这些QTL处负责调节骨矿物质密度的基因尚未被分离出来。大多数研究采用了候选基因方法。维生素D受体基因（VDR）、I型胶原蛋白α1基因（COLIA1）和雌激素受体基因（ER）α已经得到了最广泛的研究，并发现它们在调节骨矿物质密度方面发挥作用，但作用较小，可能总共只占骨矿物质密度遗传贡献的5%以下。基因对特定中间表型的影响可能各不相同，我们现在知道，并非所有影响骨矿物质密度的基因在骨折中都很重要。此外，对骨关节炎和代谢性骨综合征等其他疾病的研究，可能也会在突出与骨质疏松症重叠的基因方面取得成果。随着大规模基因检测变得更具成本效益，最近的研究结果已经说明了新方法的潜力。这些方法包括将大型跨国人群组合起来进行候选基因分析、荟萃分析、DNA池化研究和基因表达研究。
