Nguyen Tuan V, Center Jacqueline R, Eisman John A
Bone and Mineral Research Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
Curr Opin Endocrinol Diabetes Obes. 2008 Dec;15(6):481-8. doi: 10.1097/MED.0b013e32831a46be.
Description of recent progress in genetics and pharmacogenetics of osteoporosis.
Osteoporosis and its consequence of fragility fracture are characterized by highly complex phenotypes, which include bone mineral density, bone strength, bone turnover markers, and nonskeletal traits. Recent developments in the genome-wide studies using high-throughput single-nucleotide polymorphisms have yielded reliable findings. Four genome-wide studies have identified 40 single-nucleotide polymorphisms in various chromosomes that were modestly associated with either bone mineral density or fracture risk. Clinical response, including adverse reactions, to antiosteoporosis therapy (such as bisphosphonates and selective estrogen receptor modulators) is highly variable among treated individuals. Candidate gene studies have found that common polymorphic variations within the collagen I alpha 1 and vitamin D receptor genes were associated with variability in response to antiosteoporosis treatment. Moreover, a recent genome-wide study identified four single-nucleotide polymorphisms that were associated with bisphosphonate-related osteonecrosis of the jaw with relative risk being between 10 and 13.
The evaluation of osteoporosis and fracture risk is moving from a risk stratification approach to a more individualized approach, in which an individual's absolute risk of fracture is evaluable as a constellation of the individual's environmental exposure and genetic makeup. Therefore, the identification of gene variants that are associated with osteoporosis phenotypes or response to therapy can eventually help individualize the prognosis, treatment and prevention of fracture and its adverse outcomes.
描述骨质疏松症遗传学和药物遗传学的最新进展。
骨质疏松症及其脆性骨折后果具有高度复杂的表型，包括骨矿物质密度、骨强度、骨转换标志物和非骨骼特征。使用高通量单核苷酸多态性进行的全基因组研究取得了可靠成果。四项全基因组研究已在不同染色体上鉴定出40个单核苷酸多态性，这些多态性与骨矿物质密度或骨折风险存在适度关联。抗骨质疏松治疗（如双膦酸盐和选择性雌激素受体调节剂）的临床反应，包括不良反应，在接受治疗的个体中差异很大。候选基因研究发现，I型胶原蛋白α1和维生素D受体基因内的常见多态性变异与抗骨质疏松治疗反应的变异性有关。此外，最近一项全基因组研究鉴定出四个与双膦酸盐相关颌骨坏死相关的单核苷酸多态性，相对风险在10至13之间。
骨质疏松症和骨折风险评估正从风险分层方法转向更个体化的方法，即个体骨折的绝对风险可作为个体环境暴露和基因组成的综合评估。因此，识别与骨质疏松症表型或治疗反应相关的基因变异最终有助于实现骨折及其不良后果的预后、治疗和预防个体化。
