Limited Clinical Utility of a Genetic Risk Score for the Prediction of Fracture Risk in Elderly Subjects
Limited Clinical Utility of a Genetic Risk Score for the Prediction of Fracture Risk in Elderly Subjects
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DOI：
10.1002/jbmr.2314
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发表时间：
2015-01-01
影响因子：
6.2
通讯作者：
Ohlsson, Claes
中科院分区：
文献类型：
--
作者：
Eriksson, Joel;Evans, Daniel S.;Ohlsson, Claes
确定骨折风险最高的患者是很重要的。最近的一项大规模荟萃分析发现了63个与骨密度(BMD)相关的常染色体单核苷酸多态(SNPs)，其中16个也与骨折风险相关。基于这些发现，制定了两个遗传风险评分(GRS63和GRS16)。我们的目的是确定这些GRS在预测老年受试者的BMD、BMD变化和骨折风险方面的临床有效性。我们研究了两名男性(美国男性骨质疏松性骨折研究[MROS]美国，MROS瑞典)和一名女性(骨质疏松性骨折研究[SOF])老年受试者的大型前瞻性队列，观察骨密度、骨密度变化，以及放射和/或医学证实的骨折(8067名受试者，2185名非脊椎或脊椎骨折)。GRS63与BMD(3%的变异解释)相关，但与BMD变化无关。GRS63和GRS16均合并骨折。在BMD调整后，这些关联的影响大小显著减少。使用未加权的GRS63和未加权的GRS16与使用相应的加权风险分数发现的结果相似。当GRS被添加到基础模型(年龄、体重和身高)时，骨折的C-统计量(AUC)仅有轻微的改善，而当它们被添加到进一步调整BMD的模型中时，C-统计量没有发现显著的改善。将GRS添加到基础模型后，净重新分类的改进效果不大，在BMD调整的模型中，净重新分类效果显著减弱。GRS63与BMD相关，但与BMD变化无关，提示BMD的遗传决定因素与BMD变化的遗传决定因素不同。当BMD已知时，两种GRS在老年受试者中预测骨折的临床应用是有限的。(C)2014年美国骨与矿物研究学会。
It is important to identify the patients at highest risk of fractures. A recent large-scale meta-analysis identified 63 autosomal single-nucleotide polymorphisms (SNPs) associated with bone mineral density (BMD), of which 16 were also associated with fracture risk. Based on these findings, two genetic risk scores (GRS63 and GRS16) were developed. Our aim was to determine the clinical usefulness of these GRSs for the prediction of BMD, BMD change, and fracture risk in elderly subjects. We studied two male (Osteoporotic Fractures in Men Study [MrOS] US, MrOS Sweden) and one female (Study of Osteoporotic Fractures [SOF]) large prospective cohorts of older subjects, looking at BMD, BMD change, and radiographically and/or medically confirmed incident fractures (8067 subjects, 2185 incident nonvertebral or vertebral fractures). GRS63 was associated with BMD (3% of the variation explained) but not with BMD change. Both GRS63 and GRS16 were associated with fractures. After BMD adjustment, the effect sizes for these associations were substantially reduced. Similar results were found using an unweighted GRS63 and an unweighted GRS16 compared with those found using the corresponding weighted risk scores. Only minor improvements in C-statistics (AUC) for fractures were found when the GRSs were added to a base model (age, weight, and height), and no significant improvements in C-statistics were found when they were added to a model further adjusted for BMD. Net reclassification improvements with the addition of the GRSs to a base model were modest and substantially attenuated in BMD-adjusted models. GRS63 is associated with BMD, but not BMD change, suggesting that the genetic determinants of BMD differ from those of BMD change. When BMD is known, the clinical utility of the two GRSs for fracture prediction is limited in elderly subjects. (c) 2014 American Society for Bone and Mineral Research.