McCoy Thomas H, Fragomen Austin T, Hart Kamber L, Pellegrini Amelia M, Raskin Kevin A, Perlis Roy H
Center for Quantitative Health Massachusetts General Hospital and Harvard Medical School Boston MA USA.
Limb Lengthening and Complex Reconstruction Service Hospital for Special Surgery and Weill Cornell Medical College New York NY USA.
JBMR Plus. 2018 Jun 20;3(1):23-28. doi: 10.1002/jbm4.10063. eCollection 2019 Jan.
Nonunion is a clinically significant complication of fracture associated with worse outcomes, including increased pain, disability, and higher healthcare costs. The risk for nonunion is likely to be complex and multifactorial, and as such, the biology underlying such risk remains poorly understood. Genetic studies represent one approach to identify implicated biology for further investigation, but to date the lack of large cohorts for study has limited such efforts. We utilized the electronic health records of two large academic medical centers in Boston to identify individuals with fracture nonunion and control individuals with fracture but no evidence of nonunion. We conducted a genomewide association study among 1760 individuals of Northern European ancestry with upper or lower extremity fracture, including 131 with nonunion, to examine whether common variants were associated with nonunion in this cohort. In all, one locus in the Calcyon (CALY) gene exceeded a genomewide threshold for statistical significance ( = 1.95e-8), with eight additional loci associated with < 5e-7. Previously reported candidate genes were not supported by this analysis. Electronic health records should facilitate identification of common genetic variations associated with adverse orthopedic outcomes. The loci we identified in this small cohort require replication and further study to characterize mechanism of action, but represent a starting point for the investigation of genetic liability for this costly outcome.
骨不连是骨折的一种具有临床意义的并发症，与更差的预后相关，包括疼痛加剧、功能障碍以及更高的医疗费用。骨不连的风险可能很复杂且具有多因素性，因此，这种风险背后的生物学机制仍知之甚少。基因研究是识别相关生物学因素以供进一步研究的一种方法，但迄今为止，缺乏大规模研究队列限制了此类研究。我们利用波士顿两家大型学术医疗中心的电子健康记录，识别出骨不连患者以及有骨折但无骨不连证据的对照个体。我们在1760名具有北欧血统且有上肢或下肢骨折的个体中开展了一项全基因组关联研究，其中包括131名骨不连患者，以检验常见变异是否与该队列中的骨不连相关。总体而言，钙通道蛋白（CALY）基因中的一个位点超过了全基因组统计学显著性阈值（= 1.95e - 8），另有八个位点与之相关，其P值 < 5e - 7。该分析未支持先前报道的候选基因。电子健康记录应有助于识别与不良骨科预后相关的常见基因变异。我们在这个小队列中识别出的位点需要重复验证和进一步研究以明确其作用机制，但它们是对这种代价高昂的结果进行遗传易感性研究的一个起点。
