Risk of wrist fracture in women is heritable and is influenced by genes that are largely independent of those influencing BMD
Risk of wrist fracture in women is heritable and is influenced by genes that are largely independent of those influencing BMD
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DOI：
10.1359/jbmr.041015
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发表时间：
2005-01-01
影响因子：
6.2
通讯作者：
Spector, TD
中科院分区：
文献类型：
--
作者：
Andrew, T;Antioniades, L;Spector, TD
使用经典的双胞胎设计研究，我们估计女性手腕骨折的遗传贡献在统计学和临床意义上都是显著的。骨密度是高度可遗传的，但统计模型显示，这两个性状之间的共享基因很少重叠。研究发现遗传效应影响骨质疏松性骨折结果的证据相互矛盾，部分原因是在分析与年龄相关的“审查”结果时存在方法学问题。虽然通常认为骨折和低骨密度之间有共同的遗传病因，但事实并非如此。材料和方法：在一项6570名年龄在18 - 80岁之间的白人健康女性双胞胎志愿者研究中，我们确定并验证了220例非创伤性手腕骨折病例。通过使用Winbugs软件中实现的广义线性混合模型分析生存结果，我们估计了人群患病率、病例双胞胎一致性、腕部骨折（WF）易损性的遗传性以及控制年龄的WF遗传贡献。我们将前臂骨密度作为协变量纳入一些模型，以检验WFs和骨密度之间是否存在共同的遗传病因。结果：女性WFs患病率估计为3.3%，单卵双胞胎的病例一致性为0.28，异卵双胞胎的病例一致性为0.11。累加性多基因遗传率接近54%，通过分析WFs作为生存结果证实了显著的遗传病因。当骨密度作为一个协变量纳入生存分析模型时，遗传对WFs风险的影响程度几乎没有降低。结论：WFs的风险有重要的遗传贡献，但在大多数情况下，这些基因不太可能在低骨密度的发展中起直接的病因学作用。如果这些结果在其他部位得到证实，那么骨折和低骨密度将有其特定的遗传风险因素，而这两种特征之间不太可能共享。这具有重要的临床和研究意义。
Using a classical twin design study, we estimated the genetic contribution to liability of wrist fracture in women to be statistically and clinically significant. BMD is highly heritable, but statistical models showed very little overlap of shared genes between the two traits.Introduction: Studies have observed contradictory evidence for genetic effects influencing the outcome of osteoporotic fracture, in part because of the methodological problems involved in analyzing age-related "censored" outcomes. Although a shared genetic etiology is often assumed between fracture and low BMD, this has not been shown to be the case.Materials and Methods: In a study of 6570 white healthy female volunteer twins between 18 and 80 years of age, we identified and validated 220 nontraumatic wrist fracture cases. From this we estimated the population prevalence, case-wise twin concordance, heritability in liability to wrist fracture (WF), and the genetic contribution to WFs controlling for age by analyzing the survival outcome using generalized linear mixed models implemented in Winbugs software. We included forearm BMD as a co-variate in some of the models to test whether there is a shared genetic etiology between WFs and BMD.Results: The prevalence of WFs in women was estimated to be 3.3% with a case-wise concordance in monozygotic twins of 0.28 and 0.11 in dizygotic twins. The additive polygenic heritability in liability was similar to54%, and a significant genetic etiology was confirmed by analyzing WFs as a survival outcome. The magnitude of the genetic influence on risk of WFs reduced very little when BMD was included as a co-variate in the survival analysis model.Conclusions: There is an important genetic contribution to the risk of WFs, but for the most part, these genes are unlikely to play a direct etiological role in the development of low BMD. If these results are confirmed for other sites, fracture and low BMD will have their own specific genetic risk factors that are unlikely to be shared between the two traits. This has important clinical and research implications.