PDF(Pubmed)
Abstract：
Several small genetic association studies have been conducted for atypical femur fracture (AFF) without replication of results. We assessed previously implicated and novel genes associated with AFFs in a larger set of unrelated AFF cases using whole exome sequencing (WES). We performed gene-based association analysis on 139 European AFF cases and 196 controls matched for bisphosphonate use. We tested all rare, protein-altering variants using both candidate gene and hypothesis-free approaches. In the latter, genes suggestively associated with AFFs (uncorrected p-values <.01) were investigated in a Swedish whole-genome sequencing replication study and assessed in 46 non-European cases. In the candidate gene analysis, PLOD2 showed a suggestive signal. The hypothesis-free approach revealed 10 tentative associations, with XRN2, SORD, and PLOD2 being the most likely candidates for AFF. XRN2 and PLOD2 showed consistent direction of effect estimates in the replication analysis, albeit not statistically significant. Three SNPs associated with SORD expression according to the GTEx portal were in linkage disequilibrium (R2 ≥ 0.2) with an SNP previously reported in a genome-wide association study of AFF. The prevalence of carriers of variants for both PLOD2 and SORD was higher in Asian versus European cases. While we did not identify genes enriched for damaging variants, we found suggestive evidence of a role for XRN2, PLOD2, and SORD, which requires further investigation. Our findings indicate that genetic factors responsible for AFFs are not widely shared among AFF cases. The study provides a stepping-stone for future larger genetic studies of AFF.
We investigated the genetic factors contributing to atypical femur fractures (AFF), which are rare and unusual fractures in the thigh bone. These fractures are related to the use of bisphosphonates (BP), which are prescribed to prevent fractures caused by osteoporosis. Previous studies suggested potential genetic links, but their findings were not confirmed in larger groups. To address this, we analyzed genetic data from 139 European individuals with AFF and 196 individuals without AFF, all of whom used BP, using a genetic technique called whole exome sequencing. Our results suggested three genes—XRN2, SORD, and PLOD2—might be linked to AFF, although the evidence was not conclusive. Importantly, our findings suggest that AFF may be caused by different genes in different individuals. A much larger sample size is now needed to fully understand the genetic architecture of AFF. These findings may guide future research into the genetic causes of AFF.
We investigated the genetic factors contributing to atypical femur fractures (AFF), which are rare and unusual fractures in the thigh bone. These fractures are related to the use of bisphosphonates (BP), which are prescribed to prevent fractures caused by osteoporosis. Previous studies suggested potential genetic links, but their findings were not confirmed in larger groups. To address this, we analyzed genetic data from 139 European individuals with AFF and 196 individuals without AFF, all of whom used BP, using a genetic technique called whole exome sequencing. Our results suggested three genes—XRN2, SORD, and PLOD2—might be linked to AFF, although the evidence was not conclusive. Importantly, our findings suggest that AFF may be caused by different genes in different individuals. A much larger sample size is now needed to fully understand the genetic architecture of AFF. These findings may guide future research into the genetic causes of AFF.
摘要：
背景：已经对非典型股骨骨折（AFF）进行了一些小型遗传关联研究，但结果没有重复。我们使用全外显子组测序（WES）在更大的一组无关的AFF病例中评估了先前与AFF相关的新基因。
方法：我们对139例欧洲AFF病例和196例对照进行了基于基因的关联分析。我们测试了所有罕见的，使用候选基因和无假设方法的蛋白质改变变体。在后者中,在瑞典全基因组测序复制研究中研究了暗示与AFF相关的基因（未校正P值<0.01），并在46例非欧洲病例中进行了评估。
结果：在候选基因分析中，PLOD2显示提示信号。无假设方法揭示了10种试探性关联，使用XRN2，SORD，PLOD2是AFF最有可能的候选人。XRN2和PLOD2在复制分析中显示出一致的效应估计方向，尽管没有统计学意义。根据GTEx门户，与SORD表达相关的三个SNP，与先前在AFF的全基因组关联研究中报道的SNP处于连锁不平衡状态（R2≥0.2）。在亚洲病例与欧洲病例中，PLOD2和SORD的变异携带者的患病率较高。
结论：虽然我们没有发现富含破坏性变异的基因，我们发现了XRN2、PLOD2和SORD发挥作用的暗示性证据，这需要进一步调查。我们的发现表明，导致AFF的遗传因素在AFF病例中并未广泛共享。该研究为未来AFF的更大遗传研究提供了垫脚石。
我们调查了导致非典型股骨骨折（AFF）的遗传因素，这些骨折与双膦酸盐的使用有关，用于预防骨质疏松症引起的骨折。以前的研究表明潜在的遗传联系，但他们的发现没有在更大的群体中得到证实。为了解决这个问题，我们分析了139个有AFF的欧洲个体和196个没有AFF的个体的遗传数据，所有人都使用双膦酸盐，使用称为全外显子组测序（WES）的遗传技术。我们的结果表明三个基因-XRN2，SORD，和PLOD2-可能链接到AFF，虽然证据确凿.重要的是,我们的研究结果表明，AFF可能是由不同个体的不同基因引起的。现在需要更大的样本量来充分了解AFF的遗传结构。这些发现可能会指导未来对AFF遗传原因的研究。
方法：我们对139例欧洲AFF病例和196例对照进行了基于基因的关联分析。我们测试了所有罕见的，使用候选基因和无假设方法的蛋白质改变变体。在后者中,在瑞典全基因组测序复制研究中研究了暗示与AFF相关的基因（未校正P值<0.01），并在46例非欧洲病例中进行了评估。
结果：在候选基因分析中，PLOD2显示提示信号。无假设方法揭示了10种试探性关联，使用XRN2，SORD，PLOD2是AFF最有可能的候选人。XRN2和PLOD2在复制分析中显示出一致的效应估计方向，尽管没有统计学意义。根据GTEx门户，与SORD表达相关的三个SNP，与先前在AFF的全基因组关联研究中报道的SNP处于连锁不平衡状态（R2≥0.2）。在亚洲病例与欧洲病例中，PLOD2和SORD的变异携带者的患病率较高。
结论：虽然我们没有发现富含破坏性变异的基因，我们发现了XRN2、PLOD2和SORD发挥作用的暗示性证据，这需要进一步调查。我们的发现表明，导致AFF的遗传因素在AFF病例中并未广泛共享。该研究为未来AFF的更大遗传研究提供了垫脚石。
我们调查了导致非典型股骨骨折（AFF）的遗传因素，这些骨折与双膦酸盐的使用有关，用于预防骨质疏松症引起的骨折。以前的研究表明潜在的遗传联系，但他们的发现没有在更大的群体中得到证实。为了解决这个问题，我们分析了139个有AFF的欧洲个体和196个没有AFF的个体的遗传数据，所有人都使用双膦酸盐，使用称为全外显子组测序（WES）的遗传技术。我们的结果表明三个基因-XRN2，SORD，和PLOD2-可能链接到AFF，虽然证据确凿.重要的是,我们的研究结果表明，AFF可能是由不同个体的不同基因引起的。现在需要更大的样本量来充分了解AFF的遗传结构。这些发现可能会指导未来对AFF遗传原因的研究。
