Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands.
Department of Medical Sciences, Uppsala University Hospital, Uppsala 75185, Sweden.
J Bone Miner Res. 2024 Sep 2;39(9):1315-1326. doi: 10.1093/jbmr/zjae122.
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.
几项针对非典型股骨骨折（AFF）的小型遗传关联研究尚未得到结果复制。我们使用外显子组测序（WES）在更大的一组无关 AFF 病例中评估了先前与 AFF 相关的新基因。我们对 139 例欧洲 AFF 病例和 196 例与双膦酸盐使用相匹配的对照进行了基于基因的关联分析。我们使用候选基因和无假设方法测试了所有罕见的、改变蛋白质的变异。在后一种方法中，对与 AFF 有提示性关联的基因（未校正的 p 值<.01）在瑞典全基因组测序复制研究中进行了测试，并在 46 例非欧洲病例中进行了评估。在候选基因分析中，PLOD2 显示出提示性信号。无假设方法揭示了 10 个暂定关联，其中 XRN2、SORD 和 PL0D2 最有可能成为 AFF 的候选基因。XRN2 和 PL0D2 在复制分析中表现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 3 个 SNP 与先前在 AFF 全基因组关联研究中报道的 SNP 存在连锁不平衡（R2≥0.2）。根据携带 PL0D2 和 SORD 变异的携带者在亚洲与欧洲病例中的比例较高。虽然我们没有确定富含破坏性变异的基因，但我们发现了 XRN2、PL0D2 和 SORD 作用的提示性证据，这需要进一步研究。我们的研究结果表明，导致 AFF 的遗传因素在 AFF 病例中并不广泛共享。该研究为未来更大的 AFF 遗传研究提供了一个起点。
