Exon array analysis reveals genetic heterogeneity in atypical femoral fractures. A pilot study

Atraumatic subtrochanteric and diaphyseal (atypical) femoral fractures are a rare, but important adverse event in patients treated with potent anti-resortive agents. The mechanisms involved are unknown and particularly the association with genetic variants has not been explored. The aim of the study was to identify rare genetic variants that could be associated with the occurrence of these fractures. We performed a genome-wide analysis of up to 300,000 variants, mainly distributed in gene coding regions, in 13 patients with atypical femoral fractures and 268 control women, either healthy or with osteoporosis. Twenty one loci were more frequent in the fracture group, with a nominal p value between 1 × 10(-6) and 2.5 × 10(-3). Most patients accumulated two or more allelic variants, and consequently the number of risk variants was markedly different between patients and controls (p = 2.6 × 10(-22)). The results of this pilot study suggest that these fractures are polygenic and are associated with the accumulation of changes in the coding regions of several genes.