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- Title
The Contribution of Deleterious Rare Alleles in ENPP1 and Osteomalacia Causative Genes to Atypical Femoral Fracture.
- Authors
Hiroshi Furukawa; Shomi Oka; Naoki Kondo; Yasuaki Nakagawa; Naofumi Shiota; Kenji Kumagai; Keiji Ando; Tsutao Takeshita; Takenori Oda; Yoshinori Takahashi; Kazutaka Izawa; Yoichi Iwasaki; Kazuhiro Hasegawa; Hiroshi Arino; Takeshi Minamizaki; Norie Yoshikawa; Shinjiro Takata; Yasuo Yoshihara; Shigeto Tohma
- Abstract
Context: Atypical femoral fractures (AFFs) are very rare atraumatic or mild trauma fractures in the subtrochanteric region or femoral shaft. Some unique genetic variants in Asian populations might confer susceptibility to AFF, since the incidence of AFFs is higher in Asian populations. Objective: Because rare variants have been found to be causative in some diseases and the roles of osteomalacia causative genes have not been reported, we investigated rare variants in genes causing abnormal mineralization. Methods: Exome sequencing was performed to detect variants in gene coding and boundary regions, and the frequencies of deleterious rare alleles were compared between Japanese patients with AFF (n = 42) and controls of the 4.7KJPN panel of Tohoku Medical Megabank by whole genome sequencing (n = 4773). Results: The frequency of the deleterious rare allele of ENPP1 was significantly increased in AFF (P = .0012, corrected P [Pc] = .0155, OR 4.73, 95% CI 2.15-10.40). In multigene panel analysis, the frequencies of deleterious rare alleles of candidate genes were increased in AFF (P = .0025, OR 2.72, 95% CI 1.49-4.93). Principal component analysis of bone metabolism markers identified a subgroup of patients with AFF with higher frequencies of deleterious rare alleles in ENPP1 (P = 4.69 × 10–5, Pc = .0006, OR 8.47, 95% CI 3.76-19.09) and the candidate genes (P = 1.08 × 10–5, OR 5.21, 95% CI 2.76-9.86). AFF is associated with genes including ENPP1 that cause abnormal mineralization, suggesting that osteomalacia is an underlying condition predisposing to AFF and that higher incident rates of AFFs in Asian populations might be explained by the genetic risk factors including ENPP1
- Subjects
OSTEOMALACIA; FEMORAL fractures; ALLELES
- Publication
Journal of Clinical Endocrinology & Metabolism, 2022, Vol 107, Issue 5, pe1890
- ISSN
0021-972X
- Publication type
Article
- DOI
10.1210/clinem/dgac022