{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T06:55:59Z","timestamp":1768200959588,"version":"3.49.0"},"reference-count":33,"publisher":"The Endocrine Society","issue":"5","license":[{"start":{"date-parts":[[2022,1,17]],"date-time":"2022-01-17T00:00:00Z","timestamp":1642377600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"National Hospital Organization"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,4,19]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Context<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>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\u2005=\u200542) and controls of the 4.7KJPN panel of Tohoku Medical Megabank by whole genome sequencing (n\u2005=\u20054773).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The frequency of the deleterious rare allele of ENPP1 was significantly increased in AFF (P\u2005=\u2005.0012, corrected P [Pc]\u2005=\u2005.0155, 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\u2005=\u2005.0025, 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\u2005=\u20054.69 \u00d7 10\u20135, Pc\u2005=\u2005.0006, OR 8.47, 95% CI 3.76-19.09) and the candidate genes (P\u2005=\u20051.08 \u00d7 10\u20135, OR 5.21, 95% CI 2.76-9.86).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1210\/clinem\/dgac022","type":"journal-article","created":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T00:54:58Z","timestamp":1642467298000},"page":"e1890-e1898","source":"Crossref","is-referenced-by-count":7,"title":["The Contribution of Deleterious Rare Alleles in ENPP1 and Osteomalacia Causative Genes to Atypical Femoral Fracture"],"prefix":"10.1210","volume":"107","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1353-8056","authenticated-orcid":false,"given":"Hiroshi","family":"Furukawa","sequence":"first","affiliation":[{"name":"Department of Rheumatology, National Hospital Organization Tokyo National Hospital, Kiyose, 204-8585Japan"},{"name":"Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Minami-ku, Sagamihara, 252-0392Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shomi","family":"Oka","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, National Hospital Organization Tokyo National Hospital, Kiyose, 204-8585Japan"},{"name":"Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara National Hospital, Minami-ku, Sagamihara, 252-0392Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoki","family":"Kondo","sequence":"additional","affiliation":[{"name":"Division of Orthopedic Surgery, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Chuo-ku, Niigata, 951-8510Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yasuaki","family":"Nakagawa","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, National Hospital Organization Kyoto Medical Center, Fushimi-ku, Kyoto, 612-8555, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naofumi","family":"Shiota","sequence":"additional","affiliation":[{"name":"Department of Orthopedics\/Rehabilitation, National Hospital Organization Okayama Medical Center, Kita-ku, Okayama, 701-1192, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Kumagai","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, National Hospital Organization Nagasaki Medical Center, Omura, 856-8562, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Keiji","family":"Ando","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, National Hospital Organization Utano National Hospital, Ukyo-ku, Kyoto, 616-8255Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tsutao","family":"Takeshita","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, National Hospital Organization Beppu Medical Center, Beppu, 874-0011, 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