title: Exon array analysis reveals genetic heterogeneity in atypical femoral fractures. A pilot study.
abstract: 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.
authors.affiliation: Service of Traumatology and Orthopedic Surgery, Hospital U.M. Valdecilla, University of Cantabria, Santander, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Pérez-Núñez
authors.affiliation: Service of Internal Medicine, Hospital U. Río Hortega, University of Valladolid, RETICEF, Valladolid, Spain.
authors.forename: José L
authors.initials: JL
authors.lastname: Pérez-Castrillón
authors.affiliation: Unit of Legal Medicine, IDIVAL, University of Cantabria, Santander, Spain.
authors.forename: María T
authors.initials: MT
authors.lastname: Zarrabeitia
authors.affiliation: Service of Internal Medicine, Hospital U.M. Valdecilla, IDIVAL, University of Cantabria, RETICEF, Av Valdecilla sn, 39008, Santander, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: García-Ibarbia
authors.affiliation: Group of Genomic Medicine, Hospital U. Santiago, University of Santiago, CIBERER, Santiago de Compostela, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Martínez-Calvo
authors.affiliation: Service of Internal Medicine, Hospital U.M. Valdecilla, IDIVAL, University of Cantabria, RETICEF, Av Valdecilla sn, 39008, Santander, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Olmos
authors.affiliation: Service of Internal Medicine, Hospital U. Río Hortega, University of Valladolid, RETICEF, Valladolid, Spain.
authors.forename: Laisa S
authors.initials: LS
authors.lastname: Briongos
authors.affiliation: Service of Internal Medicine, Hospital U.M. Valdecilla, IDIVAL, University of Cantabria, RETICEF, Av Valdecilla sn, 39008, Santander, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Riancho
authors.affiliation: Service of Internal Medicine, Hospital U.M. Valdecilla, IDIVAL, University of Cantabria, RETICEF, Av Valdecilla sn, 39008, Santander, Spain.
authors.forename: Victoria
authors.initials: V
authors.lastname: Camarero
authors.affiliation: Orthopedic Department, Hospital Verge de Meritxell, Escaldes-Engordany, Andorra.
authors.forename: Josep M
authors.initials: JM
authors.lastname: Muñoz Vives
authors.affiliation: Group of Genomic Medicine, Hospital U. Santiago, University of Santiago, CIBERER, Santiago de Compostela, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Cruz
authors.affiliation: Service of Internal Medicine, Hospital U.M. Valdecilla, IDIVAL, University of Cantabria, RETICEF, Av Valdecilla sn, 39008, Santander, Spain. rianchoj@unican.es.
authors.forename: José A
authors.initials: JA
authors.lastname: Riancho
mesh_terms: D000217:Acyltransferases / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D018740:Genetic Heterogeneity; D055106:Genome-Wide Association Study; D053823:Hedgehog Proteins / Q000235:genetics; D006620:Hip Fractures / Q000235:genetics* / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D010024:Osteoporosis / Q000235:genetics*; D010865:Pilot Projects; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054387:Receptors, CXCR / Q000235:genetics
chemical_list: C501896:ACKR3 protein, human; D053823:Hedgehog Proteins; D054387:Receptors, CXCR; D000217:Acyltransferases; C105599:HHAT protein, human
keywords: Atypical fractures; Genetic association study; Hedgehog; Osteoporosis; Polymorphisms; Rare variants