Scott J MacInnes1, Konstantinos Hatzikotoulas, Anne Marie Fenstad, Karan Shah, Lorraine Southam, Ioanna Tachmazidou, Geir Hallan, Hårvard Dale, Kalliope Panoutsopoulou, Ove Furnes, Eleftheria Zeggini, J Mark Wilkinson. 1. S. J. MacInnes, K. Shah, J. M. Wilkinson, Department of Oncology and Metabolism, University of Sheffield, The Medical School, Sheffield, UK K. Hatzikotoulas, I. Tachmazidou, K. Panoutsopoulou, E. Zeggini, Wellcome Trust Sanger Institute, Cambridge, UK A. M. Fenstad, H. Dale, The Norwegian Arthroplasty Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway L. Southam, Wellcome Trust Centre for Human Genetics, Oxford, UK G. Hallan, O. Furnes, Department of Clinical Medicine, Faculty of Medicine, University of Bergen, Bergen, Norway.
Abstract
BACKGROUND: Periprosthetic osteolysis resulting in aseptic loosening is a leading cause of THA revision. Individuals vary in their susceptibility to osteolysis and heritable factors may contribute to this variation. However, the overall contribution that such variation makes to osteolysis risk is unknown. QUESTIONS/PURPOSES: We conducted two genome-wide association studies to (1) identify genetic risk loci associated with susceptibility to osteolysis; and (2) identify genetic risk loci associated with time to prosthesis revision for osteolysis. METHODS: The Norway cohort comprised 2624 patients after THA recruited from the Norwegian Arthroplasty Registry, of whom 779 had undergone revision surgery for osteolysis. The UK cohort included 890 patients previously recruited from hospitals in the north of England, 317 who either had radiographic evidence of and/or had undergone revision surgery for osteolysis. All participants had received a fully cemented or hybrid THA using a small-diameter metal or ceramic-on-conventional polyethylene bearing. Osteolysis susceptibility case-control analyses and quantitative trait analyses for time to prosthesis revision (a proxy measure of the speed of osteolysis onset) in those patients with osteolysis were undertaken in each cohort separately after genome-wide genotyping. Finally, a meta-analysis of the two independent cohort association analysis results was undertaken. RESULTS: Genome-wide association analysis identified four independent suggestive genetic signals for osteolysis case-control status in the Norwegian cohort and 11 in the UK cohort (p ≤ 5 x 10). After meta-analysis, five independent genetic signals showed a suggestive association with osteolysis case-control status at p ≤ 5 x 10 with the strongest comprising 18 correlated variants on chromosome 7 (lead signal rs850092, p = 1.13 x 10). Genome-wide quantitative trait analysis in cases only showed a total of five and nine independent genetic signals for time to revision at p ≤ 5 x 10, respectively. After meta-analysis, 11 independent genetic signals showed suggestive evidence of an association with time to revision at p ≤ 5 x 10 with the largest association block comprising 174 correlated variants in chromosome 15 (lead signal rs10507055, p = 1.40 x 10). CONCLUSIONS: We explored the heritable biology of osteolysis at the whole genome level and identify several genetic loci that associate with susceptibility to osteolysis or with premature revision surgery. However, further studies are required to determine a causal association between the identified signals and osteolysis and their functional role in the disease. CLINICAL RELEVANCE: The identification of novel genetic risk loci for osteolysis enables new investigative avenues for clinical biomarker discovery and therapeutic intervention in this disease.
BACKGROUND: Periprosthetic osteolysis resulting in aseptic loosening is a leading cause of THA revision. Individuals vary in their susceptibility to osteolysis and heritable factors may contribute to this variation. However, the overall contribution that such variation makes to osteolysis risk is unknown. QUESTIONS/PURPOSES: We conducted two genome-wide association studies to (1) identify genetic risk loci associated with susceptibility to osteolysis; and (2) identify genetic risk loci associated with time to prosthesis revision for osteolysis. METHODS: The Norway cohort comprised 2624 patients after THA recruited from the Norwegian Arthroplasty Registry, of whom 779 had undergone revision surgery for osteolysis. The UK cohort included 890 patients previously recruited from hospitals in the north of England, 317 who either had radiographic evidence of and/or had undergone revision surgery for osteolysis. All participants had received a fully cemented or hybrid THA using a small-diameter metal or ceramic-on-conventional polyethylene bearing. Osteolysis susceptibility case-control analyses and quantitative trait analyses for time to prosthesis revision (a proxy measure of the speed of osteolysis onset) in those patients with osteolysis were undertaken in each cohort separately after genome-wide genotyping. Finally, a meta-analysis of the two independent cohort association analysis results was undertaken. RESULTS: Genome-wide association analysis identified four independent suggestive genetic signals for osteolysis case-control status in the Norwegian cohort and 11 in the UK cohort (p ≤ 5 x 10). After meta-analysis, five independent genetic signals showed a suggestive association with osteolysis case-control status at p ≤ 5 x 10 with the strongest comprising 18 correlated variants on chromosome 7 (lead signal rs850092, p = 1.13 x 10). Genome-wide quantitative trait analysis in cases only showed a total of five and nine independent genetic signals for time to revision at p ≤ 5 x 10, respectively. After meta-analysis, 11 independent genetic signals showed suggestive evidence of an association with time to revision at p ≤ 5 x 10 with the largest association block comprising 174 correlated variants in chromosome 15 (lead signal rs10507055, p = 1.40 x 10). CONCLUSIONS: We explored the heritable biology of osteolysis at the whole genome level and identify several genetic loci that associate with susceptibility to osteolysis or with premature revision surgery. However, further studies are required to determine a causal association between the identified signals and osteolysis and their functional role in the disease. CLINICAL RELEVANCE: The identification of novel genetic risk loci for osteolysis enables new investigative avenues for clinical biomarker discovery and therapeutic intervention in this disease.
Authors: Keijo T Mäkelä; Markus Matilainen; Pekka Pulkkinen; Anne M Fenstad; Leif Havelin; Lars Engesaeter; Ove Furnes; Alma B Pedersen; Søren Overgaard; Johan Kärrholm; Henrik Malchau; Göran Garellick; Jonas Ranstam; Antti Eskelinen Journal: BMJ Date: 2014-01-13
Authors: Nizar N Mahomed; Jane A Barrett; Jeffrey N Katz; Charlotte B Phillips; Elena Losina; Robert A Lew; Edward Guadagnoli; William H Harris; Robert Poss; John A Baron Journal: J Bone Joint Surg Am Date: 2003-01 Impact factor: 5.284
Authors: J Mark Wilkinson; A Gerard Wilson; Ian Stockley; Ian R Scott; David A Macdonald; Andrew J Hamer; Gordon W Duff; Richard Eastell Journal: J Bone Miner Res Date: 2003-11 Impact factor: 6.741
Authors: Michiaki Takagi; Yasunobu Tamaki; Hiroshi Hasegawa; Yuya Takakubo; Liisa Konttinen; Veli-Matti Tiainen; Reijo Lappalainen; Yrjö T Konttinen; Jari Salo Journal: J Biomed Mater Res A Date: 2007-06-15 Impact factor: 4.396
Authors: Shane McCarthy; Sayantan Das; Warren Kretzschmar; Olivier Delaneau; Andrew R Wood; Alexander Teumer; Hyun Min Kang; Christian Fuchsberger; Petr Danecek; Kevin Sharp; Yang Luo; Carlo Sidore; Alan Kwong; Nicholas Timpson; Seppo Koskinen; Scott Vrieze; Laura J Scott; He Zhang; Anubha Mahajan; Jan Veldink; Ulrike Peters; Carlos Pato; Cornelia M van Duijn; Christopher E Gillies; Ilaria Gandin; Massimo Mezzavilla; Arthur Gilly; Massimiliano Cocca; Michela Traglia; Andrea Angius; Jeffrey C Barrett; Dorrett Boomsma; Kari Branham; Gerome Breen; Chad M Brummett; Fabio Busonero; Harry Campbell; Andrew Chan; Sai Chen; Emily Chew; Francis S Collins; Laura J Corbin; George Davey Smith; George Dedoussis; Marcus Dorr; Aliki-Eleni Farmaki; Luigi Ferrucci; Lukas Forer; Ross M Fraser; Stacey Gabriel; Shawn Levy; Leif Groop; Tabitha Harrison; Andrew Hattersley; Oddgeir L Holmen; Kristian Hveem; Matthias Kretzler; James C Lee; Matt McGue; Thomas Meitinger; David Melzer; Josine L Min; Karen L Mohlke; John B Vincent; Matthias Nauck; Deborah Nickerson; Aarno Palotie; Michele Pato; Nicola Pirastu; Melvin McInnis; J Brent Richards; Cinzia Sala; Veikko Salomaa; David Schlessinger; Sebastian Schoenherr; P Eline Slagboom; Kerrin Small; Timothy Spector; Dwight Stambolian; Marcus Tuke; Jaakko Tuomilehto; Leonard H Van den Berg; Wouter Van Rheenen; Uwe Volker; Cisca Wijmenga; Daniela Toniolo; Eleftheria Zeggini; Paolo Gasparini; Matthew G Sampson; James F Wilson; Timothy Frayling; Paul I W de Bakker; Morris A Swertz; Steven McCarroll; Charles Kooperberg; Annelot Dekker; David Altshuler; Cristen Willer; William Iacono; Samuli Ripatti; Nicole Soranzo; Klaudia Walter; Anand Swaroop; Francesco Cucca; Carl A Anderson; Richard M Myers; Michael Boehnke; Mark I McCarthy; Richard Durbin Journal: Nat Genet Date: 2016-08-22 Impact factor: 38.330
Authors: George A E Pickering; Favour Felix-Ilemhenbhio; Matthew J Clark; Klaudia Kocsy; Jonathan Simpson; Ilaria Bellantuono; Alison Gartland; Jeremy Mark Wilkinson; Konstantinos Hatzikotoulas; Endre Kiss-Toth Journal: Int J Mol Sci Date: 2022-08-16 Impact factor: 6.208