title: The causal role of smoking on the risk of hip or knee replacement due to primary osteoarthritis: a Mendelian randomisation analysis of the HUNT study.
abstract: Smoking has been associated with a reduced risk of hip and knee osteoarthritis (OA) and subsequent joint replacement. The aim of the present study was to assess whether the observed association is likely to be causal.
  
  
  
  55,745 participants of a population-based cohort were genotyped for the rs1051730 C > T single-nucleotide polymorphism (SNP), a proxy for smoking quantity among smokers. A Mendelian randomization analysis was performed using rs1051730 as an instrument to evaluate the causal role of smoking on the risk of hip or knee replacement (combined as total joint replacement (TJR)). Association between rs1051730 T alleles and TJR was estimated by hazard ratios (HRs) and 95% confidence intervals (CIs). All analyses were adjusted for age and sex.
  
  
  
  Smoking quantity (no. of cigarettes) was inversely associated with TJR (HR 0.97, 95% CI 0.97-0.98). In the Mendelian randomization analysis, rs1051730 T alleles were associated with reduced risk of TJR among current smokers (HR 0.84, 95% CI 0.76-0.98, per T allele), however we found no evidence of association among former (HR 0.97, 95% CI 0.88-1.07) and never smokers (HR 0.97, 95% CI 0.89-1.06). Neither adjusting for body mass index (BMI), cardiovascular disease (CVD) nor accounting for the competing risk of mortality substantially changed the results.
  
  
  
  This study suggests that smoking may be causally associated with the reduced risk of TJR. Our findings add support to the inverse association found in previous observational studies. More research is needed to further elucidate the underlying mechanisms of this causal association.
authors.affiliation: Communication and Research Unit for Musculoskeletal Disorders, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: m.b.johnsen@medisin.uio.no.
authors.forename: M B
authors.initials: MB
authors.lastname: Johnsen
authors.affiliation: Department of Public Health and General Practice, NTNU, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: gunnhild.vie@ntnu.no.
authors.forename: G Å
authors.initials: GÅ
authors.lastname: Vie
authors.affiliation: Communication and Research Unit for Musculoskeletal Disorders, Oslo University Hospital, Oslo, Norway; Department of Neurology, Oslo University Hospital, Oslo, Norway. Electronic address: bendik.s.winsvold@ntnu.no.
authors.forename: B S
authors.initials: BS
authors.lastname: Winsvold
authors.affiliation: Department of Public Health and General Practice, NTNU, Norwegian University of Science and Technology, Trondheim, Norway; Forensic Department and Research Centre Bröset, St. Olav's University Hospital, Trondheim, Norway. Electronic address: johan.h.bjorngaard@ntnu.no.
authors.forename: J H
authors.initials: JH
authors.lastname: Bjørngaard
authors.affiliation: K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, NTNU, Norwegian University of Science and Technology, Trondheim, Norway; Department of Endocrinology, St. Olav's University Hospital, Trondheim, Norway. Electronic address: bjorn.o.asvold@ntnu.no.
authors.forename: B O
authors.initials: BO
authors.lastname: Åsvold
authors.affiliation: K.G. Jebsen Center for Genetic Epidemiology, Department of Public Health, NTNU, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: maikenbr@ntnu.no.
authors.forename: M E
authors.initials: ME
authors.lastname: Gabrielsen
authors.affiliation: Communication and Research Unit for Musculoskeletal Disorders, Oslo University Hospital, Oslo, Norway. Electronic address: limped@ous-hf.no.
authors.forename: L M
authors.initials: LM
authors.lastname: Pedersen
authors.affiliation: Division of Orthopaedic Surgery, Oslo University Hospital, Oslo, Norway; The HUNT Research Centre, NTNU, Faculty of Medicine, Levanger, Norway. Electronic address: alf.hellevik@ntnu.no.
authors.forename: A I
authors.initials: AI
authors.lastname: Hellevik
authors.affiliation: The HUNT Research Centre, NTNU, Faculty of Medicine, Levanger, Norway. Electronic address: arnulf.langhammer@ntnu.no.
authors.forename: A
authors.initials: A
authors.lastname: Langhammer
authors.affiliation: The Norwegian Arthroplasty Register, Department of Orthopaedic Surgery, Haukeland University Hospital, Bergen, Norway; Department of Clinical Medicine, University of Bergen, Bergen, Norway. Electronic address: ove.furnes@helse-bergen.no.
authors.forename: O
authors.initials: O
authors.lastname: Furnes
authors.affiliation: Division of Orthopaedic Surgery, Oslo University Hospital, Oslo, Norway. Electronic address: GUNFLU@ous-hf.no.
authors.forename: G B
authors.initials: GB
authors.lastname: Flugsrud
authors.affiliation: Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine, NTNU, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: frank.skorpen@ntnu.no.
authors.forename: F
authors.initials: F
authors.lastname: Skorpen
authors.affiliation: Department of Public Health and General Practice, NTNU, Norwegian University of Science and Technology, Trondheim, Norway. Electronic address: pal.romundstad@ntnu.no.
authors.forename: P R
authors.initials: PR
authors.lastname: Romundstad
authors.affiliation: Communication and Research Unit for Musculoskeletal Disorders, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: kjersti.storheim@medisin.uio.no.
authors.forename: K
authors.initials: K
authors.lastname: Storheim
authors.affiliation: Faculty of Medicine, University of Oslo, Oslo, Norway; Division of Orthopaedic Surgery, Oslo University Hospital, Oslo, Norway. Electronic address: lars.nordsletten@medisin.uio.no.
authors.forename: L
authors.initials: L
authors.lastname: Nordsletten
authors.affiliation: Communication and Research Unit for Musculoskeletal Disorders, Oslo University Hospital, Oslo, Norway; Faculty of Medicine, University of Oslo, Oslo, Norway. Electronic address: j.a.zwart@medisin.uio.no.
authors.forename: J A
authors.initials: JA
authors.lastname: Zwart
mesh_terms: D019644:Arthroplasty, Replacement, Hip / Q000706:statistics & numerical data*; D019645:Arthroplasty, Replacement, Knee / Q000706:statistics & numerical data*; D015984:Causality; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D005810:Multigene Family; D009419:Nerve Tissue Proteins / Q000235:genetics; D016017:Odds Ratio; D015207:Osteoarthritis, Hip / Q000601:surgery*; D020370:Osteoarthritis, Knee / Q000601:surgery*; D020641:Polymorphism, Single Nucleotide; D016016:Proportional Hazards Models; D011978:Receptors, Nicotinic / Q000235:genetics; D012306:Risk; D012907:Smoking / Q000453:epidemiology* / Q000235:genetics
chemical_list: D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; C447158:CHRNA5 protein, human; C447159:CHRNB4 protein, human
keywords: Epidemiology; Genetic variants; Osteoarthritis; Smoking