title: Sex differences in risk and heritability estimates on primary knee osteoarthritis leading to total knee arthroplasty: a nationwide population based follow up study in Danish twins.
abstract: BACKGROUND
  Symptomatic knee osteoarthritis is a highly age and sex associated complex disease. Little is known about the causes behind this age and sex associated increase, or if genetic and environmental factors impacts differently by gender. Our study examined the risk and heritability of primary knee osteoarthritis leading to total knee arthroplasty and whether these differences were attributable to sex and age differences in heritability.
  
  
  METHODS
  All twins of known zygosity from The Danish Twin Register alive in 1997 were examined in a nationwide population based follow-up study collecting information on all twins recorded in The Danish Knee Arthroplasty from 1997 to follow-up in 2010. Our main outcomes were the cumulative incidence, probandwise concordance rates, heritability, within pair correlations in monozygotic and dizygotic twin pairs and the genetic and environmental influence estimated in models taking into account that individuals may not have had a total knee arthroplasty at follow up.
  
  
  RESULTS
  92,748 twins were eligible for analyses and 576 twins had a record of primary knee osteoarthritis in The Danish Knee Arthroplasty Register at follow-up comprising 358 female and 218 male twin cases. The risk increased particular after the age of 50 years displaying significant sex differences in the elderly. In the sex stratified analyses a discrete genetic component was found in females, but in males no genetic component could be detected. In both genders common and unique environmental factors were highly significant. In the sex-adjusted analysis an additive genetic component of 18 % (0; 62), a shared environmental component of 61 % (25; 97) and an individual environmental component of 21 % (6; 36) accounted for the variation in liability to primary total knee arthroplasty.
  
  
  CONCLUSIONS
  The risk of primary total knee arthroplasty increases significantly after the age of 50 years, in particular in females, displaying significant sex differences in the elderly. After sex-adjustment 82 % of the variation in liability to primary total knee arthroplasty was attributable to common and unique environmental factors; the remaining 18 % of this variation was attributable to additive genetic factors indicating a pivotal impact of environmental factors on this disease.
authors: Department of Occupational and Environmental Medicine, Odense University Hospital, 5000, Odense C, Denmark. soeren.skousgaard@rsyd.dk.|Department of Orthopaedic Surgery and Traumatology & Orthopedic Research Unit, Institute of Clinical Research, University of Southern Denmark, 5000, Odense C, Denmark. soeren.skousgaard@rsyd.dk.|Clinical Institute, University of Southern Denmark, 5000, Odense C, Denmark. soeren.skousgaard@rsyd.dk.
authors: Søren Glud
authors: SG
authors: Skousgaard
authors: Department of Epidemiology, Biostatistics and Biodemography, The Danish Twin Registry, University of Southern Denmark, 5000, Odense C, Denmark. ASkytthe@health.sdu.dk.
authors: Axel
authors: A
authors: Skytthe
authors: Department of Epidemiology, Biostatistics and Biodemography, The Danish Twin Registry, University of Southern Denmark, 5000, Odense C, Denmark. moeller@health.sdu.dk.
authors: Sören
authors: S
authors: Möller
authors: Department of Orthopaedic Surgery and Traumatology & Orthopedic Research Unit, Institute of Clinical Research, University of Southern Denmark, 5000, Odense C, Denmark. soeren.overgaard@rsyd.dk.|Clinical Institute, University of Southern Denmark, 5000, Odense C, Denmark. soeren.overgaard@rsyd.dk.
authors: Søren
authors: S
authors: Overgaard
authors: Department of Occupational and Environmental Medicine, Odense University Hospital, 5000, Odense C, Denmark. lars.brandt@rsyd.dk.|Clinical Institute, University of Southern Denmark, 5000, Odense C, Denmark. lars.brandt@rsyd.dk.
authors: Lars Peter Andreas
authors: LP
authors: Brandt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019645:Arthroplasty, Replacement, Knee / Q000639:trends; D003718:Denmark / Q000453:epidemiology; D004200:Diseases in Twins / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D011159:Population Surveillance; D019655:Quantitative Trait, Heritable; D012042:Registries; D012307:Risk Factors; D012727:Sex Characteristics; D014429:Twins, Dizygotic / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics; D055815:Young Adult