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.

Conclusion: 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.

Fig. 1

Flowchart of the participating twins. CPR Danish Personal Registration Number, DKR Danish Knee Arthroplasty Register, DTR Danish Twin Register, OA Osteoarthritis, TKA Total Knee Arthroplasty

Fig. 2

The threshold model

Fig. 3

Cumulative incidence for TKA in males (red dashed line) and females (black dashed line)

Fig. 4

Proband-wise concordance rate of TKA by age and sex. DZ dizygotic, Marginal background incidence in the genetically unrelated twin population, MZ monozygotic

Fig. 5

Heritability in males – the CE model

Fig. 6

Heritability in females – the ACE model

Fig. 7

Heritability on age in females