Abstract
AbstractBackgroundThe iron overload disorder haemochromatosis is primarily caused by the homozygousHFEp.C282Y variant, but the scale of excess related musculoskeletal morbidity is uncertain.MethodsWe estimated haemochromatosis-genotype associations with clinically diagnosed musculoskeletal outcomes and joint replacement surgeries in the UK Biobank community cohort. 451,143 European ancestry participants (40-70 years at baseline) were followed in hospital records (mean 11.5 years). Cox proportional hazards models estimatedHFEp.C282Y and p.H63D associations with incident outcomes.ResultsMale p.C282Y homozygotes (n=1,294) had increased incidence of osteoarthritis (n=52, HR: 2.12 [95% CI:1.61-2.80]; p=8.8*10−8), hip replacement (n=88, HR:1.84 [95% CI: 1.49-2.27]; p=1.6*10−8), knee replacement (n=61, HR:1.54 [95% CI:1.20-1.98]; p=8.4*10−4), ankle and shoulder replacement, compared to males with noHFEmutations. Lifetable estimates demonstrated 30.4% of male homozygotes were projected to develop osteoarthritis and 15.5% to have hip replacements by age 75, versus 23.0% and 8.7% respectively without mutations. Male p.C282Y homozygotes also had increased incidence of femoral fractures (n=15, HR:1.72 [95% CI: 1.03-2.87]; p=0.04) and osteoporosis (n=21, HR:1.71 [95% CI: 1.11-2.64, p=0.02), although these associations were limited to those with liver fibrosis/cirrhosis diagnoses. Female p.C282Y homozygotes had increased incidence of osteoarthritis only (n=57, HR:1.46, [95% CI: 1.12-1.89]; p=0.01). Male p.C282Y/p.H63D compound heterozygotes experienced a modest increased risk of hip replacements (n= 234, HR: 1.17 [95% CI: 1.02–1.33] p=0.02), but this did not pass multiple testing corrections.ConclusionsIn this large community cohort, the p.C282Y homozygote variant associated with substantial excess musculoskeletal morbidity in males. Wider iron overload orHFEgenotype testing may be justified, including in orthopaedic clinics serving higherHFEvariant prevalence populations.
Publisher
Cold Spring Harbor Laboratory