Musculoskeletal outcomes with Hereditary Haemochromatosis genetic variants: 11.5 year follow-up in a community cohort

BackgroundThe iron overload disorder haemochromatosis is primarily caused by the homozygous HFE p.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 estimated HFE p.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 no HFE mutations. Cumulative incidence analysis, using Kaplan-Meier lifetable probabilities demonstrated 10.4% of male homozygotes were projected to develop osteoarthritis and 15.5% to have hip replacements by age 75, versus 5.0% 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 the latter association was 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 genotype was associated with substantial excess musculoskeletal morbidity in males. Wider HFE genotype testing may be justified, including in orthopaedic clinics serving higher HFE variant prevalence populations. O_FIG O_LINKSMALLFIG WIDTH=199 HEIGHT=200 SRC="FIGDIR/small/22283577v4_ufig1.gif" ALT="Figure 1"> View larger version (84K): org.highwire.dtl.DTLVardef@a67536org.highwire.dtl.DTLVardef@593bf2org.highwire.dtl.DTLVardef@6eaee5org.highwire.dtl.DTLVardef@9c760d_HPS_FORMAT_FIGEXP M_FIG C_FIG