Osteoarthritis and analgesic consumption in haemochromatosis HFE C282Y homozygotes with normal or low iron parameters

We studied 132,525 Danish general population individuals to examine whether risk of osteoarthritis and/or use of pain-relieving medication was increased in haemochromatosis C282Y homozygotes with normal or low plasma iron, transferrin saturation, or ferritin. We genotyped all 132,525 individuals for the HFE C282Y and H63D variants. During a median follow-up of 40 years, 31,636 individuals had osteoarthritis. Risk of osteoarthritis was increased even in C282Y homozygotes with normal or low plasma iron (hazard ratio:1.37;95% confidence interval:1.12-1.68 compared to non-carriers with normal/low iron), transferrin saturation (1.55;1.10-2.16), or ferritin (1.96;1.11-3.45). Here we show that risk of osteoarthritis is increased in those C282Y homozygotes not usually recommended for genotyping according to clinical guidelines, challenging the presumption that the increased risk of osteoarthritis is mainly caused by systemic iron accumulation. Indeed, C282Y homozygotes with normal or low ferritin levels had a particularly high cumulative incidence of any osteoarthritis (24% at age 60 years, 60% at age 80 years).