Hereditary Hemochromatosis Associations with Frailty, Sarcopenia and Chronic Pain: Evidence from 200,975 Older UK Biobank Participants

Background: Iron is essential for life but contributes to oxidative damage. In Northern-European ancestry populations, HFE gene C282Y mutations are relatively common (0.3%-0.6% rare homozygote prevalence) and associated with excessive iron absorption, fatigue, diabetes, arthritis, and liver disease, especially in men. Iron excess can be prevented or treated but diagnosis is often delayed or missed. Data on sarcopenia, pain, and frailty are scarce.

Methods: Using 200,975 UK Biobank volunteers aged 60-70 years, we tested associations between C282Y homozygosity with Fried frailty, sarcopenia, and chronic pain using logistic regression adjusted for age and technical genetic covariates. As iron overload is progressive (with menstruation protective), we included specific analyses of older (65-70 years) females and males.

Results: One thousand three hundred and twelve (0.65%) participants were C282Y homozygotes; 593 were men (0.62%) and 719 were women (0.68%). C282Y homozygote men had increased likelihoods of reporting chronic pain (odds ratio [OR] 1.23: 95% confidence interval [CI] 1.05-1.45, p = .01) and diagnoses of polymyalgia rheumatica, compared to common "wild-type" genotype. They were also more likely to have sarcopenia (OR 2.38: 1.80-3.13, p = 9.70 × 10-10) and frailty (OR 2.01: 1.45-2.80, p = 3.41 × 10-05). C282Y homozygote women (n = 312, 0.7%) aged 65-70 were more likely to be frail (OR 1.73: 1.05-2.84, p = .032) and have chronic knee, hip, and back pain. Overall, 1.50% of frail men and 1.51% of frail women in the 65-70 age group were C282Y homozygous.

Conclusions: HFE C282Y homozygosity is associated with substantial excess sarcopenia, frailty, and chronic pain at older ages. Given the availability of treatment, hereditary hemochromatosis is a strong candidate for precision medicine approaches to improve outcomes in late life.