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

Abstract

BackgroundIron 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.MethodsUsing 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.ResultsOne 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.

Genetic variants that associate with cirrhosis have pleiotropic effects on human traits

“…Furthermore, using biobank PheWAS analysis, we verified known genetic pleiotropisms associated with cirrhosis promoting variants including dyslipidaemia, diabetes and body fat composition for six identified variants . Others have reported associations between HFE C282Y and arthritis, diabetes, chronic pain and brain iron accumulation, and SERPINA1 variants and hepatitis and fibrosis . Another recent study identified a SNP in MARC1 associated with cirrhosis, which was also associated with cirrhosis in UKBB ( P = .047); differences in strengths of associations are likely due to differences in statistical power and definitions of cirrhosis .…”

Sarcopenia, long‐term conditions, and multimorbidity: findings from UK Biobank participants

“…However, there are also several possibilities by which the associations may be causal. Firstly, other studies highlight that adult grip strength and some long‐term conditions have common genetic factors . Secondly, arthritis such as at the wrist joint may lead to reduced grip strength.…”

Diagnosis and management of hereditary haemochromatosis

“…Patients may present with more insidious symptoms including fatigue, mood disturbances and adynamia . A recent retrospective study of 1300 older patients with homozygous HFE C282Y gene mutations showed significant associations with chronic pain, frailty and sarcopenia .…”