Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank

This is the final published version. Available from BMJ publishing group via the DOI in this record.Data are available on application to the UK Biobank (www.ukbiobank.ac.uk/register-apply).Objective To compare prevalent and incident morbidity and mortality between those with the HFE p.C282Y genetic variant (responsible for most hereditary haemochromatosis type 1) and those with no p.C282Y mutations, in a large UK community sample of European descent. Design Cohort study. Setting 22 centres across England, Scotland, and Wales in UK Biobank (2006-10). Participants 451 243 volunteers of European descent aged 40 to 70 years, with a mean follow-up of seven years (maximum 9.4 years) through hospital inpatient diagnoses and death certification. Main outcome measure Odds ratios and Cox hazard ratios of disease rates between participants with and without the haemochromatosis mutations, adjusted for age, genotyping array type, and genetic principal components. The sexes were analysed separately as morbidity due to iron excess occurs later in women. Results Of 2890 participants homozygous for p.C282Y (0.6%, or 1 in 156), haemochromatosis was diagnosed in 21.7% (95% confidence interval 19.5% to 24.1%, 281/1294) of men and 9.8% (8.4% to 11.2%, 156/1596) of women by end of follow-up. p.C282Y homozygous men aged 40 to 70 had a higher prevalence of diagnosed haemochromatosis (odds ratio 411.1, 95% confidence interval 299.0 to 565.3, P<0.001), liver disease (4.30, 2.97 to 6.18, P<0.001), rheumatoid arthritis (2.23, 1.51 to 3.31, P<0.001), osteoarthritis (2.01, 1.71 to 2.36, P<0.001), and diabetes mellitus (1.53, 1.16 to 1.98, P=0.002), versus no p.C282Y mutations (n=175 539). During the seven year follow-up, 15.7% of homozygous men developed at least one incident associated condition versus 5.0% (P<0.001) with no p.C282Y mutations (women 10.1% v 3.4%, P<0.001). Haemochromatosis diagnoses were more common in p.C282Y/p.H63D heterozygotes, but excess morbidity was modest. Conclusions In a large community sample, HFE p.C282Y homozygosity was associated with substantial prevalent and incident clinically diagnosed morbidity in both men and women. As p.C282Y associated iron overload is preventable and treatable if intervention starts early, these findings justify re-examination of options for expanded early case ascertainment and screening.Medical Research Council (MRC)University of Exeter Medical SchoolUniversity of Conneticut Health CentreNational Centre for AgeingPublic Health Englan

Human longevity: 25 genetic loci associated in 389,166 UK biobank participants

This is the final version. Freely available on open access from Impact Journals via the DOI in this recordA public use file of data from the WLS is available from the Wisconsin Longitudinal Study, University of Wisconsin-Madison, 1180 Observatory Drive, Madison, Wisconsin 53706 and at (http://www.ssc.wisc.edu/wlsresearch/data).We undertook a genome-wide association study (GWAS) of parental longevity in European descent UK Biobank participants. For combined mothers' and fathers' attained age, 10 loci were associated (p<5*10-8), including 8 previously identified for traits including survival, Alzheimer's and cardiovascular disease. Of these, 4 were also associated with longest 10% survival (mothers age ≥90 years, fathers ≥87 years), with 2 additional associations including MC2R intronic variants (coding for the adrenocorticotropic hormone receptor). Mother's age at death was associated with 3 additional loci (2 linked to autoimmune conditions), and 8 for fathers only. An attained age genetic risk score associated with parental survival in the US Health and Retirement Study and the Wisconsin Longitudinal Study and with having a centenarian parent (n=1,181) in UK Biobank. The results suggest that human longevity is highly polygenic with prominent roles for loci likely involved in cellular senescence and inflammation, plus lipid metabolism and cardiovascular conditions. There may also be gender specific routes to longevity.This work was generously funded by an award to DM and LH by the Medical Research Council MR/M023095/1. LF is supported by the Intramural Research Program of the National Institute on Aging, U.S. National Institutes of Health. Input from CK and GK was supported by the University of Connecticut Health Center. The Health and Retirement Study (HRS) is a longitudinal project sponsored by the National Institute on Aging (NIA U01AG009740) and the Social Security Administration. This research uses data from the Wisconsin Longitudinal Study (WLS) of the University of Wisconsin-Madison. Since 1991, the WLS has been supported principally by the National Institute on Aging (AG09775, AG21079 and AG33285), with additional support from the Vilas Estate Trust, the National Science Foundation, the Spencer Foundation and the Graduate School of the University of Wisconsin-Madison

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

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.This article is freely available online, click on Publisher URL to access