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

BMJ 2019; 364 doi: (Published 16 January 2019) Cite this as: BMJ 2019;364:k5222

Linked opinion

Haemochromatosis is linked to more disease than previously thought

  1. Luke C Pilling, research fellow in genetic epidemiology1,
  2. Jone Tamosauskaite, research student1,
  3. Garan Jones, PhD researcher1,
  4. Andrew R Wood, research fellow in statistical genetics2,
  5. Lindsay Jones, academic clinical fellow1,
  6. Chai-Ling Kuo, assistant professor in biostatistics3,
  7. George A Kuchel, travelers chair in geriatrics and gerontology4,
  8. Luigi Ferrucci, scientific director5,
  9. David Melzer, professor of epidemiology and public health14
  1. 1Epidemiology and Public Health Group, University of Exeter Medical School, RD&E Wonford, Exeter EX2 5DW, UK
  2. 2Genetics of Complex Traits Group, University of Exeter Medical School, Exeter, UK
  3. 3Biostatistics Center, CT Institute for Clinical & Translational Science, University of Connecticut Health Center, Farmington, CT, USA
  4. 4Center on Aging, University of Connecticut Health Center, Farmington, CT, USA
  5. 5National Institute on Aging, Baltimore, MD, USA
  1. Correspondence to: D Melzer D.Melzer{at}
  • Accepted 27 November 2018


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.


  • Contributors: LCP performed the analysis, interpreted results, created the figures, searched literature, and cowrote the manuscript. JT performed the literature search, performed analyses, and contributed to the manuscript. GJ performed analyses and contributed to the manuscript. AW performed analyses relating to the genetic classification of participant ancestry. LJ, CK, GAK, and LF contributed to data interpretation and contributed to the manuscript. DM oversaw data analysis and interpretation and literature searching and led the writing of the manuscript. DM is the guarantor. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

  • Funding: This study was funded by an award to DM by the Medical Research Council (MR/M023095/1). DM and LCP are supported by the University of Exeter Medical School. ARW is supported by the European Research Council grant (SZ-245 50371-GLUCOSEGENES-FP7-IDEAS-ERC). LJ is an academic clinical fellow supported by the National Institute for Health Research. Input from CK and GAK was supported by the University of Connecticut Health Center. LF is supported by the Intramural Research Program of the National Institute on Ageing, US National Institutes of Health. DM is part supported by Public Health England. The funders had no input in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the article for publication. The researchers acted independently from the study sponsors in all aspects of this study.

  • Competing interests: All authors have completed the ICMJE uniform disclosure form (at and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work

  • Ethical approval: The North West Multi-Centre Research Ethics Committee approved the collection and use of UK Biobank data.

  • Data sharing: Data are available on application to the UK Biobank (

  • Transparency: The lead author (DM) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained.

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