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Cited by 198Iron Metabolism and DisordersNeurological diseases and metabolismGenetic Associations and Epidemiology

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

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Pilling, Luke C, Tamosauskaite, Jone, Jones, Garan, Wood, Andrew R, Jones, Lindsay, Kuo, Chai-Ling, Kuchel, George A, Ferrucci, Luigi +1 more·2019·BMJ
DOI 10.1136/bmj.k5222PMC PMC6334179
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Abstract

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.

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  • Previous work has taken an MR approach to investigate the association of genetic variants related to hereditary hemochromatosis with risk of 11 outcomes implicated in iron overload.

    “Previous work has taken an MR approach to investigate the association of genetic variants related to hereditary hemochromatosis with risk of 11 outcomes that are implicated in iron overload [42].”

    From Associations of genetically determined iron status across the phenome: A mendelian randomization study (2019) · cites this paper as [42]

    The Methods > Multiple testing passage says the study tested 11 outcomes previously implicated in iron overload. But Methods > Mendelian randomisation says the MR analysis covered six main incident outcomes, not all 11. The claim conflates the broader outcome analyses with the MR analysis. (LLM, conf=0.92)

    Experimental — accuracy not yet measured

  • The study pooled MR estimates obtained using all available genetic instruments for iron status, rather than focusing on those related to hereditary hemochromatosis.

    “our study pooled MR estimates obtained using all available genetic instruments for iron status, rather than focusing on those related to hereditary hemochromatosis [42]”

    From Associations of genetically determined iron status across the phenome: A mendelian randomization study (2019) · cites this paper as [42]

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Research works printed but not linked: 37

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Authors
Pilling, L. C., Tamosauskaite, J., Jones, G., Wood, A. R., Jones, L., Kuo, C.-L., Kuchel, G. A., Ferrucci, L., & Melzer, D.
Affiliations
  • University of Exeter (GB)
  • UConn Health (US)
  • National Institute on Aging (US)
Corresponding author
Melzer, David
ORCID
Venue
BMJ
Publisher
BMJ
Published
2019-01-16
Volume
364
Pages
k5222
ISSN
  • 1756-1833 (ISSN-L)
  • 0959-8138
DOI
10.1136/bmj.k5222
PMC
PMC6334179
OpenAlex
W2910310746
Cited by
198
References
2
Citations by year
2026: 18 · 2025: 28 · 2024: 32 · 2023: 24 · 2022: 26 · 2021: 32 · 2020: 22 · 2019: 16
FWCI
16.96
Type
journal article
Language
en
Update notices
correction (2019-10-23)
Open access
Licence
Locations
  • BMJ (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Figshare (submittedVersion, cc-by)
  • HighWire Press Open Archive (submittedVersion)
  • Open Research Exeter (University of Exeter) (submittedVersion, cc-by)
Funders
  • National Institute for Health and Care Research (ACF-2012-23-001)
  • Medical Research Council (MR/M023095/1, MR/M008924/1, MC_PC_17228, MR/S009892/1)
Topics
  • Health Sciences › Medicine › Hematology › Iron Metabolism and Disorders
  • Life Sciences › Neuroscience › Neurology › Neurological diseases and metabolism
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
hereditary hemochromatosis, iron overload, liver disease, rheumatoid arthritis, osteoarthritis, diabetes mellitus, cardiovascular disease, mortality, sex differences, prevalence, incident disease, UK Biobank, genetic variants, iron deficiency anemia
MeSH terms
Hemochromatosis Protein, Adult, Aged, Arthritis, Rheumatoid, Diabetes Mellitus, Female, Follow-Up Studies, United Kingdom, Hemochromatosis, Heterozygote, Homozygote, Humans, Liver Diseases, Male, Middle Aged, Mutation, Osteoarthritis, Comorbidity, Incidence, Prevalence

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