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Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank
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...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group Ltd.
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334179/ https://www.ncbi.nlm.nih.gov/pubmed/30651232 http://dx.doi.org/10.1136/bmj.k5222 |
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author | Pilling, Luke C Tamosauskaite, Jone Jones, Garan Wood, Andrew R Jones, Lindsay Kuo, Chai-Ling Kuchel, George A Ferrucci, Luigi Melzer, David |
author_facet | Pilling, Luke C Tamosauskaite, Jone Jones, Garan Wood, Andrew R Jones, Lindsay Kuo, Chai-Ling Kuchel, George A Ferrucci, Luigi Melzer, David |
author_sort | Pilling, Luke C |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6334179 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BMJ Publishing Group Ltd. |
record_format | MEDLINE/PubMed |
spelling | pubmed-63341792019-01-27 Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank Pilling, Luke C Tamosauskaite, Jone Jones, Garan Wood, Andrew R Jones, Lindsay Kuo, Chai-Ling Kuchel, George A Ferrucci, Luigi Melzer, David BMJ Research 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. BMJ Publishing Group Ltd. 2019-01-16 /pmc/articles/PMC6334179/ /pubmed/30651232 http://dx.doi.org/10.1136/bmj.k5222 Text en Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Research Pilling, Luke C Tamosauskaite, Jone Jones, Garan Wood, Andrew R Jones, Lindsay Kuo, Chai-Ling Kuchel, George A Ferrucci, Luigi Melzer, David Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank |
title | Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank |
title_full | Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank |
title_fullStr | Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank |
title_full_unstemmed | Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank |
title_short | Common conditions associated with hereditary haemochromatosis genetic variants: cohort study in UK Biobank |
title_sort | common conditions associated with hereditary haemochromatosis genetic variants: cohort study in uk biobank |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334179/ https://www.ncbi.nlm.nih.gov/pubmed/30651232 http://dx.doi.org/10.1136/bmj.k5222 |
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