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

被引:90
|
作者
Pilling, Luke C. [1 ]
Tamosauskaite, Jone [1 ]
Jones, Garan [1 ]
Wood, Andrew R. [2 ]
Jones, Lindsay [1 ]
Kuo, Chai-Ling [3 ]
Kuchel, George A. [4 ]
Ferrucci, Luigi [5 ]
Melzer, David [1 ,4 ]
机构
[1] Univ Exeter, Sch Med, RD&E Wonford, Epidemiol & Publ Hlth Grp, Exeter EX2 5DW, Devon, England
[2] Univ Exeter, Sch Med, Genet Complex Traits Grp, Exeter, Devon, England
[3] Univ Connecticut, Ctr Hlth, Biostat Ctr, CT Inst Clin & Translat Sci, Farmington, CT USA
[4] Univ Connecticut, Ctr Hlth, Ctr Aging, Farmington, CT 06030 USA
[5] NIA, Baltimore, MD 21224 USA
来源
BMJ-BRITISH MEDICAL JOURNAL | 2019年 / 364卷
基金
欧洲研究理事会; 英国医学研究理事会; 美国国家卫生研究院;
关键词
DENSITY-LIPOPROTEIN CHOLESTEROL; HFE C282Y HOMOZYGOSITY; IRON-OVERLOAD; INCREASED RISK; POPULATION; PENETRANCE; REPLACEMENT; PREVALENCE; DISEASE; MUTATIONS;
D O I
10.1136/bmj.k5222
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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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页数:12
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