目的:HFE血色病遗传变异具有不确定的临床外显率,尤其是老年人和未确诊的群体。我们估计了一个大型社区队列中p.C282Y和p.H63D变异的多种临床结局的累积发生率。
方法:前瞻性队列研究。
方法:英格兰22个评估中心,苏格兰,和威尔士在英国生物银行(2006-2010)。
方法:451270名参与者在遗传上与1000个欧洲基因组参考人群相似,在医院住院期间平均随访13.3年,癌症登记处和死亡证明数据。
方法:HFE患者临床结局和死亡率的Cox比例HRp.C282Y/p.与没有变异的H63D突变相比,按性别分层并根据年龄调整,评估中心和遗传分层。累积发病率估计为40岁至80岁。
结果:12.1%的p.C282Y+/+男性有基线(平均年龄57岁)血色病诊断,80岁时的累积发病率为56.4%。33.1%死亡,25.4%无HFE变异(HR1.29,95%CI:1.12至1.48,p=4.7×10-4);27.9%vs17.1%有关节置换,20.3%vs8.3%患有肝病,有过量的谵妄,痴呆症,和帕金森病,但不是抑郁症。协会,包括超额死亡率,在未诊断为血色病的组中相似。3.4%的p.C282Y+/+女性有基线血色素沉着症诊断,80岁时的累积发病率为40.5%。有过度事件肝病(8.9%vs6.8%;HR1.62,95%CI:1.27至2.05,p=7.8×10-5),关节置换和谵妄,在未确诊的患者中也有类似的结果。p.C282Y/p。H63D和p.H63D+/+男性或女性在基线时没有统计学意义的过度疲劳或抑郁,也没有过度事件结果。
结论:男性和女性p.C282Y纯合子的发病率比以前记录的高,包括社区中未被诊断为血色素沉着症的患者。尽管治疗被认为是有效的,但基线时血色素沉着病的诊断率较低,早期筛选鉴定p.C282Y纯合性人群的试验似乎是合理的。
OBJECTIVE: HFE haemochromatosis genetic variants have an uncertain clinical penetrance, especially to older ages and in undiagnosed groups. We estimated p.C282Y and p.H63D variant cumulative incidence of multiple clinical outcomes in a large community cohort.
METHODS: Prospective cohort
study.
METHODS: 22 assessment centres across England, Scotland, and Wales in the UK Biobank (2006-2010).
METHODS: 451 270 participants genetically similar to the 1000 Genomes European reference population, with a mean of 13.3-year follow-up through hospital inpatient, cancer registries and death certificate data.
METHODS: Cox proportional HRs of incident clinical outcomes and mortality in those with HFE p.C282Y/p.H63D mutations compared with those with no variants, stratified by sex and adjusted for age, assessment centre and genetic stratification. Cumulative incidences were estimated from age 40 years to 80 years.
RESULTS: 12.1% of p.C282Y+/+ males had baseline (mean age 57 years) haemochromatosis diagnoses, with a cumulative incidence of 56.4% at age 80 years. 33.1% died vs 25.4% without HFE variants (HR 1.29, 95% CI: 1.12 to 1.48, p=4.7×10-4); 27.9% vs 17.1% had joint replacements, 20.3% vs 8.3% had liver disease, and there were excess delirium, dementia, and Parkinson\'s disease but not depression. Associations, including excess mortality, were similar in the group undiagnosed with haemochromatosis. 3.4% of women with p.C282Y+/+ had baseline haemochromatosis diagnoses, with a cumulative incidence of 40.5% at age 80 years. There were excess incident liver disease (8.9% vs 6.8%; HR 1.62, 95% CI: 1.27 to 2.05, p=7.8×10-5), joint replacements and delirium, with similar results in the undiagnosed. p.C282Y/p.H63D and p.H63D+/+ men or women had no statistically significant excess fatigue or depression at baseline and no excess incident outcomes.
CONCLUSIONS: Male and female p.C282Y homozygotes experienced greater excess morbidity than previously documented, including those undiagnosed with haemochromatosis in the community. As haemochromatosis diagnosis rates were low at baseline despite treatment being considered effective, trials of screening to identify people with p.C282Y homozygosity early appear justified.