Epidemiology and Public Health Group, University of Exeter Medical School, RD&E Wonford, Exeter EX2 5DW, UK.
Genetics of Complex Traits Group, University of Exeter Medical School, Exeter, UK.
BMJ. 2019 Jan 16;364:k5222. doi: 10.1136/bmj.k5222.
To compare prevalent and incident morbidity and mortality between those with the 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.
Cohort study.
22 centres across England, Scotland, and Wales in UK Biobank (2006-10).
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.
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.
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% 3.4%, P<0.001). Haemochromatosis diagnoses were more common in p.C282Y/p.H63D heterozygotes, but excess morbidity was modest.
In a large community sample, 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.
在英国生物库（2006-10 年）的一个大型欧洲血统的英国社区样本中，比较具有 p.C282Y 遗传变异（导致大多数遗传性血色病 1 型）和无 p.C282Y 突变的患者的现患和新发发病率和死亡率。
队列研究。
英国英格兰、苏格兰和威尔士的 22 个中心。
451243 名年龄在 40 至 70 岁之间的欧洲血统志愿者，平均随访时间为 7 年（最长 9.4 年），通过住院诊断和死亡证明进行随访。
在有和没有血色病突变的参与者之间，根据年龄、基因分型阵列类型和遗传主成分调整疾病发生率的比值比和 Cox 风险比。由于女性铁过载引起的疾病发生较晚，因此分别分析了男性和女性。
在 2890 名纯合 p.C282Y（0.6%，即 156 分之 1）的参与者中，在研究结束时，男性中有 21.7%（95%置信区间 19.5%至 24.1%，281/1294）和女性中有 9.8%（8.4%至 11.2%，156/1596）诊断为血色病。40 至 70 岁的 p.C282Y 纯合子男性更常见诊断为血色病（比值比 411.1，95%置信区间 299.0 至 565.3，P<0.001）、肝病（4.30，2.97 至 6.18，P<0.001）、类风湿关节炎（2.23，1.51 至 3.31，P<0.001）、骨关节炎（2.01，1.71 至 2.36，P<0.001）和糖尿病（1.53，1.16 至 1.98，P=0.002），而无 p.C282Y 突变（n=175539）。在七年的随访期间，15.7%的纯合子男性至少发生了一种新发相关疾病，而无 p.C282Y 突变的男性为 5.0%（P<0.001）（女性为 10.1%和 3.4%，P<0.001）。p.C282Y/p.H63D 杂合子中血色病的诊断更为常见，但发病率增加并不明显。
在一个大型社区样本中，p.C282Y 纯合性与男性和女性现患和新发临床诊断发病率显著相关。由于 p.C282Y 相关的铁过载是可预防和可治疗的，如果早期开始干预，这些发现证明有必要重新考虑扩大早期病例发现和筛查的选择。
