Objectives To test whether haemochromatosis HFE C282Y homozygotes have increased risk of diabetes, liver disease, and heart disease even when they have normal plasma iron, transferrin saturation, or ferritin concentrations and to test whether C282Y homozygotes with diabetes, liver disease, or heart disease have increased mortality compared with non-carriers with these diseases. Design Prospective cohort study. Setting Three Danish general population cohorts: the Copenhagen City Heart Study, the Copenhagen General Population Study, and the Danish General Suburban Population Study. Participants 132 542 individuals genotyped for the HFE C282Y and H63D variants, 422 of whom were C282Y homozygotes, followed prospectively for up to 27 years after study enrolment. Main outcome measure Hospital contacts and deaths, retrieved from national registers, covering all hospitals and deaths in Denmark. Results Comparing C282Y homozygotes with non-carriers, hazard ratios were 1.72 (95% confidence interval (CI) 1.24 to 2.39) for diabetes, 2.22 (1.40 to 3.54) for liver disease, and 1.01 (0.78 to 1.31) for heart disease. Depending on age group, the absolute five year risk of diabetes was 0.54-4.3% in C282Y homozygous women, 0.37-3.0% in non-carrier women, 0.86-6.8% in C282Y homozygous men, and 0.60-4.80% in non-carrier men. When studied according to levels of iron, transferrin saturation, and ferritin in a single blood sample obtained at study enrolment, risk of diabetes was increased in C282Y homozygotes with normal transferrin saturation (hazard ratio 2.00, 95% CI 1.04 to 3.84) or ferritin (3.76, 1.41 to 10.05) and in C282Y homozygotes with normal levels of both ferritin and transferrin saturation (6.49, 2.09 to 20.18). C282Y homozygotes with diabetes had a higher risk of death from any cause than did non-carriers with diabetes (hazard ratio 1.94, 95% CI 1.19 to 3.18), but mortality was not increased in C282Y homozygotes without diabetes. The percentage of all deaths among C282Y homozygotes that could theoretically be prevented if excess deaths in individuals with a specific disease were eliminated (the population attributable fraction) was 27.3% (95% CI 12.4% to 39.7%) for diabetes and 14.4% (3.1% to 24.3%) for liver disease. Risk of diabetes or liver disease was not increased in H63D heterozygotes, H63D homozygotes, C282Y heterozygotes, or C282Y/H63D compound heterozygotes. Conclusions Haemochromatosis C282Y homozygotes with normal transferrin saturation and/or ferritin, not recommended for HFE genotyping according to most guidelines, had increased risk of diabetes. Furthermore, C282Y homozygotes with diabetes had higher mortality than non-carriers with diabetes, and 27.3% of all deaths among C282Y homozygotes were potentially attributable to diabetes. These results indicate that prioritising detection and treatment of diabetes in C282Y homozygotes may be relevant. Statistical code or technical details can be made available from the corresponding author at andreas.glenthoej@regionh.dk. To comply with data privacy regulations, access to original data is possible only in case of collaborative agreement.

中文翻译：

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血色病 HFE C282Y 纯合性且铁浓度正常、转铁蛋白饱和度或铁蛋白浓度正常的个体的死亡率和糖尿病、肝病和心脏病风险：前瞻性队列研究


目的 测试血色病 HFE C282Y 纯合子患糖尿病、肝病和心脏病的风险是否增加，即使他们的血浆铁、转铁蛋白饱和度或铁蛋白浓度正常，并测试患有糖尿病、肝病或心脏病的 C282Y 纯合子是否增加死亡率与患有这些疾病的非携带者相比。设计 前瞻性队列研究。设置 三个丹麦一般人群队列：哥本哈根城市心脏研究、哥本哈根一般人群研究和丹麦一般郊区人口研究。参与者 132 542 名针对 HFE C282Y 和 H63D 变体进行基因分型的个体，其中 422 名是 C282Y 纯合子，在研究登记后长达 27 年进行前瞻性随访。主要结局指标 医院接触者和死亡人数，从国家登记册中检索，涵盖丹麦的所有医院和死亡人数。结果 将 C282Y 纯合子与非携带者进行比较，糖尿病的风险比为 1.72 （95% 置信区间 （CI） 1.24 至 2.39），肝病风险比为 2.22 （1.40 至 3.54），心脏病风险比为 1.01 （0.78 至 1.31）。根据年龄组的不同，C282Y 纯合子女性患糖尿病的绝对五年风险为 0.54-4.3%，非携带者女性为 0.37-3.0%，C282Y 纯合子男性为 0.86-6.8%，非携带者男性为 0.60-4.80%。根据研究登记时获得的单个血液样本中的铁、转铁蛋白饱和度和铁蛋白水平进行研究时，转铁蛋白饱和度正常的 C282Y 纯合子（风险比 2.00,95% CI 1.04 至 3.84）或铁蛋白（3.76,1.41 至 10.05）和铁蛋白和转铁蛋白饱和度水平正常的 C282Y 纯合子（6.49， 2.09 到 20.18）。 患有糖尿病的 C282Y 纯合子比患有糖尿病的非携带者死于任何原因的风险更高 （风险比 1.94,95% CI 1.19 至 3.18），但无糖尿病的 C282Y 纯合子的死亡率没有增加。如果消除特定疾病个体的超额死亡（群体归因分数），理论上可以预防的 C282Y 纯合子中所有死亡的百分比为糖尿病 27.3% （95% CI 12.4% 至 39.7%）和肝病 14.4% （3.1% 至 24.3%）。H63D 杂合子、 H63D 纯合子、 C282Y 杂合子或 C282Y/H63D 复合杂合子患糖尿病或肝病的风险没有增加。结论 血色病 C282Y 纯合子具有正常的转铁蛋白饱和度和/或铁蛋白，根据大多数指南，不推荐用于 HFE 基因分型，患糖尿病的风险增加。此外，患有糖尿病的 C282Y 纯合子的死亡率高于患有糖尿病的非携带者，并且 C282Y 纯合子中 27.3% 的死亡可能归因于糖尿病。这些结果表明，优先检测和治疗 C282Y 纯合子中的糖尿病可能是相关的。统计代码或技术详细信息可从 andreas.glenthoej@regionh.dk 的通讯作者处获得。为了遵守数据隐私法规，只有在达成合作协议的情况下才能访问原始数据。