Epidemiology and Public Health GroupUniversity of ExeterExeterUK.
Hepatology. 2022 Dec;76(6):1735-1745. doi: 10.1002/hep.32575. Epub 2022 Jun 17.
The iron overload condition hereditary hemochromatosis (HH) can cause liver cirrhosis and cancer, diabetes, and arthritis. Males homozygous for the p.C282Y missense mutation in the Homeostatin Iron Regulator (HFE) gene have greatest risk; yet, only a minority develop these conditions. We aimed to determine whether common genetic variants influencing iron levels or liver disease risk in the general population also modify clinical penetrance in HFE p.C282Y and p.H63D carriers.
We studied 1294 male and 1596 female UK Biobank HFE p.C282Y homozygous participants of European ancestry with medical records up to 14 years after baseline assessment. Polygenic scores quantified genetic effects of blood iron biomarkers and relevant diseases (identified in the general population). Analyses were also performed in other HFE p.C282Y/p.H63D genotype groups.
In male p.C282Y homozygotes, a higher iron polygenic score increased the risk of liver fibrosis or cirrhosis diagnoses (odds ratio for the top 20% of iron polygenic score vs. the bottom 20% = 4.90: 95% confidence intervals, 1.63-14.73; p = 0.005), liver cancer, and osteoarthritis but not diabetes. A liver cirrhosis polygenic score was associated with liver cancer diagnoses. In female p.C282Y homozygotes, the osteoarthritis polygenic score was associated with increased osteoarthritis diagnoses and type-2 diabetes polygenic score with diabetes. However, the iron polygenic score was not robustly associated with diagnoses in p.C282Y female homozygotes or in other p.C282Y/p.H63D genotypes.
HFE p.C282Y homozygote penetrance to clinical disease in a large community cohort was partly explained by common genetic variants that influence iron and risks of related diagnoses in the general population, including polygenic scores in HH screening and diagnosis, may help in estimating prognosis and treatment planning.
铁过载疾病遗传性血色素沉着症（HH）可导致肝硬化和肝癌、糖尿病以及关节炎。载脂蛋白 C282Y 错义突变纯合子的男性具有最大的患病风险；然而，仅有少数人会发展出这些病症。我们旨在确定影响一般人群铁水平或肝脏疾病风险的常见遗传变异是否也能改变 HFE p.C282Y 和 p.H63D 携带者的临床外显率。
我们研究了 1294 名男性和 1596 名女性英国生物库 HFE p.C282Y 纯合子参与者，这些参与者具有欧洲血统，且在基线评估后长达 14 年的医疗记录。多基因评分量化了血液铁生物标志物和相关疾病（在一般人群中确定）的遗传效应。还在其他 HFE p.C282Y/p.H63D 基因型组中进行了分析。
在男性 p.C282Y 纯合子中，较高的铁多基因评分增加了肝纤维化或肝硬化诊断的风险（处于铁多基因评分最高 20%的个体与最低 20%的个体相比的优势比=4.90:95%置信区间为 1.63-14.73;p=0.005），以及肝癌和骨关节炎，但不包括糖尿病。肝硬化多基因评分与肝癌诊断相关。在女性 p.C282Y 纯合子中，骨关节炎多基因评分与骨关节炎诊断的增加相关，而 2 型糖尿病多基因评分与糖尿病相关。然而，铁多基因评分与女性 p.C282Y 纯合子或其他 p.C282Y/p.H63D 基因型的诊断并无关联。
在一个大型社区队列中，HFE p.C282Y 纯合子对临床疾病的外显率部分由影响一般人群铁和相关诊断风险的常见遗传变异所解释，包括 HH 筛查和诊断中的多基因评分，可能有助于估计预后和治疗计划。
