Penetrance of HFE haemochromatosis variants to clinical disease: polygenic risk score associations in UK Biobank
Penetrance of HFE haemochromatosis variants to clinical disease: polygenic risk score associations in UK Biobank
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HFE 血色病变异与临床疾病的外显率：英国生物银行的多基因风险评分关联
DOI：
10.1101/2022.03.08.22272084
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发表时间：
2022
期刊：
影响因子：
--
通讯作者：
Pilling L
中科院分区：
文献类型：
--
作者：
Pilling L
背景遗传性血色病（Hereditary Hemochromatosis，HH）可引起肝硬化、癌症、糖尿病和关节炎.在欧洲人中，大多数HH疾病发生在男性HFEp. C282 Y纯合子中，但在一般人群中只有少数纯合子发生这些疾病。我们的目的是确定普通人群中影响铁水平或肝脏、糖尿病或关节炎诊断风险的常见遗传变异是否也会改变HFEp.C282Y和p.H63D携带者的临床患病率。方法对1，294名男性和1，596名女性英国生物库欧洲血统HFEp.C282Y纯合子参与者进行研究，基线评估后电子病历长达14年。多基因风险评分（PRS）量化了对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。在10,699 p.C282Y/p.H63D复合heterozygotes.ResultsIn男性p.C282Y纯合子，较高的铁PRS增加肝纤维化或肝硬化诊断的风险（铁PRS的前20%的比值比为4.90：95%置信区间为1.63至14.73，p=0.005与底部20%），肝癌，骨关节炎，但不是糖尿病。肝硬化PRS也与肝癌诊断增加相关，2型糖尿病PRS增加2型糖尿病的风险。在女性p.C282Y纯合子中，骨关节炎PRS与骨关节炎诊断增加相关，2型糖尿病PRS与2型糖尿病相关。结论HFEp. C282 Y纯合子与临床疾病的相关性可能是由影响铁的常见遗传变异和相关诊断风险所导致的。在HH筛查和诊断中包括PRS可能有助于估计预后和治疗计划。概述用两三句话概括文章的主要信息，用简单的英语向非医学观众描述你的发现。遗传性血色病是一种铁超负荷状态，是北方欧洲人最常见的遗传性疾病;每150人中就有1人携带两个最高风险突变（称为HFEp.C282Y）的拷贝。只有少数携带高风险HH变体的人实际上会患上铁过载疾病，如肝癌、肝硬化、糖尿病和关节炎。我们测试了在整个人群中对铁水平影响较小的已知遗传变异是否会改变具有HH高风险变异的人的铁过载相关疾病的风险。我们对与铁超载引起的每种疾病相关的变异进行了类似的测试。高铁的遗传风险增加显著增加了突变携带者患肝纤维化、肝硬化和癌症的可能性。在未来，这些信息可以帮助早期识别有风险的血色病患者。
BackgroundThe iron overload condition Hereditary Heamochromatosis (HH) can cause liver cirrhosis and cancer, diabetes and arthritis. In Europeans, most HH disease occurs in maleHFEp.C282Y homozygotes, yet only a minority of homozygotes in the general population develop these conditions. We aimed to determine whether common genetic variants influencing iron levels or risks for liver, diabetes or arthritis diagnoses in the general population also modify clinical penetrance inHFEp.C282Y and p.H63D carriers.Methods1,294 male and 1,596 female UK Biobank European-ancestryHFEp.C282Y homozygous participants with electronic medical records up to 14 years after baseline assessment were studied. Polygenic risk scores (PRS) quantified genetic effects on blood iron biomarkers and relevant diseases (identified in the general population). Analyses were repeated in 10,699 p.C282Y/p.H63D compound heterozygotes.ResultsIn male p.C282Y homozygotes, higher iron PRS increased risk of liver fibrosis or cirrhosis diagnoses (top 20% of iron PRS had Odds Ratio 4.90: 95% Confidence Intervals 1.63 to 14.73, p=0.005 versus bottom 20%), liver cancer, and osteoarthritis, but not diabetes. The liver cirrhosis PRS also associated with increased liver cancer diagnoses, and greater type-2 diabetes PRS increased risk of type-2 diabetes. In female p.C282Y homozygotes, osteoarthritis PRS was associated with increased osteoarthritis diagnoses, and type-2 diabetes PRS with type-2 diabetes. However, the iron PRS was not robustly associated with diagnoses in p.C282Y homozygote females, or in other p.C282Y/p.H63D genotypes.ConclusionsHFEp.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 PRS in HH screening and diagnosis may help in estimating prognosis and treatment planning.Lay SummaryTwo or three sentences summarizing the main message of the article expressed in plain English to describe your findings to a non-medical audience.Hereditary Haemochromatosis, an iron overload condition, is the most common genetic disease in Northern Europeans; 1 in 150 people carry two copies of the highest risk mutation (calledHFEp.C282Y).Only a minority of those with high risk HH variants actually develop iron overload diseases, such as liver cancer, cirrhosis, diabetes and arthritis. We tested whether known genetic variants with smaller effects on iron levels in the whole population modify risk of iron overload related disease in those with the HH high risk variants. We did similar tests for variants linked to each of the diseases caused by iron overload.Increased genetic risk for higher iron significantly raised the likelihood of liver fibrosis, cirrhosis and cancer in mutation carriers. In the future this information could help identify at-risk haemochromatosis patients early.
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影响因子：
7.7
作者：
Bowden J;Spiller W;Del Greco M F;Sheehan N;Thompson J;Minelli C;Davey Smith G
通讯作者：
Davey Smith G
怀疑的遗传性血色素症患者的HFE基因型，铁蛋白水平和转移蛋白饱和度。
影响因子：
3.5
作者：
Sandnes M;Vorland M;Ulvik RJ;Reikvam H
通讯作者：
Reikvam H
影响因子：
5
作者：
Fry A;Littlejohns TJ;Sudlow C;Doherty N;Adamska L;Sprosen T;Collins R;Allen NE
通讯作者：
Allen NE
影响因子：
158.5
作者：
Adams, PC;Reboussin, DM;Thomson, E
通讯作者：
Thomson, E
影响因子：
3
作者：
Adams, P. C.
通讯作者：
Adams, P. C.