Genetic modifiers of penetrance to liver endpoints in HFE hemochromatosis: Associations in a large community cohort.
Genetic modifiers of penetrance to liver endpoints in HFE hemochromatosis: Associations in a large community cohort.
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DOI：
10.1002/hep.32575
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发表时间：
2022-12
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影响因子：
--
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中科院分区：
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铁超负荷条件遗传性血色病（HH）可导致肝硬化和癌症，糖尿病和关节炎。在Homeostatin Iron Regulator（HFE）基因中p.C282Y错义突变的纯合子男性具有最大的风险;然而，只有少数人发展这些条件。我们的目的是确定影响普通人群铁水平或肝脏疾病风险的常见遗传变异是否也会改变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UK Biobank HFE p.C282Y纯合子欧洲血统参与者，基线评估后长达14年的医疗记录。多基因评分量化了血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（铁多基因评分前20%与后20%的比值比= 4.90：95%置信区间，1.63-14.73; p = 0.005）、肝癌和骨关节炎的风险，但不增加糖尿病的风险。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和2型糖尿病多基因评分增加相关。然而，铁多基因评分与p.C282Y女性纯合子或其他p.C282Y/p.H63D基因型的诊断无关。 在一个大型社区队列中，HFE p.C282Y纯合子对临床疾病的易感性部分解释为影响一般人群中铁和相关诊断风险的常见遗传变异，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。在稳态铁调节因子（HFE）基因中错义突变p.C282Y纯合子的男性中，携带更多其他增加铁的遗传变异体的人显着提高了肝脏终点诊断的可能性。
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. Within males homozygous for the missense mutation p.C282Y in the Homeostatic Iron Regulator (HFE) gene those carrying greater number of other iron‐increasing genetic variants had significantly raised likelihood of diagnosis of liver endpoints.
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影响因子：
64.8
作者：
Bycroft C;Freeman C;Petkova D;Band G;Elliott LT;Sharp K;Motyer A;Vukcevic D;Delaneau O;O'Connell J;Cortes A;Welsh S;Young A;Effingham M;McVean G;Leslie S;Allen N;Donnelly P;Marchini J
通讯作者：
Marchini J
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：
30.8
作者：
Mahajan A;Taliun D;Thurner M;Robertson NR;Torres JM;Rayner NW;Payne AJ;Steinthorsdottir V;Scott RA;Grarup N;Cook JP;Schmidt EM;Wuttke M;Sarnowski C;Mägi R;Nano J;Gieger C;Trompet S;Lecoeur C;Preuss MH;Prins BP;Guo X;Bielak LF;Below JE;Bowden DW;Chambers JC;Kim YJ;Ng MCY;Petty LE;Sim X;Zhang W;Bennett AJ;Bork-Jensen J;Brummett CM;Canouil M;Ec Kardt KU;Fischer K;Kardia SLR;Kronenberg F;Läll K;Liu CT;Locke AE;Luan J;Ntalla I;Nylander V;Schönherr S;Schurmann C;Yengo L;Bottinger EP;Brandslund I;Christensen C;Dedoussis G;Florez JC;Ford I;Franco OH;Frayling TM;Giedraitis V;Hackinger S;Hattersley AT;Herder C;Ikram MA;Ingelsson M;Jørgensen ME;Jørgensen T;Kriebel J;Kuusisto J;Ligthart S;Lindgren CM;Linneberg A;Lyssenko V;Mamakou V;Meitinger T;Mohlke KL;Morris AD;Nadkarni G;Pankow JS;Peters A;Sattar N;Stančáková A;Strauch K;Taylor KD;Thorand B;Thorleifsson G;Thorsteinsdottir U;Tuomilehto J;Witte DR;Dupuis J;Peyser PA;Zeggini E;Loos RJF;Froguel P;Ingelsson E;Lind L;Groop L;Laakso M;Collins FS;Jukema JW;Palmer CNA;Grallert H;Metspalu A;Dehghan A;Köttgen A;Abecasis GR;Meigs JB;Rotter JI;Marchini J;Pedersen O;Hansen T;Langenberg C;Wareham NJ;Stefansson K;Gloyn AL;Morris AP;Boehnke M;McCarthy MI
通讯作者：
McCarthy MI
影响因子：
9.8
作者：
Milet, Jacqueline;Dehais, Valrie;Mosser, Jean
通讯作者：
Mosser, Jean
影响因子：
158.5
作者：
Adams, PC;Reboussin, DM;Thomson, E
通讯作者：
Thomson, E