Discovery of genetic modifier for the development of cirrhosis in hereditary haemochromatosis

发现遗传性血色病发展为肝硬化的基因修饰剂

• 批准号: 497319075
• 负责人: Dr. Stephan Buch
• 金额: --
• 依托单位: Institut für Klinische Pharmakologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/497319075?language=en
• 关键词: Discovery; genetic; modifier; development; cirrhosis

Project summaryBackground: Hereditary haemochromatosis (HH) is the most common autosomal recessively inherited metabolic disease in people of European descent. HH is characterized by excessive accumulation of iron in parenchymal cells. The liver is the site of highest iron deposition and subsequent organ damage. Cirrhosis of the liver represents the main factor of increased mortality in symptomatic HH. HH is predominantly attributable to a cysteine to tyrosine substitution at position 282 within the HFE gene. Although common, this genetic polymorphism is not always phenotypically expressed. New cohort data have shown that in some haemochromatosis patients cirrhosis may already occur at lower levels of iron overload, while other people with severe iron overload do not have cirrhosis on specimens of liver obtained by biopsy. Thus, C282Y homozygosity is a necessary but not sufficient condition for the development of haemochromatosis associated disease symptoms. To date, no comprehensive genetic research has been conducted on modifying genetic factors for the development of cirrhosis in HH.Aims: The proposed research project aims to identify genetic risk modifiers of cirrhosis development in hereditary haemochromatosis. For that reason, this project will perform the first comprehensive genome-wide association study (GWAS) for cirrhosis susceptibility loci in C282Y homozygous individuals. Overall, the project aims to enhance the understanding of disease mechanisms and pathways of cirrhosis development in HH. Own preceding work: The applicant has contributed to the genetics of hereditary haemochromatosis in a very visible way in the last years by the discovery of three common risk genes for the development of cirrhosis in HH. To date, the applicants and associated collaborators have collected >2400 unrelated C282Y homozygous individuals recruited from hepatological and internal medicine departments from nine European countries. The applicant builds on his expertise in successful gene identification in complex disorders.Work plan: Two complementary experimental designs will be pursued to identify genetic risk modifiers of cirrhosis. The first study will perform a discovery GWAS in a large multicenter hospital-based patient cohort (N 2400). State-of-the-art imputation technology will enable the detection of genome-wide association signals and fine-mapping. Additional targeted sequencing at delineated risk loci will be used to detect low frequency high-impact variants. The second GWAS approach will use non-invasive markers of liver fibrosis for risk gene discovery in HFE C282Y homozygous individuals from European Biobank repositories.Conclusion: The proposed project offers a unique possibility to further understand mechanisms by which genetic variants confer the risk for developing cirrhosis in HH.

项目概要背景：遗传性血色病（HH）是欧洲人最常见的常染色体隐性遗传性代谢病。HH的特征是铁在实质细胞中过度积聚。肝脏是铁沉积最高和随后器官损伤的部位。肝硬化是症状性HH死亡率增加的主要因素。HH主要归因于HFE基因内第282位的半胱氨酸被酪氨酸取代。虽然常见，这种遗传多态性并不总是表型表达。新的队列数据表明，在一些血色病患者中，肝硬化可能已经在较低水平的铁过载下发生，而其他严重铁过载的人通过活检获得的肝脏标本没有肝硬化。因此，C282Y纯合性是血色病相关疾病症状发展的必要条件，但不是充分条件。迄今为止，没有全面的遗传研究已进行修改遗传因素的肝硬化的发展在HH。Aims：拟议的研究项目旨在确定遗传性血色病肝硬化发展的遗传风险修饰。因此，该项目将在C282Y纯合子个体中进行第一次全面的全基因组关联研究（GWAS）。总的来说，该项目旨在加强对HH肝硬化发展的疾病机制和途径的理解。自己的前期作品：申请人在过去几年中通过发现HH中发生肝硬化的三种常见风险基因，以非常明显的方式对遗传性血色病的遗传学做出了贡献。到目前为止，申请人和相关合作者已经从9个欧洲国家的肝病和内科招募了>2400名无关的C282Y纯合子个体。申请人建立在他的专业知识在复杂disorders.Work成功的基因鉴定：两个互补的实验设计将被追求，以确定肝硬化的遗传风险修饰。第一项研究将在一个大型多中心医院患者队列（N 2400）中进行发现GWAS。最先进的插补技术将能够检测全基因组关联信号和精细定位。在划定的风险基因座处的额外靶向测序将用于检测低频高影响变体。第二种GWAS方法将使用非侵入性肝纤维化标志物在来自欧洲生物库的HFE C282 Y纯合个体中发现风险基因。结论：拟议的项目提供了一种独特的可能性，可以进一步了解遗传变异赋予HH发生肝硬化风险的机制。