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

背景：遗传性血色沉着症(HH)是欧洲人后裔中最常见的常染色体隐性遗传性代谢性疾病。HH的特征是实质细胞中铁的过度积累。肝脏是铁沉积和随后的器官损伤最多的地方。肝硬变是症状性HH病死率升高的主要因素。HH主要归因于HFE基因第282位半胱氨酸到酪氨酸的替代。虽然常见，但这种遗传多态并不总是表现出表型。新的队列数据显示，在一些血色沉着症患者中，较低水平的铁超载可能已经发生了肝硬变，而另一些严重铁超载的人在通过活检获得的肝脏样本上没有发生肝硬变。因此，C282Y纯合子是发生血色病相关疾病症状的必要条件，但不是充分条件。目的：本研究旨在确定遗传性血色素沉着症中肝硬变发生的遗传危险因素。为此，该项目将在C282Y纯合子个体中进行第一个全面的全基因组关联研究(GWAS)，以确定肝硬化易感基因。总体而言，该项目旨在加强对HH肝硬变发病机制和发展途径的了解。自己之前的工作：在过去的几年里，申请人通过发现三个共同的HH肝硬化发展风险基因，以非常明显的方式对遗传性血色素沉着症的遗传学做出了贡献。到目前为止，申请者和相关的合作者已经从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。申请者以他在复杂疾病中成功的基因识别的专业知识为基础。工作计划：将进行两个互补的实验设计来识别肝硬变的遗传风险修饰因素。第一项研究将在以医院为基础的大型多中心患者队列(N 2400)中发现GWAS。最先进的分配技术将使全基因组关联信号的检测和精细绘图成为可能。描述的风险基因的额外定向测序将用于检测低频率、高影响的变异。第二种方法将使用非侵入性的肝纤维化标记物在来自欧洲生物库的HFE C282Y纯合子个体中发现风险基因。结论：拟议的项目为进一步了解基因变异导致HH发展为肝硬化的风险提供了独特的可能性。

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.