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

• Applicant: Dr. Stephan Buch
• Subject Area: Gastroenterology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 497319075

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.

• DFG Programme: Research Grants
• International Connection: Italy, Switzerland
• Cooperation Partners: Dr. Paola Dongiovanni, Ph.D.; Professor Dr. Felix Stickel