Whole genome sequence interpretation for lipids to discover new genes and mechanisms for coronary artery disease

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PROJECT SUMMARY/ABSTRACT Coronary artery disease (CAD) is one of the leading causes of death worldwide. Family hypercholesterolemia (FH) is an extreme case of inherited hypercholesterolemia and an important risk factor for CAD. FH is caused by a single mutation in known cholesterol-related genes, and carriers of these mutations are exposed to severe hypercholesterolemia and develop CAD at an early age. Early intervention has been shown to reduce the progression of atherosclerosis and prolong CAD-free survival. Therefore, early diagnosis and treatment are important in the management of FH. Current guidelines recommend genetic screening and genotype-based risk stratification for people with severe hypercholesterolemia, as well as specific therapies. However, current genetic diagnostic criteria are limited to genes/variants that have already been described. Recent investigations, including ours, suggest that the diagnostic yield of genetic testing for FH is limited (< 2% of individuals with severe hypercholesterolemia). Furthermore, only ~2% have a similarly strong polygenic contribution despite studies indicating a sizable contribution of genetics to FH. From these findings, Dr. Koyama hypothesize that undiscovered FH alleles exist and may be important for diagnosis, surveillance, and treatment. With the aim of improving genetic diagnostic yields for FH and capturing potential carriers currently undiagnosed, Dr. Koyama proposes to develop an updated diagnostic criteria of FH using the population-scale genome sequence cohorts and comprehensive variant interpretation framework. In this proposal, first, Dr. Koyama will refine the list of FH associated variants/genes by associating ultrarare coding variants in the whole exome datasets. Second, Dr. Koyama will extend the analysis to the noncoding variants which were not conferred in the current diagnostic criteria using the whole genome sequencing dataset. Finally, Dr. Koyama will integrate common and rare genetic risk stratification models to comprehensively describe the genetic risk of hyperlipidemia. This project is built on Dr. Koyama’s clinical/research skills and experiences and allows him to gain more experience in genetic research in the cardiovascular disease. Under the mentorship of primary mentor Dr. Pradeep Natarajan, the Director of Preventive Cardiology and co-mentor Dr. Patrick Ellinor, the Chief of Cardiology of Massachusetts General Hospital, Dr. Koyama will significantly benefit from rich scientific resources and collaborations at the Broad Institute of MIT and Harvard and at the Division of Cardiology at the Massachusetts General Hospital.