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

Coronary artery disease (CAD) is a leading cause of death worldwide. Familial hypercholesterolemia (FH) is an extreme form of inherited hypercholesterolemia and an important risk factor for CAD. FH is caused by pathogenic variants in known cholesterol-related genes, and carriers are exposed to severe hypercholesterolemia and often develop CAD at an early age. Early intervention reduces the progression of atherosclerosis and prolongs CAD-free survival; therefore, early diagnosis and treatment are essential in the management of FH. Current guidelines recommend genetic screening and genotype-based risk stratification for individuals with severe hypercholesterolemia, as well as specific therapies. However, current genetic diagnostic criteria are limited to previously described genes and variants. Recent investigations, including our own, suggest that the diagnostic yield of genetic testing for FH is low (<2% of individuals with severe hypercholesterolemia). Furthermore, only ~2% appear to have a comparably strong polygenic contribution, despite evidence of a substantial genetic influence on FH. Based on these findings, Dr. Koyama hypothesizes that undiscovered FH alleles exist and may be important for diagnosis, surveillance, and treatment. To improve the genetic diagnostic yield for FH and capture currently undiagnosed carriers, Dr. Koyama proposes to develop updated diagnostic criteria for FH using population-scale genome sequencing cohorts and a comprehensive variant-interpretation framework. In this proposal, Dr. Koyama will (1) extend rare-variant analyses to noncoding variants that are not covered by current diagnostic criteria using whole-genome sequencing data, and (2) integrate commonand rare-variant risk-stratification models to more comprehensively describe genetic risk for hyperlipidemia. This project builds on Dr. Koyama's clinical and research experience and will allow him to further develop expertise in cardiovascular genetic research. He will benefit from the rich scientific resources and collaborations at MGB Personalized Medicine and will lead this clinically meaningful project independently. Project Number: 4R00HL169733-03 | Fiscal Year: 2026 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Satoshi Koyama | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $249,000 | Activity Code: R00 | Study Section: NSS View on NIH RePORTER: https://reporter.nih.gov/project-details/4R00HL16973303