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

> **NIH NIH K99** · BROAD INSTITUTE, INC. · 2024 · $164,980

## Abstract

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.

## Key facts

- **NIH application ID:** 10906227
- **Project number:** 5K99HL169733-02
- **Recipient organization:** BROAD INSTITUTE, INC.
- **Principal Investigator:** Satoshi Koyama
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $164,980
- **Award type:** 5
- **Project period:** 2023-09-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10906227

## Citation

> US National Institutes of Health, RePORTER application 10906227, Whole genome sequence interpretation for lipids to discover new genes and mechanisms for coronary artery disease (5K99HL169733-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10906227. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*