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From genetic association to function: pleiotropic novel genes and variants linking lipid metabolism and cardiovascular diseases

Award Number: R35HL172107
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2024
PERIOD OF PERFORMANCE END DATE: 03/31/2031

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From genetic association to function: pleiotropic novel genes and variants linking lipid metabolism and cardiovascular diseases - PROJECT SUMMARY Human genetic investigations have nominated hundreds of novel genomic loci harboring genes that influence a range of cardiovascular (CV) diseases and their risk factors, including plasma lipids. However, only a fraction of these novel loci have been investigated to determine the causal genes and underlying molecular mechanisms leading to increased risk of—or protection from—CV disease. While LDL reduction is effective in reducing risk of atherosclerotic cardiovascular disease, other common cardiovascular diseases such as peripheral arterial disease, abdominal aortic aneurysm, and aortic stenosis have no effective non-surgical medical therapies. Importantly, a growing body of human genetic data has identified that even beyond CAD, these additional CV diseases have significant genetic associations with genomic loci/genes/variants that are also associated with plasma lipid traits. This research program is focused on a systematic approach to fill some of the major gaps in knowledge that link these human genomic loci to new biology, disease pathogenesis and potential therapeutic targets. The goal is to provide a roadmap for how the hundreds of novel loci/genes/variants associated with CVD might ultimately be investigated in an efficient manner. The focus will be on genes associated with both plasma lipid traits and at least one major cardiovascular disease. Due to the liver’s primary role in lipid and lipoprotein metabolism, the investigators will target liver-expressed genes. Furthermore, they will leverage naturally- occurring protein-coding variation in genes that influence plasma lipids and CVD in order to gain greater insight into the structure-function relationships of these proteins and relationship to phenotypes. This is an ambitious program of research with two major Research Foci: Focus 1: Interrogation of novel putatively causal genes at loci associated with both lipid traits and CV disease. Through systematic data ingestion and analyses of large- scale GWAS and sequencing data, the study team will generate (and refine) a prioritized list of liver-expressed genes at loci significantly associated with plasma lipids and at least one CV disease. Cell-based and murine model systems will be used, accompanied by human studies, to validate causal genes and gain insight into the physiological and molecular mechanisms by which they exert their influence. Focus 2: Leveraging protein-coding variants to provide insight into structure-function properties of proteins influencing lipid traits and CV disease. Through systematic analyses of large-scale public and private genomic data linked to phenotypes, the investigators will develop a prioritized list of novel protein-coding variants associated with lipids and CVD and perform comparative functional studies in model systems and in human carriers. The outcome of these studies is expected to establish a firm biological basis for a substantial number of novel genes/proteins and protein- coding variants that influence plasma lipoprotein metabolism and CV disease. The intent is to establish a paradigm by which novel genes/variants associated with NHLBI-related phenotypes can be efficiently validated and rapidly provided to the broader scientific community for further investigation.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $1,111,752 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	2	4/22/2025	NON-COMPETING CONTINUATION	$1,000,576
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	001	2	7/3/2025	NON-COMPETING CONTINUATION	$111,176
														Subtotal = $1,111,752

Issue Date FY: 2024 ( Subtotal = $1,123,889 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cardiovascular Diseases Research	000	1	2/12/2024	NEW	$1,123,889
														Subtotal = $1,123,889

Grand Total All Awards = $2,235,641

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From genetic association to function: pleiotropic novel genes and variants linking lipid metabolism and cardiovascular diseases

Award Number: R35HL172107

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 04/01/2024

PERIOD OF PERFORMANCE END DATE: 03/31/2031

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