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Application of a novel polygenic risk score to the study of diabetic cardiomyopathy in diverse populations

Award Number: R21HL161718
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Application of a novel polygenic risk score to the study of diabetic cardiomyopathy in diverse populations - Summary Type 2 diabetes (T2D) is an important risk factor for heart failure (HF) independent of traditional risk factors for cardiovascular disease. However, lowering hemoglobin A1c levels has little effect on reducing HF risk among T2D patients. These findings highlight the importance of primordial prevention strategies to curb T2D-related HF and suggest that pathophysiologic mechanisms independent of hyperglycemia may link these conditions. Hence, molecular phenotyping to better predict T2D and articulate biological pathways relating T2D to HF are critically needed and in line with recommendations by the American Heart Association and Heart Failure Society of America urging further research into the shared genomic susceptibility of these conditions. Recently, a novel genome-wide polygenic risk score (PRS) that combined contributions of millions of genetic variants showed promise for classifying individuals according to T2D status. However, its value for longitudinally predicting the development of T2D from childhood was not assessed and its generalizability was limited to European populations. We hypothesize that a PRS developed using large-scale multi-ancestry genomics datasets will have optimal risk prediction accuracy and be applicable to ancestrally diverse samples. We further hypothesize that the serum metabolomes of individuals with high genetic risk for T2D contain endogenous molecules reflecting mechanisms of diabetic cardiomyopathy, an important T2D-related HF endophenotype. Therefore, the objectives of this proposed study are to develop a PRS to predict T2D risk from early life to midlife and to identify mechanisms underlying diabetes-induced HF. Our PRS will be generated by combining summary statistics from a multi-ethnic GWAS of T2D among more than 1.4 million participants with linkage disequilibrium data from a nationally representative sample of US adults (Aim 1a). Following PRS testing using individual level genomic data from ~600,000 multi-ancestry participants, we will apply our PRS to biracial cohorts of the Bogalusa Heart Study (BHS; n=1,808) and Coronary Artery Risk Development in Young Adults (n=2,341) with measures of glycemic status and glucose lowering medication across the lifespan. Leveraging these unique resources, we will be the first to evaluate the clinical utility of genomic information in the prediction of T2D in childhood and early adulthood (Aim 1b). Finally, we will perform mediation analyses to identify circulating metabolites and metabolic pathways linking genetically elevated T2D risk to subclinical measures of HF leveraging combined sample of 10,929 BHS and the Trans-omics for Precision Medicine program participants (Aim 2). This innovative multi-omics study will likely aid in developing targeted primordial interventions by providing a genomic algorithm to identify individuals at high risk for T2D at an early age and prior to the manifestation of clinical risk factors. Further, our findings may reveal novel molecular mechanisms for diabetic cardiomyopathy, helping to guide pharmaceutical development to treat this condition.


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 = -$17,502 )
2025	2023	THE ADMINISTRATORS OF TULANE EDUCATIONAL FUND	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	2	12/17/2024	NON-COMPETING CONTINUATION	-$17,502
														Subtotal = -$17,502

Issue Date FY: 2023 ( Subtotal = $122,007 )
2023	2023	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	2	7/7/2023	NON-COMPETING CONTINUATION	$122,007
														Subtotal = $122,007

Issue Date FY: 2022 ( Subtotal = $122,007 )
2022	2022	ADMINISTRATORS OF THE TULANE EDUCATIONAL FUND, THE	6823 SAINT CHARLES AVE	NEW ORLEANS	LA	70118	ORLEANS	USA	Cardiovascular Diseases Research	000	1	7/21/2022	NEW	$122,007
														Subtotal = $122,007

Grand Total All Awards = $226,512

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Application of a novel polygenic risk score to the study of diabetic cardiomyopathy in diverse populations

Award Number: R21HL161718

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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