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Genetic Architecture of Natriuretic Peptides and Blood Pressure Response

Award Number: R01HL184037
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/04/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2031

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Genetic Architecture of Natriuretic Peptides and Blood Pressure Response - PROJECT SUMMARY Natriuretic peptides (NPs) are vital cardiac-derived hormones that play key roles in natriuresis, vascular function, and blood pressure (BP) regulation. Recent evidence has also highlighted that low NP levels are associated with a higher risk of cardiometabolic diseases such as hypertension. Our prior research combining data from population cohorts and clinical trials has demonstrated that NP levels vary by sex, race, and obesity. Apart from these factors, NP levels are known to be highly heritable, with up to half of the variance in NP levels being explained by genetics. Previous studies on the genetic determinants of NP levels were limited by their focus on diseased populations, use of genotyping array data, or lack of genetic diversity, and they often did not account for factors like sex and ancestry. The availability of whole genome sequencing (WGS) data from a multiethnic cohort of individuals provides an opportunity to advance the discovery of novel genomic loci and rare variants regulating NP levels. In the proposed study, we will leverage data from the TransOmics for Precision Medicine cohorts, UK Biobank, and All of Us Research Program to comprehensively study the genetic architecture of NP levels, including the common, rare, and structural variants. We will conduct fine mapping to identify causal variants and perform functional analyses to prioritize genes associated with NPs. Additionally, the summary statistics of the common variant analysis will be used to develop several iterations of NP polygenic risk scores (PGS) utilizing standardized methodologies. The best-performing NP PGS will be validated, and the association of genetically determined NP levels with cardiometabolic and cardiovascular disease will be examined. The NP PGS will then be used to conduct a Mendelian randomization analysis to examine the causal role of NPs in cardiometabolic disease. Using this NP PGS, we will explore the clinical implications of genetically determined NP levels on the BP response to salt and volume loading by conducting a genotype-first trial. We will recruit 200 hypertensive individuals (age ≥18 years; 50% females) with low NP PGS (1st tertile; N=100) and high NP PGS (3rd tertile; N=100). Participants will receive 1 week each of high and low-sodium diets in a random sequence using a crossover stratified design. At the end of each diet period, the participants will undergo a volume loading (normal saline infusion) protocol. Each diet period will be followed by a 1-week washout period. The primary outcomes will be differences in the change in 24-hour ambulatory systolic BP and NP levels after a high salt diet compared with the low salt diet between the genotype groups. We will also assess the difference in the change in NP levels following the volume loading after high and low-salt diets between the genotype groups. This comprehensive study aims to elucidate the genetic determinants of NP levels and their impact on BP and NP response to dietary and volume loading, potentially leading to individualized NP-based therapies for cardiovascular disease prevention and management.


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: 2026 ( Subtotal = $734,986 )
2026	2026	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Cardiovascular Diseases Research	000	1	8/6/2026	NEW	$734,986
														Subtotal = $734,986

Grand Total All Awards = $734,986

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Genetic Architecture of Natriuretic Peptides and Blood Pressure Response

Award Number: R01HL184037

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/04/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2031

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