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Molecularly-informed polygenic scores for the prediction of response to omega-3 fatty acid supplementation

Award Number: R03DK145936
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/18/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Molecularly-informed polygenic scores for the prediction of response to omega-3 fatty acid supplementation - PROJECT SUMMARY/ABSTRACT Omega-3 fatty acids (N3FA) have evidence for prevention of type 2 diabetes, chronic kidney disease, and other cardiometabolic diseases, acting via established anti-inflammatory and lipid-related mechanisms. N3FA supplements, primarily fish oil, are safe and inexpensive, making them highly compelling for clinical use. However, N3FA intervention trials have shown mixed results, with substantial heterogeneity in treatment effects across population groups. It is important to understand the contribution of genetics to this heterogeneity in N3FA response so that N3FA supplements can be targeted to the individuals who will benefit most. Gene-environment interaction (GxE) analysis can capture this type of genetically driven heterogeneity in observational datasets, but requires appropriate interaction-focused methods and large datasets to achieve sufficient statistical power. Recent work has shown improvements in GxE detection by leveraging molecular quantities, such as plasma N3FA status, and the use of interaction-focused polygenic scores (iPGS) that aggregate over individually small GxE signals genome-wide. We hypothesize that polygenic and molecularly-informed GxN3FA interaction testing can inform genetic scores that predict changes in cardiometabolic risk factors (CRFs) in response to N3FA supplementation in targeted trials. We propose to explore this hypothesis through two aims. First, we will generate a series of molecularly-informed iPGS quantifying differences in the magnitude of N3FA-CRF association across large-scale observational data sets. GxE meta-analysis will be conducted in eight TOPMed cohorts and the UKB for five key glycemic, inflammatory, and lipid CRFs. Separate models will consider genetic modification of the standard (N3FA-CRF), “absorption” (N3FA-plasma N3FA), and “transduction” (plasma N3FA- CRF) relationships. Meta-analyzed interaction estimates will be aggregated into iPGS, with iPGS optimization and interaction replication conducted in the All of Us cohort. Second, we will test whether observational GxE- based genetic predictors predict the CRF response to N3FA supplementation in an intervention trial context. We will generate iPGS using genetic data from the FAS fish oil supplementation trial (N=208) and test whether these iPGS predict six-week changes in the same set of CRFs. This work promises to both provide preliminary data supporting the generation of genetic and omics data in samples from large intervention trials in future work, and provide a methodological model for similar explorations of other dietary traits.


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 = $123,750 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	5/25/2026	NEW	$123,750
														Subtotal = $123,750

Grand Total All Awards = $123,750

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Molecularly-informed polygenic scores for the prediction of response to omega-3 fatty acid supplementation

Award Number: R03DK145936

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/18/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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