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A Genotype-Stratified Mechanistic Trial of Omega-3 Fatty Acids and FADS Variants in Diet-Induced Inflammation

Award Number: R01AT008621
ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2015
PERIOD OF PERFORMANCE END DATE: 01/31/2030

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A Genotype-Stratified Mechanistic Trial of Omega-3 Fatty Acids and FADS Variants in Diet-Induced Inflammation - Disregard of genetically-linked biological variation in the design and interpretation of clinical trials of marine omega-3 (n-3) highly unsaturated fatty acid (HUFA) supplementation and specifically limited inclusion of individuals carrying high-activity fatty-acid-desaturase (FADS1) alleles may have masked potential health benefits of individuals at elevated risk for cardiovascular and other chronic diseases. Our work over the past decade has revealed that genetic variation throughout the FADS gene cluster, and the resulting allele-frequency differences among population strata, are significant drivers of the effectiveness of n-3 HUFA supplementation. FADS1 are the rate-limiting steps in the conversion of dietary n-6 and n-3 polyunsaturated fatty acids (PUFA), linoleic acid (LA) and α-linolenic acid (ALA), respectively, to n-6 and n-3 HUFAs, including arachidonic acid (ARA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and their biologically active oxylipin metabolites. Importantly, the FADS1/2 gene cluster variation was recently identified as the largest multimorbidity locus in the human genome. A central discovery from our work and others is the differential synthesis of HUFAs and metabolism to bioactive lipids across genotype-defined strata. Groups enriched for the high-activity FADS1 rs174537-GG allele exhibit efficient conversion of dietary LA to ARA and its pro-inflammatory/pro-thrombotic oxylipins. Evidence in support of this work comes from our genotype subgroup analysis of the VITAL n-3 HUFA supplementation trial affirming that carriers of the high-activity allele, but not lower-activity carriers, randomized to n-3 supplementation demonstrated an ~80 % reduction in myocardial infarction (MI). We then applied two machine-learning methods to matched VITAL cohorts and found strong evidence that n-3 supplementation significantly decreased MI only in high-activity allele carriers (odds ratio 0.178; 95 % CI 0.046–0.69). These data lead to this proposal’s central hypothesis that gene–diet interactions drive a pathogenic imbalance in ARA versus EPA and DHA and their oxylipin products, particularly in high-activity allele carriers. We postulate that n-3 HUFA supplementation will decrease the ratio of ARA to EPA and DHA, providing a major benefit to these individuals. We propose a two-site randomized, double-blind, placebo-controlled, crossover n-3 HUFA supplementation trial that leverages the varied allele-frequency distributions across individuals to test this hypothesis. Specifically, we will supplement participants stratified by FADS genotypes at rs174537 with EPA-enriched n-3 HUFAs and evaluate changes in the balance of HUFA-containing lipids and oxylipin products, as well as inflammatory and clinical biomarkers linked to chronic disease. This trial will provide critical mechanistic evidence for genotypelinked biological heterogeneity in differential biological response to n-3 HUFAs. Such mechanistic data are essential to the future design of definitive precision nutrition clinical trials to prevent chronic diseases and reduce residual cardiometabolic risk.


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 = $781,765 )
2026	2026	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Research and Training in Complementary and Integrative Health	000	8	6/1/2026	NON-COMPETING CONTINUATION	$781,765
														Subtotal = $781,765

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Research and Training in Complementary and Integrative Health	000	7	8/6/2025	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $808,270 )
2024	2024	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Research and Training in Complementary and Integrative Health	001	7	9/12/2024	COMPETING CONTINUATION	$808,270
2024	2020	UNIVERSITY OF ARIZONA	845 N PARK AVE RM 538	TUCSON	AZ	85721	PIMA	USA	Research and Training in Complementary and Integrative Health	000	6	12/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $808,270

Issue Date FY: 2022 ( Subtotal = -$59 )
2022	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Research and Training in Complementary and Integrative Health	000	6	2/15/2022	NON-COMPETING CONTINUATION	$0
2022	2018	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Research and Training in Complementary and Integrative Health	002	3	6/29/2022	NON-COMPETING CONTINUATION	-$59
2022	2017	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Research and Training in Complementary and Integrative Health	003	2	6/29/2022	NON-COMPETING CONTINUATION	$0
2022	2017	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Research and Training in Complementary and Integrative Health	001	2	6/29/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = -$59

Issue Date FY: 2020 ( Subtotal = $554,302 )
2020	2020	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Research and Training in Complementary and Integrative Health	000	6	5/25/2020	NON-COMPETING CONTINUATION	$554,302
														Subtotal = $554,302

Issue Date FY: 2019 ( Subtotal = $1,004,233 )
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Research and Training in Complementary and Integrative Health	008	5	8/30/2019	SUPPLEMENT FOR EXPANSION	$383,750
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Research and Training in Complementary and Integrative Health	004	5	3/14/2019	NON-COMPETING CONTINUATION	$0
2019	2019	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Research and Training in Complementary and Integrative Health	003	5	3/8/2019	NON-COMPETING CONTINUATION	$607,836
2019	2018	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Research and Training in Complementary and Integrative Health	005	3	4/10/2019	NON-COMPETING CONTINUATION	-$282,284
2019	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Research and Training in Complementary and Integrative Health	006	4	4/10/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$282,284
2019	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Research and Training in Complementary and Integrative Health	001	4	1/25/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$492,933
2019	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Research and Training in Complementary and Integrative Health	007	4	7/8/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2018	UNIVERSITY OF ARIZONA	888 N EUCLID AVE RM 510	TUCSON	AZ	85719	PIMA	USA	Research and Training in Complementary and Integrative Health	002	4	2/7/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2019	2018	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Research and Training in Complementary and Integrative Health	000	3	1/24/2019	NON-COMPETING CONTINUATION	-$480,286
														Subtotal = $1,004,233

Issue Date FY: 2018 ( Subtotal = $773,509 )
2018	2018	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Research and Training in Complementary and Integrative Health	001	3	3/14/2018	NON-COMPETING CONTINUATION	$0
2018	2018	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Research and Training in Complementary and Integrative Health	000	3	2/1/2018	NON-COMPETING CONTINUATION	$696,157
2018	2018	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Research and Training in Complementary and Integrative Health	002	3	4/20/2018	NON-COMPETING CONTINUATION	$77,352
														Subtotal = $773,509

Issue Date FY: 2017 ( Subtotal = $668,940 )
2017	2017	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Research and Training in Complementary and Integrative Health	002	2	3/23/2017	NON-COMPETING CONTINUATION	$484
2017	2017	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Research and Training in Complementary and Integrative Health	003	2	7/5/2017	NON-COMPETING CONTINUATION	$66,410
2017	2017	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Research and Training in Complementary and Integrative Health	001	2	3/1/2017	NON-COMPETING CONTINUATION	$602,046
2017	2016	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Research and Training in Complementary and Integrative Health	000	1	10/28/2016	NEW	$0
														Subtotal = $668,940

Issue Date FY: 2016 ( Subtotal = $770,209 )
2016	2016	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Research and Training in Complementary and Integrative Health	000	1	11/20/2015	NEW	$715,262
2016	2016	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Research and Training in Complementary and Integrative Health	001	1	12/9/2015	NEW	$54,947
2016	2016	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Research and Training in Complementary and Integrative Health	002	1	2/19/2016	NEW	$0
														Subtotal = $770,209

Grand Total All Awards = $5,361,169

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A Genotype-Stratified Mechanistic Trial of Omega-3 Fatty Acids and FADS Variants in Diet-Induced Inflammation

Award Number: R01AT008621

ORGANIZATION: CENTER FOR DRUG EVALUATION AND RESEARCH, NIH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2015

PERIOD OF PERFORMANCE END DATE: 01/31/2030

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