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Proteomics of Cardiometabolic and Renal Traits in African Americans

Award Number: R01HL133870
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2017
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Proteomics of Cardiometabolic and Renal Traits in African Americans - Project Summary/Abstract During the initial funding period, we applied aptamer-based proteomic analysis (SomaLogic) to investigate cardiometabolic disease among African Americans (AAs) in the Jackson Heart Study (JHS). In published studies, we identified novel biomarkers that are associated with the development of left ventricular hypertrophy, CHF and with CKD over a decade before the onset of clinical disease, including plasma proteins that are differentially associated with outcomes in individuals of predominantly African vs. European ancestry. We also described how whole genome sequence analysis of the plasma proteome in individuals with African ancestry increases our power to detect novel genetic determinants. In addition to identifying over 100 new locus-protein associations, the associations suggest new mechanisms of genetically mediated diseases linked to African ancestry. We identified a novel association between variants in APOL1 and the protein CKAP2, as well as an association between ATTR amyloidosis and RBP4 levels in community dwelling individuals without CHF. In unpublished work, we have also identified novel determinants of incident CHD, including Secreted Transmembrane Protein 1 (SECTM1), a poorly characterized protein with potential chemotactic activity for monocytes. In follow-up in silico analyses, SNPs associated with circulating SECTM1 levels are also associated with the monocyte percentage of white blood cells in large human databases. Further, our pilot experiments in mice demonstrate that short term administration of recombinant SECTM1a (mouse homologue) increases pro- atherogenic and inflammatory Ly6Chi circulating monocytes, as well as monocyte progenitors in the bone marrow. These data suggest that SECTM1 may be a novel regulator of monocyte biology that contributes to CHD. More broadly, we have shown that large-scale proteomic profiling in well-characterized populations can identify proteins and pathways that may be causal for adverse cardiometabolic conditions. In this renewal, we will first extend our discovery efforts of novel biomarkers of incident CHD and its risk factors using the recently expanded, highly specific Olink 3,000-plex platform (Aim 1), which includes >2100 proteins that have not been assayed in a large number of AAs. In Aim 2, fine mapping of protein-associated genetic variants, co-localization studies with established CHD-associated variants, and Mendelian Randomization experiments will be used to assess causality of protein-associated variants for CHD, CKD, and other cardiometabolic conditions. For both Aims 1 & 2, findings will be replicated in a multi-ethnic population (MESA), and extended through multi-omic analyses involving extensive metabolomic data available in both JHS and MESA. Putative causal variants that emerge from these analyses will be validated in model systems in Aim 3, with initial studies focusing on SECTM1’s atherogenic potential in mouse models. In addition to SECTM1, we anticipate follow-up investigations of two other proteins highlighted by our discovery work. All data from this multi- institutional collaboration will be made publicly available in real time for the entire scientific community.


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 = $725,782 )
2026	2026	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	001	8	3/30/2026	NON-COMPETING CONTINUATION	$22,217
2026	2026	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	8	2/27/2026	NON-COMPETING CONTINUATION	$703,565
														Subtotal = $725,782

Issue Date FY: 2025 ( Subtotal = $494,567 )
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	001	7	7/3/2025	NON-COMPETING CONTINUATION	$49,457
2025	2025	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	7	3/26/2025	NON-COMPETING CONTINUATION	$445,110
														Subtotal = $494,567

Issue Date FY: 2024 ( Subtotal = $569,531 )
2024	2024	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	001	6	2/21/2024	COMPETING CONTINUATION	$569,531
2024	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC.	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	5	12/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $569,531

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	5	9/9/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	5	9/1/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	UNIVERSITY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Cardiovascular Diseases Research	001	3	8/13/2021	NON-COMPETING CONTINUATION	-$130,876
2021	2019	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	002	4	8/13/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$130,876
2021	2019	UNIVERSITY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Cardiovascular Diseases Research	000	3	8/12/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $721,062 )
2020	2020	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	002	5	8/25/2020	NON-COMPETING CONTINUATION	$721,062
2020	2019	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	001	4	8/24/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2020	2019	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	000	4	3/19/2020	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $721,062

Issue Date FY: 2019 ( Subtotal = $1,163,555 )
2019	2019	UNIVERISTY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Cardiovascular Diseases Research	001	3	9/16/2019	NON-COMPETING CONTINUATION	-$1,032,510
2019	2019	UNIVERISTY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Cardiovascular Diseases Research	000	3	2/15/2019	NON-COMPETING CONTINUATION	$1,163,607
2019	2019	BETH ISRAEL DEACONESS MEDICAL CENTER, INC	330 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cardiovascular Diseases Research	002	4	9/17/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,032,458
														Subtotal = $1,163,555

Issue Date FY: 2018 ( Subtotal = $1,442,862 )
2018	2018	UNIVERISTY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Cardiovascular Diseases Research	001	2	5/15/2018	NON-COMPETING CONTINUATION	$28,856
2018	2018	UNIVERISTY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Cardiovascular Diseases Research	000	2	2/27/2018	NON-COMPETING CONTINUATION	$1,414,006
														Subtotal = $1,442,862

Issue Date FY: 2017 ( Subtotal = $1,579,430 )
2017	2017	UNIVERISTY OF MISSISSIPPI MEDICAL CENTER	2500 N STATE ST	JACKSON	MS	39216	HINDS	USA	Cardiovascular Diseases Research	000	1	3/31/2017	NEW	$1,579,430
														Subtotal = $1,579,430

Grand Total All Awards = $6,696,789

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Proteomics of Cardiometabolic and Renal Traits in African Americans

Award Number: R01HL133870

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2017

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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