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Identification of the role of HDL function in human cardiovascular disease through proteomics and genetics

Award Number: R01HL136373
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Clinical and epidemiological studies show a robust, inverse association of HDL cholesterol (HDL-C) levels with coronary heart disease (CHD) risk. However, raising HDL-C does not seem to provide therapeutic benefits, indicating that HDL-C levels are not a reliable measure of the cardio-protective effects of HDL. Moreover, the relationship between HDL-C and stroke risk is not clear with studies showing an inverse, direct, or lack of association. Recently, in mostly white cohorts, the cholesterol efflux capacity (CEC) of HDL correlated with both the prevalence and incidence of CHD independently of plasma levels of HDL-C and APOA1 (the major structural protein of HDL). On the other hand, increased HDL CEC was associated with increased stroke risk. Our preliminary data show no association between stroke risk and plasma HDL-C levels but a robust reduction in HDL CEC in stroke patients indicates that HDL's function might be a more relevant metric for assessing the stroke risk. Moreover, our preliminary results suggest that although African Americans have higher HDL-C levels they suffer from greater CHD risk, therefore, it is imperative to determine if HDL CEC associates with CHD risk better than HDL-C. We propose to determine if measures of HDL CEC do indeed provide value for CHD or stroke risk prediction in a racially balanced cohort. Studies in mostly white cohorts highlight that changes in HDL function are a reflection of changes in the HDL proteome. Therefore, identification of the protein cargo signature responsible for loss of HDL CEC in a bi- racial cohort may provide biomarkers of clinical validity that indicate CHD or stroke risk tailored to each race. To evaluate the predictive value of sterol efflux capacity of HDL and the protein signature that associates with dysfunctional HDL, we will use a case-control cohort (with 1000 each healthy, stroke and CHD cases) within The REasons for Geographic And Racial Differences in Stroke (REGARDS) Study. This is a NIH-sponsored national, longitudinal study of risk factors for stroke in over 30,000 African-American and Caucasian American men and women over 45 years of age, with a high prevalence of stroke and CHD. Due to unique composition of the REGARDS population we will be able to determine the impact of race and sex on our measures. Our preliminary data in mice using the 100-strain Hybrid Mouse Diversity Panel, developed by our collaborator, Dr. Jake Lusis of UCLA, successfully identified significant QTLs that modulate sterol efflux. It is therefore important to understand whether genetic mapping of sterol efflux trait identifies new CHD and stroke- related polymorphisms in humans. The data produced by this study would 1) determine the impact of race and sex on HDL function and the HDL proteome, 2) form the basis for development of clinical assays for assessing the role of HDL in cardiovascular disease, 3) facilitate race-specific prediction of CHD and stroke 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: 2024 ( Subtotal = $0 )
2024	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cardiovascular Diseases Research	000	5	4/17/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $446,111 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cardiovascular Diseases Research	000	5	12/9/2021	NON-COMPETING CONTINUATION	$401,499
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cardiovascular Diseases Research	001	5	5/31/2022	NON-COMPETING CONTINUATION	$44,612
														Subtotal = $446,111

Issue Date FY: 2021 ( Subtotal = $509,831 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cardiovascular Diseases Research	001	4	5/18/2021	NON-COMPETING CONTINUATION	$50,984
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cardiovascular Diseases Research	000	4	1/29/2021	NON-COMPETING CONTINUATION	$458,847
														Subtotal = $509,831

Issue Date FY: 2020 ( Subtotal = $515,572 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cardiovascular Diseases Research	001	3	3/7/2020	NON-COMPETING CONTINUATION	$25,779
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cardiovascular Diseases Research	000	3	1/15/2020	NON-COMPETING CONTINUATION	$489,793
														Subtotal = $515,572

Issue Date FY: 2019 ( Subtotal = $516,713 )
2019	2019	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cardiovascular Diseases Research	000	2	12/31/2018	NON-COMPETING CONTINUATION	$516,713
														Subtotal = $516,713

Issue Date FY: 2018 ( Subtotal = $438,081 )
2018	2018	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Cardiovascular Diseases Research	000	1	1/5/2018	NEW	$438,081
														Subtotal = $438,081

Grand Total All Awards = $2,426,308

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Identification of the role of HDL function in human cardiovascular disease through proteomics and genetics

Award Number: R01HL136373

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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