Abstract

High density lipoprotein cholesterol (HDL-C) levels are thought to protect against cardiovascular disease. This may or may not be true in certain populations. The long-term goal of this research project is to determine if a deficiency in the lipoprotein receptor, scavenger receptor class B type I or SR-BI, is a cause of high levels of HDL-C and, perhaps paradoxically, an increased risk for cardiovascular disease.
In specific aim 1, we will perform in vitro experiments to examine the mechanism(s) by which certain SR-BI gene (SCARB1) variants affect SR-BI protein expression.
In specific aim 2, we will continue recruiting subjects with HDL-C levels above 60 mg/dl (this is because levels above 60 mg/dl are thought to be cardioprotective) and obtaining blood specimens to measure cholesterol levels, DNA, and monocyte-derived macrophage that express SR-BI protein. We will examine the association of genetic variations within the SCARB1 gene with lipid levels, macrophage SR-BI protein and RNA expression and SR-BI function (as measured by the uptake of cholesteryl esters from radiolabeled HDL). We will also examine the association of SCARB1 polymorphisms and lipid levels and subclinical atherosclerosis in participants of the Multi-Ethnic Study of Atherosclerosis (MESA) and in subjects with premature myocardial infarction (Myocardial Infarction Genetics Consortium Study). The results from our studies will provide further insight into the role of SR-BI on lipid levels and cardiovascular disease in subjects with elevated levels of HDL-C, in a larger population (MESA) well-represented by persons of Caucasian, African-American, Hispanic and Asian ancestry, and in subjects with premature myocardial infarction.

Public Health Relevance

High density lipoproteins (HDL) are considered the """"""""healthy"""""""" or """"""""good"""""""" fraction of the blood cholesterol levels. However, heart disease can occur despite a person having desirable levels of HDL. Our study will examine whether variations in the gene for the HDL receptor, scavenger receptor class B type I or SR-BI, might be associated with good levels of HDL and heart disease.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL075646-05A2
Application #
7983748
Study Section
Special Emphasis Panel (ZRG1-VH-G (02))
Program Officer
Goldberg, Suzanne H
Project Start
2004-04-01
Project End
2014-05-31
Budget Start
2010-07-05
Budget End
2011-05-31
Support Year
5
Fiscal Year
2010
Total Cost
$807,900
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Golden, Diana; Kolmakova, Antonina; Sura, Sunitha et al. (2016) Lymphocyte activation gene 3 and coronary artery disease. JCI Insight 1:e88628
Manichaikul, Ani; Wang, Xin-Qun; Musani, Solomon K et al. (2015) Association of the Lipoprotein Receptor SCARB1 Common Missense Variant rs4238001 with Incident Coronary Heart Disease. PLoS One 10:e0125497
DeAngelis, Anthony M; Roy-O'Reilly, Meaghan; Rodriguez, Annabelle (2014) Genetic alterations affecting cholesterol metabolism and human fertility. Biol Reprod 91:117
Manichaikul, Ani; Naj, Adam C; Herrington, David et al. (2012) Association of SCARB1 variants with subclinical atherosclerosis and incident cardiovascular disease: the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol 32:1991-9
Constantineau, Jason; Greason, Erin; West, Michael et al. (2010) A synonymous variant in scavenger receptor, class B, type I gene is associated with lower SR-BI protein expression and function. Atherosclerosis 210:177-82
Naj, Adam C; West, Michael; Rich, Stephen S et al. (2010) Association of scavenger receptor class B type I polymorphisms with subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis. Circ Cardiovasc Genet 3:47-52
Cherian-Shaw, Mary; Puttabyatappa, Muraly; Greason, Erin et al. (2009) Expression of scavenger receptor-BI and low-density lipoprotein receptor and differential use of lipoproteins to support early steroidogenesis in luteinizing macaque granulosa cells. Endocrinology 150:957-65
Lipari, Christopher W; Garcia, Jairo E; Zhao, Yulian et al. (2009) Nitric oxide metabolite production in the human preimplantation embryo and successful blastocyst formation. Fertil Steril 91:1316-8
West, Michael; Greason, Erin; Kolmakova, Antonina et al. (2009) Scavenger receptor class B type I protein as an independent predictor of high-density lipoprotein cholesterol levels in subjects with hyperalphalipoproteinemia. J Clin Endocrinol Metab 94:1451-7
Roberts, Caroline G P; Shen, Haiqing; Mitchell, Braxton D et al. (2007) Variants in scavenger receptor class B type I gene are associated with HDL cholesterol levels in younger women. Hum Hered 64:107-13

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