Precursor conditions or subclinical markers provide an opportunity to understand the early determinants of atherosclerosis. Traditional vascular risk factors predict less than a half of variance in carotid plaque and a half of individuals experience plaque progression despite treatment of traditional vascular risk factors according to current guidelines. Individuals with progression of subclinical atherosclerosis have twice the risk of stroke, myocardial infarction or death over 5 years, compared to those with stable plaque or regression. Atherosclerosis is a complex condition with a substantial genetic contribution. Specific genetic polymorphisms involved in regulation of subclinical carotid atherosclerosis and their extreme unexplained phenotypes are not known. A search for new alleles that either accelerate or protect from atherosclerosis, using extreme unexplained phenotypes of subclinical atherosclerosis will help identifying novel factors which may ultimately lead to innovative therapeutic targets for atherosclerosis and reduce risk of stroke, myocardial infarction and other consequences of atherosclerosis. The specific primary aims of the proposed research are to: (1) identify individuals with unexplained subclinical atherosclerosis (USAth) and unexplained protection against atherosclerosis (UPAth) by generating standardized residual scores in the multivariable regression model from traditional vascular risk factors and carotid artery plaque area burden, a subclinical carotid artery phenotype collected among 1,200 Caribbean Hispanic stroke-free individuals;(2) identify alleles that are associated with USAth and UPAth by performing a genome wide association study;(3) validate these findings in an independent sample of a family-based cohort and in the SHARe Project, and (4) perform follow-up studies of the top 2 most significant SNPs/CNVs identified in both samples to identify the underlying causative variation. The strengths of this proposal include the wealth of baseline data (including carotid ultrasound imaging) that has already been collected as a part of the population-based Northern Manhattan study, the evaluation of innovative risk factors, DNA repository available, carotid imaging performed according to the standardized scanning protocols, a capability of sophisticated ultrasound imaging analyses, genotyping and genetic analyses, and dual PI responsibility to assure a completion of the high quality phenotyping (Dr. T. Rundek, neurology) and genotyping (Dr. S. Blanton, genomics). New quantitative traits developed in this study, "unexplained subclinical atherosclerosis" and "unexplained protection against subclinical atherosclerosis", will make possible to identify novel and previously unsuspected genetic associations for those contributing to the excessive atherosclerosis, and those protective from atherosclerosis.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01NS065114-05
Application #
8672699
Study Section
Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
Program Officer
Gwinn, Katrina
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
Rundek, Tatjana; Brown, Devin L (2014) Socioeconomic status and subclinical atherosclerosis: are we closing disparity gaps? Stroke 45:948-9
Della-Morte, David; Wang, Liyong; Beecham, Ashley et al. (2014) Novel genetic variants modify the effect of smoking on carotid plaque burden in Hispanics. J Neurol Sci 344:27-31
Wang, Liyong; Rundek, Tatjana; Beecham, Ashley et al. (2014) Genome-wide interaction study identifies RCBTB1 as a modifier for smoking effect on carotid intima-media thickness. Arterioscler Thromb Vasc Biol 34:219-25
Rundek, Tatjana; Blanton, Susan H; Bartels, Susanne et al. (2013) Traditional risk factors are not major contributors to the variance in carotid intima-media thickness. Stroke 44:2101-8
Kuo, Frank; Gardener, Hannah; Dong, Chuanhui et al. (2012) Traditional cardiovascular risk factors explain the minority of the variability in carotid plaque. Stroke 43:1755-60
Wang, Liyong; Yanuck, Danielle; Beecham, Ashley et al. (2011) A candidate gene study revealed sex-specific association between the OLR1 gene and carotid plaque. Stroke 42:588-92
Gardener, Hannah; Beecham, Ashley; Cabral, Digna et al. (2011) Carotid plaque and candidate genes related to inflammation and endothelial function in Hispanics from northern Manhattan. Stroke 42:889-96