Abstract

Atherosclerotic vascular disease is a major source of morbidity and mortality. Inflammation plays an important role in atherosclerosis. The tools to systematically study the extent to which genetic variation determines risk of and progression of atherosclerosis are only now becoming available. The general aim of this project is to evaluate the role of genetic variation in inflammatory pathway genes at 29 loci on the risk and progression of carotid artery atherosclerotic disease (CAAD). Genes to be evaluated include those potentially involved in plaque initiation and progression. We will evaluate SNPs informative for the common locus haplotypes. Choice of informative polymorphisms for evaluation is based on the genes' evolutionary history. We will evaluate progression effects in subjects with CAAD followed longitudinally by noninvasive magnetic resonance (MR) techniques over 3 years. Risk will be evaluated by case-control comparisons. In additions to evaluating genetic polymorphisms, we will evaluate the intervening phenotypes of protein level for fibrinogen, C-reactive protein, serum amyloid A, and interleukin-6. Independence of genetic predictors from traditional cardiovascular risk factors will be evaluated. The major specific aims are:
Aim 1. Test for inflammatory genetic effects and protein level in CAAD progression in 550 subjects with CAAD (275 with 15-49% and 275 with 50-79% baseline CAAD stenosis) evaluated by 3-year magnetic resonance image follow-up of percent lumen stenosis;
Aim 2. Determine whether the variation in the inflammatory genes or protein levels predicts 810 case vs. 810 control status with a case distribution of 335 subject with 15-49%, 275 with 50-75% and 200 with >80% carotid artery stenosis at baseline. Age (onset of vascular disease for cases, current age for controls)-, sex-, race-, and hospital-matched controls will have less than 15% stenosis on carotid duplex ultrasound. Genes that are implicated in disease may eventually allow targeted therapy.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL074366-02
Application #
6800801
Study Section
Epidemiology and Disease Control Subcommittee 2 (EDC)
Program Officer
Bookman, Ebony B
Project Start
2003-09-15
Project End
2007-08-31
Budget Start
2004-09-01
Budget End
2005-08-31
Support Year
2
Fiscal Year
2004
Total Cost
$704,850
Indirect Cost

  Institution

Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
605799469
City
Seattle
State
WA
Country
United States
Zip Code
98195

  Publications

Richter, Rebecca J; Jarvik, Gail P; Furlong, Clement E (2010) Paraoxonase 1 status as a risk factor for disease or exposure. Adv Exp Med Biol 660:29-35
Ober, Carole; Nord, Alex S; Thompson, Emma E et al. (2009) Genome-wide association study of plasma lipoprotein(a) levels identifies multiple genes on chromosome 6q. J Lipid Res 50:798-806
Richter, Rebecca J; Jarvik, Gail P; Furlong, Clement E (2009) Paraoxonase 1 (PON1) status and substrate hydrolysis. Toxicol Appl Pharmacol 235:1-9
Reiner, Alexander P; Wurfel, Mark M; Lange, Leslie A et al. (2008) Polymorphisms of the IL1-receptor antagonist gene (IL1RN) are associated with multiple markers of systemic inflammation. Arterioscler Thromb Vasc Biol 28:1407-12
Wurfel, Mark M; Gordon, Anthony C; Holden, Tarah D et al. (2008) Toll-like receptor 1 polymorphisms affect innate immune responses and outcomes in sepsis. Am J Respir Crit Care Med 178:710-20
Richter, Rebecca J; Jarvik, Gail P; Furlong, Clement E (2008) Determination of paraoxonase 1 status without the use of toxic organophosphate substrates. Circ Cardiovasc Genet 1:147-52
Crawford, Dana C; Nord, Alex S; Badzioch, Michael D et al. (2008) A common VLDLR polymorphism interacts with APOE genotype in the prediction of carotid artery disease risk. J Lipid Res 49:588-96
Carlson, Christopher S; Heagerty, Patrick J; Nord, Alex S et al. (2007) TagSNP evaluation for the association of 42 inflammation loci and vascular disease: evidence of IL6, FGB, ALOX5, NFKBIA, and IL4R loci effects. Hum Genet 121:65-75
Saam, Tobias; Yuan, Chun; Chu, Baocheng et al. (2007) Predictors of carotid atherosclerotic plaque progression as measured by noninvasive magnetic resonance imaging. Atherosclerosis 194:e34-42
Carty, Cara L; Heagerty, Patrick; Nakayama, Karen et al. (2006) Inflammatory response after influenza vaccination in men with and without carotid artery disease. Arterioscler Thromb Vasc Biol 26:2738-44

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