This project represents a collaborative effort among investigators of the University of Washington, the University of Vermont, University of North Carolina, and Johns Hopkins. While the therapeutic benefits of anti-thrombotic and anti-inflammatory therapies suggest a major role for clotting and inflammation in the etiology of myocardial infarction (MI) and stroke, the genetic determinants of the pro-thrombotic and pro-inflammatory components of cardiovascular disease (CVD) risk remain poorly characterized. By building on candidate gene-CVD clinical and intermediate phenotype association results from our first grant cycle, the proposed renewal application links biologic advances in thrombosis and vascular inflammation pathways, functional genomics, population and statistical genetics, with the unique resources of Cardiovascular Health Study (CHS), a large, biracial cohort of older adults. Through the CHS main contract, 5,888 older adults have been followed for over 15 years, with the accrual of large number (>2,000) of clinical CVD events. Data on baseline traditional risk factors, subclinical disease, and several important inflammation/thrombosis biomarkers (fibrinogen, C-reactive protein, factor VII, and others) are also available. Through the proposed renewal, we plan to perform additional measurements of 8 plasma thrombosis biomarkers, selected on basis of our preliminary findings and rigorously defined biologic criteria, which will be utilized as intermediate phenotypes to strengthen evidence for CVD event-candidate gene association. By integrating existing candidate gene genotype data from the first cycle with >2,000 candidate genes from the NHLBI-supported CARE study and existing CHS genome-wide data (Illumina Human Hap 370CNV), we propose to evaluate thoroughly the association of thrombosis/inflammation genes with intermediate phenotypes and incident MI and stroke. Additional strengths of the application include excellent candidate gene SNP coverage in whites and African-Americans, and a flexible analytic approach that includes assessment of single- and multi-locus genotypes, haplotypes, gene-environment and gene-gene interaction. Validation of findings will occur through replication genotyping in additional cohorts with large numbers of CVD events (ARIC, Honolulu Heart Program, Women's Health Initiative), as well as in vitro and bioinformatics assessment of associated SNPs.
While the therapeutic benefits of anti-thrombotic therapies suggest a major role for clotting and inflammation in the etiology of coronary disease and stroke, the specific genetic determinants that underlie the predisposition toward vascular inflammation and thrombosis associated with cardiovascular risk remains largely unknown in older adults. Understanding the molecular background of these common but complex atherothrombotic disorders may help identify older individuals at high cardiovascular risk because of genetic or environmental differences in the inflammatory or thrombotic response to advanced atherosclerosis and may provide new directions for prevention and treatment of MI and stroke.
|Schick, Ursula M; Auer, Paul L; Bis, Joshua C et al. (2015) Association of exome sequences with plasma C-reactive protein levels in >9000 participants. Hum Mol Genet 24:559-71|
|Lange, Leslie A; Willer, Cristen J; Rich, Stephen S (2015) Recent developments in genome and exome-wide analyses of plasma lipids. Curr Opin Lipidol 26:96-102|
|Olson, N C; Butenas, S; Lange, L A et al. (2015) Coagulation factorÂ XII genetic variation, exÂ vivo thrombin generation, and stroke risk in the elderly: results from the Cardiovascular Health Study. J Thromb Haemost 13:1867-77|
|Naik, Rakhi P; Derebail, Vimal K; Grams, Morgan E et al. (2014) Association of sickle cell trait with chronic kidney disease and albuminuria in African Americans. JAMA 312:2115-25|
|Keller, Margaux F; Reiner, Alexander P; Okada, Yukinori et al. (2014) Trans-ethnic meta-analysis of white blood cell phenotypes. Hum Mol Genet 23:6944-60|
|Ellis, Jaclyn; Lange, Ethan M; Li, Jin et al. (2014) Large multiethnic Candidate Gene Study for C-reactive protein levels: identification of a novel association at CD36 in African Americans. Hum Genet 133:985-95|
|Matteini, A M; Li, J; Lange, E M et al. (2014) Novel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults. Cytokine 65:10-6|
|Sabater-Lleal, Maria; Huang, Jie; Chasman, Daniel et al. (2013) Multiethnic meta-analysis of genome-wide association studies in >100 000 subjects identifies 23 fibrinogen-associated Loci but no strong evidence of a causal association between circulating fibrinogen and cardiovascular disease. Circulation 128:1310-24|
|Johnsen, Jill M; Auer, Paul L; Morrison, Alanna C et al. (2013) Common and rare von Willebrand factor (VWF) coding variants, VWF levels, and factor VIII levels in African Americans: the NHLBI Exome Sequencing Project. Blood 122:590-7|
|Chen, Zhao; Tang, Hua; Qayyum, Rehan et al. (2013) Genome-wide association analysis of red blood cell traits in African Americans: the COGENT Network. Hum Mol Genet 22:2529-38|
Showing the most recent 10 out of 40 publications