BA14 - Inflammation and thrombosis gene pathways and cardiovascular disease

Investigator Names and Contact Information

Alexander Reiner (apreiner@uw.edu)

Introduction/Intent

Cardiovascular disease (CVD) is now the leading cause of morbidity and mortality among women as well as men. Therefore, understanding the molecular basis of coronary heart disease (CHD) and stroke is of major public health importance. Vascular inflammation and thrombosis are key determinants of CHD and stroke risk. Yet, the specific genetic risk factors related to thrombosis and inflammation remain poorly characterized. Identification of novel genetic risk markers may allow targeting of men and women likely to benefit from additional anti-thrombotic or anti-inflammatory therapies such as long-term oral anticoagulation. Since female hormones are known to influence a variety of thrombosis and inflammatory mediators, identification of thrombosis and inflammation gene-hormone therapy (HRT) interactions on CVD risk may help to refine the indications for HRT use in post-menopausal women.

To identify genetic CVD risk factors, they ideally must be (1) comprehensively evaluated and replicated in multiple, large, well-characterized study populations using consistent data collection procedures and phenotype definitions, and (2) integrated with intermediate phenotypes according to relevant biologic pathways, as well as with additional sources of functional genomic information.

The main goal of the study is to identify and validate genetic variants that contribute to CVD risk, particularly the common (minor allele frequency ≥ 5%) low-penetrance, low-risk alleles that increase or decrease a person’s susceptibility to vascular inflammation, plaque rupture, and thrombosis. This will be accomplished by typing common variants in CVD genes using the Illumina CARE CVD55 SNP panel in a total of 2,500 CHD cases, 2,500 stroke cases and 2,500 controls from the WHI Observational Study and Hormone Trial. Genotyping for the same 55K CVD candidate gene variants are currently being performed in 9 other NHLBI-funded CVD cohort studies through the CARE project. The combined availability of genotype data and CVD clinical and intermediate phenotypes from several very large, prospective population-based cohorts allows us to efficiently accomplish our first main specific aims, which are:

1. To identify and externally validate associations between common patterns of nucleotide variation in thrombosis and inflammation genes and (a) risk of incident clinical CVD events; (b) existing thrombosis and inflammation biomarker phenotypes that have been measured in WHI and other NHLBI cohorts.

2. To further assess the biologic mechanism of any (validated) candidate gene SNP association by performing (a) combined genotype - intermediate phenotype - clinical CVD outcome (“Mendelian randomization”) analyses across WHI and available CARE cohorts; (b) candidate SNP genotype – gene expression and promoter analysis in silico and in vitro.

3. The genetic determinants of CVD related to inflammation and thrombosis differ according to (a) hormone therapy; (b) the presence of other genetic variants that might affect risk by increasing or decreasing a person’s susceptibility to vascular inflammation and thrombosis.

Results/Findings See WHI Publications: 1215, 1508, 1795. WHI publications by study lists published WHI papers that have been generated by ancillary studies. A complete list of WHI papers is available in the Bibliography section of this website.