Cardiovascular disease and stroke remain major public health issues with a disproportionate impact on minority populations and less is known about Hispanics. While our knowledge of vascular risk factors has improved, little is known regarding genetic influences. Evaluation of quantitative cardiovascular precursor phenotypes will facilitate gene discovery and family-based studies provide unique advantages in identifying genetic variants, especially rare variants, associated with these traits. The goal of the Family Study of Carotid Atherosclerosis and Stroke Risk is to identify genetic determinants of specific cardiovascular and stroke risk phenotypes which are precursors to cardiovascular disease and stroke. The family study database consists of 1390 subjects from 100 high-cardiovascular risk Dominican families with systematic evaluations of phenotypes (carotid ultrasound and echocardiography), extensive data collection of traditional and behavioral risk factors including diet, blood and DNA stored, a microsatellite genome wide scan at CIDR, and fine mapping results on various QTLs. We propose to further characterize variants (both common and rare) and genes that contribute to inter-individual variations in carotid intima media thickness, carotid plaque, left ventricular mass, and left atrial diameter by utilizing our extensive Dominican Family Study database. Using next generation sequencing technology, we will pursue peak-wide exome sequencing for our traits and gene-wide sequencing for candidate genes of interest within our selected regions. Regions of interest have been identified in our linkage studies for each of these complex traits. We have prioritized 20 informative families with any trait-specific peak LOD score >0.4. Importantly, we have the unique ability to combine our Family Study with a validation association study drawn from an independent cohort of Dominicans from our Northern Manhattan Study (NOMAS) who have had identical trait measurements and clinical follow-up. To validate the findings from the peak-wide exome sequencing stage of the families, genes with multiple variants contributing to any of the quantitative traits will be sequenced in unrelated Dominicans in NOMAS. Other validations are planned using the Cohorts for Heart and Aging Research in Genomic Epidemiology and the non-Dominican subjects in NOMAS. Additionally, we propose to re-contact the Dominican subjects in our family study to record any follow-up cardiovascular and stroke events. We will evaluate the association between any selected variants and the risk of stroke, MI or vascular death in the NOMAS cohort. These studies have the potential to identify novel genes underlying complex risk phenotypes in the rapidly growing Hispanic population and help design innovative approaches to modification of risk of cardiovascular disease and stroke.
Cardiovascular disease and stroke are the leading causes of death in the US and have tremendous social and financial consequences. These are complex diseases with strong genetic underpinnings and remain major public health threats especially among the rapidly growing but understudied Hispanic population. The proposed study aims will investigate new genetic determinants using next generation sequencing for subclinical carotid disease and echocardiographic traits among extended Dominican families to help fill gaps in our knowledge of the genetics of cardiovascular disease and stroke risk in minority groups.
|Wang, Liyong; Beecham, Ashley; Dueker, Nicole et al. (2015) Sequencing of candidate genes in Dominican families implicates both rare exonic and common non-exonic variants for carotid intima-media thickness at bifurcation. Hum Genet 134:1127-38|
|Romano, Jose G; Sacco, Ralph L (2015) Decade in review-stroke: progress in acute ischaemic stroke treatment and prevention. Nat Rev Neurol 11:619-21|
|Tietjen, Gretchen E; Rundek, Tatjana (2015) Migraine and cryptogenic stroke: The clot thickens. Neurology 85:1436-7|
|Rundek, Tatjana; Brown, Devin L (2014) Socioeconomic status and subclinical atherosclerosis: are we closing disparity gaps? Stroke 45:948-9|
|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|
|Della-Morte, David; Beecham, Ashley; Dong, Chuanhui et al. (2012) Association between variations in coagulation system genes and carotid plaque. J Neurol Sci 323:93-8|
|Dong, Chuanhui; Beecham, Ashley; Wang, Liyong et al. (2012) Follow-up association study of linkage regions reveals multiple candidate genes for carotid plaque in Dominicans. Atherosclerosis 223:177-83|
|Wang, Liyong; Beecham, Ashley; Zhuo, Degen et al. (2012) Fine mapping study reveals novel candidate genes for carotid intima-media thickness in Dominican Republican families. Circ Cardiovasc Genet 5:234-41|
|Della-Morte, David; Beecham, Ashley; Rundek, Tatjana et al. (2011) A follow-up study for left ventricular mass on chromosome 12p11 identifies potential candidate genes. BMC Med Genet 12:100|
|Dong, Chuanhui; Della-Morte, David; Wang, Liyong et al. (2011) Association of the sirtuin and mitochondrial uncoupling protein genes with carotid plaque. PLoS One 6:e27157|
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