Arterial Tone and Reactivity:
Studies of Vascular Aging
GeneSTAR has an interest in vascular properties as a general underpinning to all of the various cardiovascular phenoyptes that make up the substrate for coronary, cerebrovascular, and peripheral arterial disease.
The ARTERY study is based on the evidence that in older animals and humans, dysfunctional arterial changes including vascular stiffening and endothelial impairment are present in all vascular beds. These changes may be present at younger ages in highly susceptible individuals, predisposing them to earlier-onset cardiovascular morbidity and mortality. While arterial dysfunction increases with age, little is known about why some individuals manifest vascular impairment while relatively young and others retain preserved vascular function at older ages.
ARTERY is based on the premise that genetic variants are a significant determinant of the presence of vascular dysfunction in younger individuals and preservation of vascular function at older ages. Thus, persons with premature vascular dysfunction may have an identifiable genetic profile, more likely so in a study of a high risk population with known familial susceptibility to early-onset vascular disease.
We are examining the hypothesis that genes contribute to vascular dysfunction across a broad range of ages in GeneSTAR, a 2-generational cohort where genotyping is available. The overall goal is to study 1500 family members, including siblings of the original probands, adult offspring of the siblings or probands, and the co-parents of the offspring, for characterization of primary outcomes representing arterial functional changes, including aortic pulse wave velocity, carotid artery stiffness, and post-ischemic brachial artery flow-mediated dilatation (FMD) in the context of covariables (known atherosclerotic risk factors and inflammatory biomarkers.) We are examining known variants in candidate genes and signals from the GWAS and Whole genome sequencing that are associated with vascular dysfunction and markers of vascular aging. We will determine whether novel genetic loci are associated with younger age vascular dysfunction and also with successful preservation of arteries in older age individuals in families with a history of premature CAD. Such families are more likely than individuals from general population studies to be enriched with premature vascular dysfunction and also with susceptibility genes. However, family members are still sufficiently heterogeneous with regard to the vascular phenotype that genetic models can be tested. The overall objectives of this program of vascular research are to:
- determine whether there is an association between specific haplotypes or genotypes of selected mechanism-derived candidate genes and age-specific percentile levels of vascular properties, characterized by carotid artery stiffness and FMD (based on percentile for current age group), signifying the range from younger age dysfunction to successful older age vascular preservation.
- determine associations between specific haplotypes or genotypes of selected mechanism-derived candidate genes and age-specific levels of the vascular properties taking into account putatively influential covariables including the inflammatory markers (hs-CRP, IL-6, and MCP-1) and traditional atherogenic risk factors (lipids, blood pressure, glucose, obesity [body mass index]).
- determine associations of loci in the genome-wide SNP scan (excluding those SNPs in the selected candidate genes above) and age-specific percentile levels of the vascular properties, characterized by carotid artery stiffness and FMD, signifying the range from younger age dysfunction to successful older age vascular preservation, respectively.
- replicate a priority list of detected associations in two population based studies, including the Framingham Heart Study (FHS) for white subjects and the Multi-Ethnic Study of Atherosclerosis (MESA) for both white and African American subjects.
Dhananjay (Jay) Vaidya, MBBS, PhD, MPH
Associate Profesor Medicine, Epidemiology