The genetic response to short-term interventions affecting cardiovascular function: Rationale and design of the Heredity and Phenotype Intervention (HAPI) Heart Study

Division of Endocrinology, Department of Medicine, Diabetes and Nutrition, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
American heart journal (Impact Factor: 4.56). 06/2008; 155(5):823-8. DOI: 10.1016/j.ahj.2008.01.019
Source: PubMed

ABSTRACT The etiology of cardiovascular disease (CVD) is multifactorial. Efforts to identify genes influencing CVD risk have met with limited success to date, likely because of the small effect sizes of common CVD risk alleles and the presence of gene by gene and gene by environment interactions.
The HAPI Heart Study was initiated in 2002 to measure the cardiovascular response to 4 short-term interventions affecting cardiovascular risk factors and to identify the genetic and environmental determinants of these responses. The measurements included blood pressure responses to the cold pressor stress test and to a high salt diet, triglyceride excursion in response to a high-fat challenge, and response in platelet aggregation to aspirin therapy.
The interventions were carried out in 868 relatively healthy Amish adults from large families. The heritabilities of selected response traits for each intervention ranged from 8% to 38%, suggesting that some of the variation associated with response to each intervention can be attributed to the additive effects of genes.
Identifying these response genes may identify new mechanisms influencing CVD and may lead to individualized preventive strategies and improved early detection of high-risk individuals.

Download full-text


Available from: Evadnie Rampersaud, Jun 21, 2015
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: We performed a genome-wide scan in a homogeneous Arab population to identify genomic regions linked to blood pressure (BP) and its intermediate phenotypes during mental and physical stress tests. The Oman Family Study subjects (N = 1277) were recruited from five extended families of ~10 generations. Hemodynamic phenotypes were computed from beat-to-beat BP, electrocardiography and impedance cardiography. Multi-point linkage was performed for resting, mental (word conflict test, WCT) and cold pressor (CPT) stress and their reactivity scores (s), using variance components decomposition-based methods implemented in SOLAR. Genome-wide scans for BP phenotypes identified quantitative trait loci (QTLs) with significant evidence of linkage on chromosomes 1 and 12 for WCT-linked cardiac output (LOD = 3.1) and systolic BP (LOD = 3.5). Evidence for suggestive linkage for WCT was found on chromosomes 3, 17 and 1 for heart rate (LOD = 2.3), DBP (LOD = 2.4) and left ventricular ejection time (LVET), respectively. For △WCT, suggestive QTLs were detected for CO on chr11 (LOD = 2.5), LVET on chr3 (LOD = 2.0) and EDI on chr9 (LOD = 2.1). For CPT, suggestive QTLs for HR and LVET shared the same region on chr22 (LOD 2.3 and 2.8, respectively) and on chr9 (LOD = 2.3) for SBP, chr7 (LOD = 2.4) for SV and chr19 (LOD = 2.6) for CO. For △CPT, CO and TPR top signals were detected on chr15 and 10 (LOD; 2.40, 2.08) respectively. Mental stress revealed the largest number of significant and suggestive loci for normal BP reported to date. The study of BP and its intermediate phenotypes under mental and physical stress may help reveal the genes involved in the pathogenesis of essential hypertension.
    Twin Research and Human Genetics 06/2011; 14(3):257-67. DOI:10.1375/twin.14.3.257 · 1.92 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Knowledge of the extent and distribution of linkage disequilibrium (LD) is critical to the design and interpretation of gene mapping studies. Because the demographic history of each population varies and is often not accurately known, it is necessary to empirically evaluate LD on a population-specific basis. Here we present the first genome-wide survey of LD in the Old Order Amish (OOA) of Lancaster County Pennsylvania, a closed population derived from a modest number of founders. Specifically, we present a comparison of LD between OOA individuals and US Utah participants in the International HapMap project (abbreviated CEU) using a high-density single nucleotide polymorphism (SNP) map. Overall, the allele (and haplotype) frequency distributions and LD profiles were remarkably similar between these two populations. For example, the median absolute allele frequency difference for autosomal SNPs was 0.05, with an inter-quartile range of 0.02-0.09, and for autosomal SNPs 10-20 kb apart with common alleles (minor allele frequency > or =0.05), the LD measure r(2) was at least 0.8 for 15 and 14% of SNP pairs in the OOA and CEU, respectively. Moreover, tag SNPs selected from the HapMap CEU sample captured a substantial portion of the common variation in the OOA ( approximately 88%) at r(2) > or =0.8. These results suggest that the OOA and CEU may share similar LD profiles for other common but untyped SNPs. Thus, in the context of the common variant-common disease hypothesis, genetic variants discovered in gene mapping studies in the OOA may generalize to other populations.
    Genetic Epidemiology 02/2010; 34(2):146-50. DOI:10.1002/gepi.20444 · 2.95 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Exaggerated cardiovascular reactivity to stressful stimuli may be a risk factor for the development of hypertension. The genetic influence on blood pressure (BP) reactivity to stress and its control mechanisms has been receiving considerable support. This study aims at examining the heritability of BP and its intermediate hemodynamic phenotypes to acute stress in a homogeneous Arab population. Parameters were computed from continuous BP, electrocardiography and impedance cardiography measurements, during rest, word conflict (WCT) and cold pressor (CPT) tests. Heritability estimates (h(2)) were obtained using the variance components-based approach implemented in the SOLAR software package. Reactivity scores for WCT and CPT increased significantly (P < .05) for systolic (SBP), diastolic (DBP), heart rate (HR), cardiac output (CO), and total peripheral resistance (TPR). They decreased significantly (P < .05) for stroke volume (SV), left ventricular ejection time (LVET), end diastolic (EDI) and cardiac contractility (IC) indices. Univariate analysis detected heritability estimates that ranged from 0.19-0.35 for rest, 0.002-0.40 for WCT and 0.08-0.35 for CPT. In this unique cohort, resting as well as challenged cardiovascular phenotypes are significantly influenced by additive genetic effects. Heritability estimates for resting phenotypes are in a relatively narrow range, while h(2) for their reactivity is somewhat broader with lower estimates. Further analyses of this study may offer important opportunities for gene finding in hypertension. WHAT IS KNOWN ABOUT THE TOPIC: (1) cardiovascular reactivity to stress predicts cardiovascular disease; (2) genetic susceptibility plays an important role in stress reactivity. Family studies using the cold pressure test reported significant heritability for blood pressure. (1) this cohort is from five highly consanguineous isolated Arab pedigrees with genetically verified genealogical records and environmental homogeneity; (2) This is the first study to estimate heritability of detailed intermediate hemodynamic phenotypes that make up normal blood pressure.
    Twin Research and Human Genetics 12/2009; 12(6):541-8. DOI:10.1375/twin.12.6.541 · 1.92 Impact Factor