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

Mitchell, Braxton D.; McArdle, Patrick F.; Shen, Haiqing; Rampersaud, Evadnie; Pollin, Toni I.; Bielak, Lawrence F.; Jaquish, Cashell E.; Douglas, Julie A.; Roy-Gagnon, Marie-Hélène; Sack, Paul; Naglieri, Rosalie; Hines, Scott; Horenstein, Richard B.; Chang, Yen; Post, Wendy S.; Ryan, Kathleen A.; Brereton, Nga; Pakyz, Ruth E.; Sorkin, John D.; Damcott, Coleen M.; O’Connell, Jeffrey R.; Mangano, Christina Mora; Corretti, Mary C.; Vogel, Robert A.; Herzog, William R.; Weir, Matthew R.; Peyser, Patricia A.; Shuldiner, Alan R.

doi:10.1016/j.ahj.2008.01.019

Cited by 105 publications

(122 citation statements)

References 14 publications

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“…HAPI Heart Study. This study was initiated in 2002 to measure the cardiovascular response to 4 short-term interventions affecting cardiovascular health and to identify the genetic and environmental determinants of these responses (10). Before any intervention, baseline BP was obtained manually with the subject in the sitting position after he or she had been sitting quietly for 5 min, and the average of 3 of these measurements was used for analysis.…”

Section: Methodsmentioning

confidence: 99%

Whole-genome association study identifies STK39 as a hypertension susceptibility gene

Wang

O’Connell

McArdle

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Hypertension places a major burden on individual and public health, but the genetic basis of this complex disorder is poorly understood. We conducted a genome-wide association study of systolic and diastolic blood pressure (SBP and DBP) in Amish subjects and found strong association signals with common variants in a serine/threonine kinase gene, STK39. We confirmed this association in an independent Amish and 4 non-Amish Caucasian samples including the Diabetes Genetics Initiative, Framingham Heart Study, GenNet, and Hutterites (meta-analysis combining all studies: n ‫؍‬ 7,125, P < 10 ؊6 ). The higher BP-associated alleles have frequencies > 0.09 and were associated with increases of 3.3/1.3 mm Hg in SBP/DBP, respectively, in the Amish subjects and with smaller but consistent effects across the non-Amish studies. Cellbased functional studies showed that STK39 interacts with WNK kinases and cation-chloride cotransporters, mutations in which cause monogenic forms of BP dysregulation. We demonstrate that in vivo, STK39 is expressed in the distal nephron, where it may interact with these proteins. Although none of the associated SNPs alter protein structure, we identified and experimentally confirmed a highly conserved intronic element with allele-specific in vitro transcription activity as a functional candidate for this association. Thus, variants in STK39 may influence BP by increasing STK39 expression and consequently altering renal Na ؉ excretion, thus unifying rare and common BP-regulating alleles in the same physiological pathway.blood pressure ͉ essential hypertension ͉ genome-wide association study ͉ SPAK ͉ STK39

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Section: Methodsmentioning

confidence: 99%

Whole-genome association study identifies STK39 as a hypertension susceptibility gene

Wang

O’Connell

McArdle

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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277

271

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“…23 The Old Order Amish are a genetically homogeneous closed founder population of European descent. This generally healthy population lives an active lifestyle with substantial environmental homogeneity.…”

Section: Hapi Heart Studymentioning

confidence: 99%

“…21 Confirmation of results was sought in the Framingham Heart Study Offspring Cohort (FHS) 22 and in the cross-sectional Heredity and Phenotype Intervention (HAPI) Heart Study. 23 Table 1 shows the baseline characteristics of the various study samples. Whereas mean estimated GFR (eGFR) was similar across studies, the proportion of people with at least stage 3 CKD (eGFR Ͻ60 ml/min per 1.73 m 2 ) 24 was 3.0% among ARIC white, 2.8% among ARIC black, 1.5% among HAPI, and 8.2% among FHS participants, the oldest study sample.…”

mentioning

confidence: 99%

TCF7L2 Variants Associate with CKD Progression and Renal Function in Population-Based Cohorts

Köttgen¹,

Hwang²,

Rampersaud³

et al. 2008

Journal of the American Society of Nephrology

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Genetic variants may increase susceptibility to both diabetes and kidney disease. Whether known diabetes-associated variants in the transcription factor 7-like 2 (TCF7L2) gene are associated with chronic kidney disease (CKD) progression and markers of kidney function is unknown. Participants of the Atherosclerosis Risk in Communities Study (ARIC; n ϭ 11,061 self-identified white and n ϭ 4014 black), Framingham Heart Offspring Cohort (FHS; n ϭ 2468), and Heredity and Phenotype Intervention Heart Study (HAPI; n ϭ 861) were genotyped at five (ARIC) and two (FHS) common TCF7L2 variants. The diabetes-conferring risk alleles at rs7903146 and rs7901695 were significantly associated with CKD progression among ARIC participants overall and among those without baseline diabetes. The overall adjusted hazard ratios per rs7903146 T allele were 1.17 (95% confidence interval [CI] 1.04 to 1.32) for white individuals and 1.20 (95% CI 1.03 to 1.41) for black individuals. Similarly, the overall hazard ratios per rs7901695 C allele were 1.19 (95% CI 1.06 to 1.34) for white individuals and 1.27 (95% CI 1.09 to 1.48) for black individuals. The FHS cohort supported these results: The rs7903146 T allele was significantly associated with lower estimated GFR (P ϭ 0.01) and higher cystatin C (P ϭ 0.004) in adjusted analyses overall and among those without diabetes. In the HAPI cohort, the rs7901695 C allele was significantly associated with lower estimated GFR in adjusted analyses (P ϭ 0.049), as were several variants upstream and downstream of TCF7L2 (P Ͻ 0.003). No identified variant in the ARIC or FHS cohorts was associated with albuminuria. In conclusion, several population-based samples suggest that variants in the TCF7L2 gene are associated with reduced kidney function or CKD progression, overall and specifically among participants without diabetes.

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“…They hypothesized that the variation is due to genetic variation in pathways other than thromboxane synthesis. 165 volunteers from the hereditary and phenotype intervention (HAPI) heart study [8] were given 81 mg of aspirin once a day for 2 weeks. GC-MS and LC-MS were performed on serum samples before and after 2 weeks of aspirin ingestion.…”

Section: Aspirinmentioning

confidence: 99%

Metabolomics: A Tool Ahead for Understanding Molecular Mechanisms of Drugs and Diseases

2014

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To refer to metabolomics as a new field is injustice to ancient doctors who used ants to diagnose the patients of diabetes having glycosuria. Measuring the levels of molecules in biological fluids believing them to be the representatives of biochemical pathways of carbohydrates, fats, proteins, nucleic acids or xenobiotic metabolism and deciphering meaningful data from it is what can be called as metabolomics, just as high glucose in urine suggests diabetes mellitus. Genomics, epigenetics, proteomics, transcriptomics finally converge to metabolomics, which are the signatures of mechanisms of bodily processes which is why understanding this science can have many applications. Just as a heap of stones does not make a house, having data of metabolite levels does not make it a science. Analyzing this data would help us in constructing biochemical pathways and their interactions. Analyzing the changes caused by a drug in the metabolite levels would help us in deriving the mechanisms by which the drug acts. Comparing metabolite levels in diseased with non-diseased, good-responders with poor-responders to a particular drug can help in identifying new markers of a disease or response to a drug respectively. Also, metabolite levels of an endogenous substrate can tell us the status of a person's metabolizing enzymes and help in drug dose titration. Generating hypothesis by identifying the new molecular markers and testing their utility in clinics seems to be the most promising approach in future. This review narrates the modes of quantifying and identifying metabolome, its proposed applications in diagnosis, monitoring and understanding the diseases and drug responses. We also intend to identify hindrances in using metabolomics in clinical studies or experiments.

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

Cited by 105 publications

References 14 publications

Whole-genome association study identifies STK39 as a hypertension susceptibility gene

Whole-genome association study identifies STK39 as a hypertension susceptibility gene

TCF7L2 Variants Associate with CKD Progression and Renal Function in Population-Based Cohorts

Metabolomics: A Tool Ahead for Understanding Molecular Mechanisms of Drugs and Diseases

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