Family Blood Pressure Program - GENOA
Condition: Cardiovascular Diseases; Heart Diseases; Hypertension; Coronary Arteriosclerosis
MeSH terms: Cardiovascular Diseases; Heart Diseases; Arteriosclerosis; Coronary Artery Disease; Myocardial Ischemia
Study type: Observational

Summary: 
      To localize, identify, and evaluate common polymorphic variation in genes involved in
      determining interindividual differences in blood pressure (BP) levels and essential
      hypertension status in three racial groups: African-Americans, Mexican-Americans, and
      Non-Hispanic Whites. The study consists of a six grant network, which in turn is part of an
      NHLBI initiative, the Family Blood Pressure Program (FBPP) consisting of four networks.
    

Detailed description: 
      BACKGROUND:

      Hypertension, a complex disease involving the interplay of genetic and environmental factors,
      affects an estimated 50 million Americans and is a major predisposing factor for myocardial
      infarction, vascular disease, stroke, and renal failure. It has been estimated from
      segregation analysis and twin studies that approximately 45 percent of the interindividual
      differences in blood pressure are accounted for by genetic differences. The identification of
      the genes whose variants contribute to high blood pressure will have far-reaching effects on
      our understanding of the pathophysiology of the circulation and may suggest new preventive
      measures and rational therapeutic approaches.

      One of the principal advantages of the genetic approach is that it identifies primary
      molecular defects. As a result, it will be possible to stratify the general hypertensive
      population into subgroups based on genotype and intermediate phenotype and thereby evaluate
      preventive strategies and therapeutic approaches in more homogeneous groups. In addition, the
      identification of hypertensive genes also provides the basis for an understanding of the
      interactions between genes and environmental factors. It is very likely that particular
      environmental variables exert their effects only in the presence of certain genotypes.

      Until recently, the techniques for dissecting the genetic determinants of high blood pressure
      were not available or were not developed to an extent that would make the Family Blood
      Pressure Program initiative feasible. However, several recent advances in technology and
      analytical methods, together with the rapid construction of genetic maps, have substantially
      improved the chances of detecting these genetic factors.

      The concept for the Family Blood Pressure Program was conceived in the Report of the Expert
      Panel on Genetic Strategies for Heart, Lung, and Blood Diseases. The initiative was approved
      by the Arteriosclerosis, Hypertension, and Lipid Metabolism Advisory Committee (AHLMAC) in
      March, 1993. The genetic-epidemiological aspects were approved by the Clinical Applications
      and Prevention Advisory Committee (CAPAC) in February, 1993. The Request for Applications was
      released in March, 1994. Awards were made in September, 1995.

      DESIGN NARRATIVE:

      GENOA, the Genetic Epidemiology Network of Arteriopathy, consists of a network of three field
      centers and biochemical and genetic core labs to study the common polymorphic genetic
      variations to determine individual differences in blood pressure and essential hypertension
      in 1,500 sibling pairs in three racial groups. Linkage analyses are performed using an
      extensive array of candidate genes and anonymous markers throughout the genome.

      Each collaborating investigator is responsible for an essential element of the network: Eric
      Boerwinkle for genotyping and linkage analyses, Robert Ferrell for genotyping, Craig Hanis
      for recruiting Mexican-Americans, Richard Hutchinson for recruiting African-Americans, Sharon
      Kardia for cladistic and prediction analyses and data management, and Stephen Turner for
      recruiting Non-Hispanic whites and measuring physiologic variables. Between 1995 and 2000,
      the network carried out five specific aims to localize and characterize the genetic
      determinants of high blood pressure. Aim 1 used robust sibling pair linkage methods in 500
      hypertensive sibling pairs in each racial group (a total of 1,500 sibling pairs) to localize
      genes influencing interindividual differences in the occurrence of essential hypertension.
      Aims 2 and 3 took advantage of previously collected blood pressure and intermediate predictor
      trait data from 1,488 normotensive sibling pairs from the Rochester Family Heart Study to
      localize genes contributing to essential hypertension. The linkage analyses (Aims 1-3) used
      both an extensive array of candidate genes and a large number of anonymous markers throughout
      the genome. Aim 4 used multiple diallelic sequence polymorphisms and cladistic analyses
      within a linked gene to identify haplotypes for further DNA sequencing in order to identify
      candidate functional DNA sequence variation contributing to interindividual differences in BP
      levels and essential hypertension status. Aim 5 evaluated the ability of candidate functional
      DNA sequence variation to predict essential hypertension status in the three racial groups.

      The study was renewed in September 2000 to pursue two lines of investigation. The first was
      to identify and characterize genes contributing to atherosclerotic coronary heart disease
      using electron beam computed tomography (EBCT) to quantify coronary artery calcification as a
      measure of preclinical disease. Robust sibling-pair linkage methods were used to determine
      whether any of the more than 375 highly polymorphic tandem repeat marker loci spanning the
      genome were linked to genes influencing EBCT measures of coronary artery calcification in at
      least 500 GENOA sibships from Rochester, Minnesota. Association analysis was used to
      determine whether biallelic markers of DNA sequence variation in candidate genes identified
      by GENOA or others to influence blood pressure level or diagnostic category also influence
      EBCT measures of coronary artery calcification in at least 500 GENOA participants from
      Rochester, Minnesota. The second line of investigation extended analytical methods (linkage
      disequilibrium regression and combinatorial partitioning) to more finely localize positional
      candidate genes and loci, and to identifying gene-gene and gene-environment interaction
      effects influencing the measured Family Blood Pressure Program and GENOA phenotypes.

      In the next phase of the FBPP extending the study through FY 2008, a major emphasis is placed
      on making the Program a shared resource for hypertension researchers in the United States and
      throughout the world. In Aim 1, the intestigators will build, maintain and update a publicly
      available knowledge-base to facilitate research by non-FBPP investigators on the genetics of
      hypertension, its risk factors and its complications. In Aim 2, they will use
      state-of-the-art genetic linkage analysis methods to identify additional linkage regions
      using subgroups of pedigrees and physiologically relevant combinations of phenotypes that
      will aid in localizing hypertension genes. In Aim 3, they will use a combination of
      bioinformatics, a dense array of SNPs, and state-of-the-art data analysis to follow-up
      regions of interest and identify the underlying hypertension genes. The regions to be
      followed-up include those identified during the current phase of the FBPP and Aim 2 of this
      renewal phase. In Aim 4, they will evaluate the hypertension genes identified in Aim 3 for
      their association with multiple measures reflecting the cardiovascular and renal
      complications of hypertension, including left ventricular mass and microalbuminuria. It is
      the long-term goal of the FBPP to have the hypertension genetics community develop a
      comprehensive picture of the genetic architecture of human hypertension, including its risk
      factors, complications, and response to treatment.