Family Blood Pressure Program - HyperGEN
Condition: Cardiovascular Diseases; Heart Diseases; Hypertension
MeSH terms: Cardiovascular Diseases; Heart Diseases
Study type: Observational

Summary: 
      To map and identify the major genetic determinants of hypertension and to study possible
      interactions between genetic and non-genetic factors in defined populations. HyperGEN
      initially consisted of a nine 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:

      The network consists of five field centers, a central biochemistry laboratory, a molecular
      genetics laboratory, and a data coordinating center to study an equal sample of Black and
      non-Black families with two or more hypertensive siblings, untreated relatives, and controls
      for genetic association and sib-sib linkage studies. The studies, using samples from the
      Family Heart Study (FHS) and the Atherosclerosis Risk in Communities (ARIC) study, include
      determination and characterization of genes promoting hypertension and interaction with
      non-genetic factors.

      Beginning in 1996, Donna Arnett, principal investigator of the University of Minnesota
      echocardiographic center under R01HL55673 , is performing a targeted echocardiographic exam
      on 3,100 HyperGEN participants in five field centers as part of the HyperGEN clinical
      examination. She is examining the genetics of left ventricular hypertrophy. Her study
      characterizes left ventricular structure and function, defines left ventricular structural
      phenotypes based on four geometric patterns (normal geometry, concentric remodeling,
      concentric left ventricular hypertrophy, and eccentric left ventricular hypertrophy). She
      examines a highly select group of candidate genes and their association with left ventricular
      mass and geometric pattern. Using quantitative trait loci analyses, she is testing for
      linkage of 240 anonymous, evenly spaced genetic markers with left ventricular mass and
      geometric patterns. She is also evaluating interactions between genes and potential risk
      factors for left ventricular hypertrophy, including insulin, glucose, blood pressure response
      to mental and physical stressors, dietary and urinary electrolytes, and obesity. The grant
      was not part of the original initiative. Approximately $2,093,000 support will be provided
      for this grant, broken down as follows: FY 1996 - $652,085; FY 1997 - $628,979; FY 1998 -
      $433,000; FY 1999 - $379,000.

      The Family Blood Pressure Program, including HyperGEN, was renewed in FY 2000. The Family
      Blood Pressure Program as a whole carried out five specific aims in the renewal period. These
      aims were grouped according to two complementary themes: First, the investigators created and
      analyzed a database of blood pressure-related phenotype and genotype data from all FBPP
      participants (Aim 1). Within linked regions, they identified allelic variation within
      positional candidate genes and evaluated the relationship of these polymorphisms with blood
      pressure levels and hypertension status (Aims 2 and 3). Second, they used quantitative
      measures of target organ damage to identify genes that influence susceptibility to develop
      hypertensive heart and kidney diseases (Aims 4 and 5). In addition to the Program specific
      aims, each network, including HyperGEN, carried out its own specific aims alone, based on
      unique aspects of their population and interests and expertise of the investigators.

      The HyperGEN network has taken the lead in studying associated subphenotypes of hypertension
      and will study the following: measures of metabolic intermediates such as plasma insulin,
      glucose and lipid levels, and red cell sodium-lithium transport; co-morbidity with diseases
      of possible common etiology such as diabetes, obesity, and hypertension-associated kidney
      disease; degree of specific target organ damage; differential response to environmental
      input; and left ventricular hypertrophy and other phenotypes measured by echocardiography.
      Co-morbid conditions and measures of end-organ damage will be used as stratifying variables.
      Genes that influence variation in measures of metabolic intermediates, blood pressure
      response to stressors, and left ventricular hypertrophy will be studied in linkage and
      association studies. Environmental exposures (medication use, activity level, smoking) will
      be used as covariates. These measurements will allow for the identification of genes that
      influence variation in these subphenotypes, some of which may overlap with genes that
      influence blood pressure levels per se, and others which may be specific to the associated
      phenotype, nearly all of which have heritabilities equivalent to or greater than blood
      pressure by itself.

      The HyperGen was extended through August, 2008 to make the Program a shared resource for
      hypertension researchers in the United States and throughout the world. In Aim 1, the
      investigators 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.
    

Observational model: Family-Based
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        (A) sample of hypertensive sibships with at least two members diagnosed with hypertension
        before the age of 60 (probands); (B) random sample of age-matched persons from the same
        base populations, from which normotensive controls could be drawn; (C) unmedicated,
        normotensive adult offspring of one of the hypertensive siblings.
      
Biospecimen description: 
      Tissue suitable for DNA extraction