Family Blood Pressure Program - HyperGEN
Family Blood Pressure Program - HyperGEN
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.
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.
Inclusion criteria for probands: Onset of hypertension by age 60 years and the presence of
 at least one additional hypertensive sibling who was willing to participate. Hypertension
 was defined according to systolic BP ≥140 or diastolic BP ≥90 in at least two different
 evaluations, or treatment for hypertension. Volunteers with type 1 diabetes or renal
 failure were excluded.

 Inclusion criteria for subsequent recruits: Criteria as indicated in Study Population
 Description (i.e., criteria based on familial relationships, hypertension and
 antihypertensive medication status).