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.
