Family Blood Pressure Program - GenNet Network

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 centers: two field centers, a rat genotyping center, a human genotyping center with statistical genetics and informatics, and a genetic analysis center. After genetic loci regulating blood pressure are identified, genomic markers are used to study genetic linkage with red blood cell lithium-sodium countertransport, hyperkinetic hyperadrenergic state, and the renin-angiotensin system in sibships and tested in several Black populations.

The well-characterized Tecumseh population was utilized as a first step in determining genetic linkage to hypertension, using the quantitative trait locus (QTL) approach. A total of 250 white sibships in the Tecumseh population were examined using 400 anonymous markers and candidate genes. Approximately 100 markers that demonstrated linkage were used to examine 250 African-American sibships in Maywood, Illinois. Fifty refined candidate markers were used to study several extant Black populations in Jamaica and Nigeria, as well as individuals in the other two populations. A unique feature of the network is the inclusion of a rat genotyping center. Crosses of inbred hypertensive and normotensive rats are used to identify genomic regions linked to hypertension. The regions are then used to identify homologous human candidate genes in addition to those already selected from previous research.

The GenNet Network was renewed in September 2000 to continue studies of hypertension-associated phenotypes in United States whites, African Americans, Mexican Americans, and West Africans and Caribbeans. 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 influenced susceptibility to develop hypertensive heart and kidney diseases (Aims 4 and 5). In addition to the Program specific aims, each network, including GenNet, carried out its own specific aims alone, based on unique aspects of their population and interests and expertise of the investigators. In GenNet, progress has been made in the identification of single nucleotide polymorphisms (SNPs) in candidate genes and work was underway to develop rapid genotyping methods in individual and pool samples. The search for genes in diverse human populations was complemented by mapping studies in rat strains, in which linked regions that overlap with regions showing evidence for linkage in the human studies were selected for positional cloning.

In the next phase of the FBPP ending in August, 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 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.