Family Blood Pressure Program - SAPPHIRe 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 study focused attention on an Asian population in order to reduce heterogeneity of the genetic background. In 1995, a genetic network was established in the San Francisco Bay Area, Hawaii, and Taiwan, recruiting an estimated 1,700 affected hypertensive sibpairs plus several multigenerational hypertensive pedigrees of Asian Pacific Chinese and Japanese. Linkage analysis was used to map and identify the genes for hypertension in this ethnic group. A new genetic map of the human genome with 2041 ordered polymorphic markers with an average interval of less than 3 cM had been reported. Such a dense map of polymorphic markers made it plausible to propose linkage analysis of complex traits. A total genomic search was performed on 1700 affected sibpairs and family members. In addition, the candidate gene approach was also used. To address the possibility of heterogeneity of the hypertensive trait, a number of intermediate phenotypes was studied that may help identify more homogeneous subgroups of hypertension. For example, Asians and Pacific Islanders had an increased risk for hypertension, dyslipidemia, and glucose intolerance (Syndrome X) that were associated with hyperinsulinemia. Therefore, hypertension was investigated according to insulin sensitivity vs. resistance as well as other intermediate phenotypes related to hypertension pathophysiology such as renin, Ang II, and endothelin. The hypothesis was that by focusing on possible hypertensive subsets with well defined phenotypes, the possibility was enhanced of gene identification for hypertension in these patients. The third approach examined the hypothesis that there existed a dominant locus determining hypertension in a subset of affected individuals using the analysis of multigenerational pedigrees with 10-13 meiosis separating affected members. If such a subset existed, this approach would reduce the likelihood of heterogeneity and increase the probability of revealing genetic linkage. Once major gene loci were identified, it was important to determine the prevalence of these loci in the overall population and the risk associated with their loci for the development of hypertension. Therefore, the genetic epidemiology of the loci were studied using epidemiological methodologies such as association studies and case control analysis on well characterized populations in Hawaii and Taiwan that had been studied prospectively for many years.

The Family Blood Pressure Program, including the SAPPHIRe Network, 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 SAPPHIRe, carried out its own specific aims alone, based on unique aspects of their population and interests and expertise of the investigators.

SAPPHIRe investigators refined the hypertensive phenotype in the study population by assessing the intermediate phenotype of insulin resistance using the oral glucose tolerance test and steady state plasma glucose assay. They also used novel molecular genetic approaches to enrich genomic DNA for common genetic variations and develop proteomic approaches to identify proteins that were differentially expressed in plasma and urine of the SAPPHIRe participants.

In the next phase of the FBPP which extends through 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.