ADVANCE Atherosclerotic Disease Vascular
Function and Genetic Epidemiology

Introduction to ADVANCE

ADVANCE is a large epidemiological study of genetic and non-genetic determinants of coronary artery disease (CAD) that started in 2000 as a collaborative effort between researchers at Stanford University and Kaiser Permanente of Northern California. The overarching goal of the study is to improve our ability to prevent, diagnose and treat CAD. The initial study, including recruitment of over 3,600 subjects as well as a genetic association study of approximately 100 candidate genes, was funded by a grant from the Donald W. Reynolds Foundation. Since then, we have expanded our efforts and in 2006 were awarded a grant from the National Heart, Lung and Blood Institute (NHLBI) to pursue a whole genome association (WGA) study of CAD in our cohorts.

Aim

Atherosclerotic coronary artery disease (CAD) is the leading cause of death in the developed world. Progression of CAD is highly variable and is governed by both environmental factors and genetic determinants. We have known for some time that the contribution of genetics to CAD is at least equal to that of environmental risk factors. The genetic risk is thought to be due to an unfavorable combination of genetic variations in multiple genes; but the genes that control this variability in susceptibility to disease are not well characterized.

The Falk Center

The aim of the ADVANCE Study (Atherosclerotic Disease, VAscular functioN, and genetiC Epidemiology) is to provide better care for patients with atherosclerotic coronary heart disease through the application of modern genetic approaches. As such, projects utilize both genetic as well as epidemiological strategies to identify genetic polymorphisms associated with atherosclerosis. Our short-term goal is to use new genetic information to improve the diagnosis, risk stratification and application of standard therapies for patients with atherosclerotic heart disease. Our long-term goal is to develop insights into the pathophysiology of coronary disease based on genetic information that will lead to novel and improved approaches to prevention and treatment of heart disease.

Overview

Patients with atherosclerosis represent a heterogeneous group of individuals, with diseases that progress at significantly different rates and in distinctly different patterns. Treatment for patients with atherosclerotic heart disease remains suboptimal largely due to our fundamental lack of understanding regarding the molecular basis of the disease process. Differences in the natural history of the atherosclerotic disease process, and variation in the individual response to therapy, reflect in part differences in the genes that are responsible for the initiation and modification of the disease. For complex diseases such as atherosclerosis, the application of modern genetic tools provides the greatest hope for improved diagnosis and treatment.

With the primary aim of uncovering novel genetic determinants of CAD and of acute myocardial infarction (MI), investigators at Stanford University and Kaiser Permanente of Northern California (KPNC) initiated the ADVANCE study in October, 2000. Cases and controls were identified from over 2.9 million enrollees in KPNC, an ethnically diverse population representative of the local and statewide population 1, 2. Eligible subjects were identified using the KPNC electronic databases and those who agreed to participate were interviewed and examined at one of several clinics in the San Francisco Bay Area. To allow for several pre-specified contrasts, a specialized recruitment strategy was devised. Between October 28, 2001 and December 31, 2003, we assembled a study including over 3,600 subjects with detailed clinical information and blood for DNA and protein studies (see Cohorts).

ADVANCE Phase I

At the time of the ADVANCE Phase I study, there were technological limitations that made it impossible to survey the entire human genome for genetic polymorphisms that are associated with coronary disease. Thus, initially our approach focused on a more limited candidate gene based approach. We selected candidate genes on the basis of results of local genomic experiments 3-5 and an extensive review of the literature 3, 4, 5. Single nucleotide polymorphisms (SNPs) were identified in each of the candidate gene loci through a process of SNP discovery, and a subset of these SNPs were genotyped in all participants in the ADVANCE Study to compare case and control groups with the respect to the acquisition or progression of atherosclerotic disease.

Details regarding the candidate genes, SNPs and genotyping strategy studied in ADVANCE Phase I are available by selecting the tab for ADVANCE Phase I.

The first phase of ADVANCE was funded through a generous grant from the Donald W. Reynolds Foundation, Las Vegas from October, 2000 until June, 2006.

ADVANCE Phase II

The study of complex genetic diseases like CAD has proven to be a tremendous challenge. The most efficient approach to identifying susceptibility genes involves looking for correlation between a specific allele and disease in cases and controls (association design). Until recently, association studies were restricted to a “candidate gene” approach where variants, typically single nucleotide changes or polymorphisms (also called SNPs) in genes are evaluated on a gene by gene basis, such as was done in the first phase of the ADVANCE study. While an important first step, candidate gene studies are limited by pre-defined hypotheses. A complementary approach is to use a more comprehensive and unbiased approach to look at variation in all genes in the genome through a Whole Genome Association (WGA) study which has only recently become possible after the sequencing of the genome, large scale SNP identification projects and the development of genotyping platforms capable of examining hundreds of thousands of SNPs at once.

In ADVANCE Phase II, we will perform a high density WGA scan using over 550,000 SNPs on a population of highly selected and characterized cohort of young individuals with premature CAD from ADVANCE. To validate positive associations from the WGA scan, we will perform targeted regional genotyping in a cohort of older individuals with clinically significant CAD and a similar group of control subjects as well as replication in the independent INTERHEART study. The identification of CAD susceptibility genes is potentially of tremendous value to public health because these efforts could change our ability to both diagnose and treat CAD. See ADVANCE Phase II tab for more details.

This phase of ADVANCE is largely being funded by a grant from the NHLBI that will run from October 1, 2006 through July 31, 2009.

Potential Collaboration

ADVANCE Investigators welcome proposals from outside investigators for collaborative studies (please see Ancillary Studies tab for more details).

References

  1. Hiatt RA, Friedman GD. Characteristics of patients referred for treatment of end-stage renal disease in a defined population. Am J Public Health 1982; 72:829-33.
  2. Krieger N. Overcoming the absence of socioeconomic data in medical records: validation and application of a census-based methodology. Am J Public Health 1992; 82:703-10.
  3. Tabibiazar R, Wagner RA, Ashley EA, et al. Signature patterns of gene expression in mouse atherosclerosis and their correlation to human coronary disease. Physiol Genomics 2005; 22:213-26.
  4. Spin JM, Nallamshetty S, Tabibiazar R, et al. Transcriptional profiling of in vitro smooth muscle cell differentiation identifies specific patterns of gene and pathway activation. Physiol Genomics 2004; 19:292-302.
  5. Ho M, Yang E, Matcuk G, et al. Identification of endothelial cell genes by combined database mining and microarray analysis. Physiol Genomics 2003; 13:249-62.

Stanford Medicine Resources:

Footer Links: