UCSF Researchers Are Mapping DNA from 100,000 People for Unique Kaiser Database

By Jeffrey Norris

Mother Nature’s tightly held secrets to healthy aging are in danger of being wrested away. The genes we inherit, the lives we lead and the places we live all affect our chances to evade major diseases and to maintain health as we grow older.

Neil Risch

To help sort out how variations in these contributing factors influence health risks, Kaiser Permanente’s Division of Research is creating one of the world’s largest genetic and environmental information resources for health research, called the Research Program on Genes, Environment, and Health (RPGEH). “This is going to be the largest and most comprehensive database for doing genetic epidemiology research,” says Neil Risch, PhD, head of the Institute for Human Genetics at UCSF and co-chair of the Department of Epidemiology. Risch is an adjunct investigator at the Kaiser Permanente Division of Research and co-director of the RPGEH. In September 2009, the RPGEH and UCSF received $25 million in federal stimulus funds. The source was a new, two-year grant from the National Institutes of Health. The funds will enable Risch and colleagues to genotype DNA from 100,000 RPGEH participants. The genotyping project is a collaboration between the UCSF Institute for Human Genetics and the RPGEH. As a result of this funding, in just a few years, scientists around the world will be able to tap into a new data resource, which will be the biggest of its kind to focus on genetic variation and environmental exposures in an older population. The average age of individuals whose genetic information will be genotyped for the project is 65. More than 125,000 Kaiser members already have contributed saliva samples to the RPGEH for DNA genotyping. “We are grateful that so many Kaiser Permanente members in Northern California see the long-term potential in building this kind of a resource for scientific research,” says Cathy Schaefer, PhD, executive director of the RPGEH. “Our participants make this program possible. They are making a real contribution to better health for future generations by participating in this program.” The foundation for the RPGEH is another, pre-existing and ever-growing clinical database -- Kaiser Permanente’s electronic health record, HealthConnect™. This is the largest civilian database of its kind. For many Kaiser Permanente members, it has information spanning decades and includes information on clinical diagnosis and treatment as well as lab-test results and prescription information. This rich resource now is matched with UCSF researchers’ expertise in detecting DNA differences among individuals. The UCSF Genomics Core Facility, under the direction of Pui-Yan Kwok, MD, PhD, will manage the genotyping of the DNA. “The RPGEH is going to be an evolving database,” Risch says. “Even if the genes in the database remain the same, the clinical information is being updated constantly.” “If you tried to create a database like this from scratch, it would be enormously expensive,” he adds. The database will be a gateway to discoveries that are likely to lead to insights into new treatments for common diseases such as diabetes, asthma, heart disease and cancer – conditions that are well-represented among the Northern California members of Kaiser Permanente. “This two-year project is mainly about creating the infrastructure,” Risch says. “The bigger payoff is going to come later, after the data is collected.” Already there are commercial “microarray” chips available to track genetic variation in human research studies. These gene chips – which look a bit like microscope slides – contain markers to detect genetic variability in DNA samples at points throughout the entire human genome. The chips provide a means to survey all DNA on all of our chromosomes. The latest versions include up to a million markers to detect genetic variations. The markers are spaced throughout the 3 billion DNA alphabet building blocks, called base pairs, which spell out the human genome. Risch and his RPGEH colleagues have enlisted chip maker Affymetrix of Santa Clara, Calif. to make a customized chip. The deluxe chip will include additional markers to enhance researchers’ power to track down important genetic variations that exist within human populations. The new markers have been selected based on recent discoveries of human genetic variations from the NIH-sponsored 1000 Genomes Project and on earlier discoveries of genetic links to disease risk and responses to drug treatment. Many of the new markers are uncommon in the population overall, but are more prevalent in certain ethnic groups, among whom they may have a greater impact on disease risk and treatment response. “We want to make sure we have genome-wide coverage,” Risch says. “But we also want to be able to follow-up on prior studies on a whole variety of human diseases, which have pointed to particular locations within the genome.” Because the customized gene chip will incorporate additional, closely spaced markers in these regions of special interest, it will be used to generate data that researchers far and wide can use to zoom in more closely on specific changes in DNA that may contribute to risks for the diseases they study. Risch hopes that researchers using the database also will identify genes or lifestyle factors that increase the likelihood of living a long, healthy life. “We have a lot of people in the database who are in their 80s and 90s. It’s a great opportunity to look at healthy aging.”