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Kaiser, UC San Francisco working on gene catalog of healthcare members

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SAN FRANCISCO—Kaiser Permanente, an early adopter of electronic medical records, says that it has underway a massive project in California that will eventually paint a clear picture of the genetic and environmental factors that influence the health of 100,000 of its members.

The massive collection of data, gathered in collaboration with the University of California, San Francisco (UCSF), and processed with new genotyping technology from Santa Clara, Calif.-based Affymetrix, will soon be available to outside researchers who study how different genetic and environmental factors influence disease. The research was conducted by the university's Research Program on Genes, Environment and Health (RPGEH), which is designed to facilitate epidemiologic studies of both genetic and environmental influences on common health conditions, such as heart disease, diabetes, cancer, asthma, mental health disorders and many others.

In roughly 15 months, the research team collected and analyzed the genomes of 100,000 Kaiser members, who range in age from 18 to 107. The team used gene microarrays—small chips designed to quickly detect hundreds of thousands of genetic variations across the genome. In addition, computerized medical records of the patients provided additional data to complete a picture of factors influencing the volunteers' health.

Kaiser's Sarah Rowell, associate director of research operations for the RPGEH, says the study cohort provided a balanced group of study participants.

"The cohort is ethnically diverse and has an average age of 65," she says. "The participants are 58 percent female and 42 percent male. The length of membership ranges from approximately two to 45 years. More than half, or 51 percent of the cohort has 20 or more years of health plan enrollment."

Dr. Neil Risch, director of the UCSF Institute of Human Genetics, says the pace of the project was only possible because of the alignment of a number of critical factors: Kaiser's extensive health records and thousands of willing participants from the diverse Northern California region; new genotyping technology from Affymetrix which produces scalable genomic analysis tools; and a history of collaboration between Kaiser and UCSF, two research institutions with complementary strengths for this project.

To complete the genotyping project in two years, as required by the funding, Kaiser first had to build a new, high-throughput laboratory in Oakland, Calif., to extract DNA from the saliva samples in 15 months. The extracted DNA was transferred to Risch's labs, which worked with Affymetrix to create custom Axiom arrays for genotyping 675,000 to 900,000 genetic markers—comprised of single nucleotide (SNPs) and insertion-deletion polymorphisms—across all 100,000 samples.

Risch adds that Affymetrix was chosen for a number of factors important to this project.

"We had a large project and were required by the grant to complete it in 15 months, so we needed to collaborate with a company that would enable us to achieve that," he says. "Affymetrix recently developed a new, high-throughput and less expensive genotyping system called Axiom, which requires less reagent handling and tech time. They also allowed us to design our own custom arrays for this project, with 675,000 SNPs per array or more, with high genome-wide coverage and coverage of target SNPs.

"We performed pilots to confirm that saliva-derived DNA would genotype well with the Axiom platform, so we also knew this system would do what we needed," he continues. "Hence, because of the flexibility of array design, high-throughput and reduced costs, we chose to partner with Affymetrix and the Axiom system for this project. Our resulting genotypes, from saliva derived DNA, are high-quality, with high call rates and high reproducibility rates."

As part of the study the length of participants' telomeres, which are part of a chromosome linked to aging, is also under examination. This represents the largest telomere study to date.

By combining that information with prescriptions, for example, researchers could examine how genetics influence blood pressure and the effectiveness of medication.

Researchers will also add to the mix environmental data, such as air-quality and water-quality records, based on knowledge of where participants lived and when.

The team will continue to follow participants as long as they receive healthcare from Kaiser. Future studies may investigate how accurately telomere length can predict longevity or healthy aging.

Data from the genotyping project will be processed and cataloged by RPGEH and UCSF scientists over the next year so it can be made available to researchers in late 2012.

Kaiser's Rowell says a mailed survey was Kaiser's first step in recruitment. Respondents to the survey were sent a consent form and information about the program in the mail. Members who returned a signed consent form were sent a saliva collection kit. The consent form explains the purpose of the program and all procedures, as well as potential benefits and risks. It also tells participants what is expected of research participants.

A toll-free phone line was available to respond to any member questions about the program or the materials.

"Participation in the RPGEH is completely voluntary," Rowell says. "All participants must provide written informed consent before providing a saliva sample and may withdraw from the program at any time."
Strict attention to privacy and applicable laws was an important consideration.

"All research conducted by the Division of Research and the RPGEH is designed to maintain the privacy and confidentiality of participants' personal information. Consistent with federal standards for human subjects research, research conducted at Kaiser Permanente is reviewed and approved by our organization's institutional review board to assure that it is maintains appropriate respect for individuals' safety, welfare and rights as research participants."

The law also requires that participants sign the Authorization to Use and Disclose Protected Health Information, which is required by the Health Information Portability and Accountability Act (HIPAA).
The genotyping project was made possible by a two-year, $24.8 million grant awarded in September 2009 to the Kaiser Permanente RPGEH and UCSF by the U.S. National Institutes of Health. Funding for the grant came from three sources: the National Institute on Aging, the National Institute of Mental Health and the Office of the Director.

The UCSF Institute for Human Genetics serves as a focal point for campus-wide activities in human genetics and has faculty members engaged in human genetics research spanning the four schools: Medicine, Nursing, Pharmacy and Dentistry. The major aim of the Institute is to create an exciting, productive and collaborative environment for research and training in human genetics, and to provide institutional support and resources, such as the Genomics Core Facilities, for faculty research and for teaching in a number of UCSF graduate and medical school programs.

Kaiser Permanente's Northern California Division of Research launched the RPGEH in 2005 and initiated enrollment of participants from the Northern California region's three million Kaiser Permanente members in 2007. The research program has enrolled more than 188,000 members and plans to enroll a total of 500,000 Kaiser members by 2014, which will make it one of the largest and most diverse population-based biobanks in the world.

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