November 30, 2011 (Montreal, Quebec) — The Kaiser Permanente Northern California Research Program on Genes, Environment, and Health (RPGEH) is poised to provide unprecedented opportunities to advance knowledge of genetic and environmental predictors of disease and treatment responses, including age-related diseases and the process of aging. Some of this research has already begun.

In a press conference held here during the 12th International Congress of Human Genetics and the 61st American Society of Human Genetics Annual Meeting, several members of the RPGEH research team described recent findings and future goals made possible by having the largest biobank in the United States, which can be used to perform countless genomic analyses and to link genomic data to comprehensive electronic records (EMR) and environmental exposure data.

To date, the team has obtained approximately 170,000 biospecimens from RPGEH survey participants.

Funding from the Robert Wood Johnson Foundation Pioneer Portfolio and the National Institutes of Health (NIH) in 2009 provided the impetus to perform genome-wide genotyping and telomere-length analysis of 100,000 RPGEH participants; this has now been successfully completed.

As noted by Neil Risch, PhD, codirector of the RPGEH and director of the University of California at San Francisco (UCSF) Institute for Human Genetics, the group first had to develop 4 novel, ethnic-specific arrays to accommodate the ancestral diversity in their sample (one quarter of the cohort is minorities, and includes people of African, West Asian, South Asian, East Asian, Pacific Island, and Native American ancestry).

Over a record-breaking period of 14 months, which is the time the NIH gave them to perform the genotyping and telomere-length analysis, the team genotyped more than 675,000 single-nucleotide polymorphisms (SNPs) for each of the 100,000 subjects. Preliminary results indicate that the cohort contains 10,000 to 20,000 first-, second-, and third-degree relative pairs.

"By looking at how often a pair of individuals had the exact same genotype across all those SNPs, or how often they shared 1 allele out of 2 at a given site, we found about 66 identical twin pairs, about 3300 parent–child pairs, about 2000 sibling pairs, and close to 3000 second-degree relative pairs," Dr. Risch reported. He anticipates that there will probably be about 12,000 pairs of related individuals in the cohort overall. Having this number of related individuals in their cohort is really a "treasure trove," because it will allow researchers to estimate how heritable a given trait is much more accurately than is currently possible, he explained.

Tandem Repeats of DNA

As for the telomere analysis, it's important to appreciate what telomeres are and what they do, noted Kyle Lapham, research specialist in the Blackburn Lab at the UCSF Institute for Human Genetics. "Telomeres are tandem repeats of DNA at the end of chromosomes," he explained.

Every time a cell divides, "it can't copy all the DNA [in the cell], so it needs to bind to something past it in order to copy what is behind it," he added. The telomerase enzyme replenishes these end caps and keeps the DNA at a somewhat constant length. Telomeres also prevent cells from recognizing double-stranded breaks and attacking the DNA.

"Telomeres control how many times a cell can divide. How long a cell can divide is how long a cell can live, and how long a cell can live tends to correlate with how long you can live, so telomere length has wide-reaching effects on the organism," Mr. Lapham said. In their analysis of 100,000 DNA samples extracted from saliva, the UCSF team showed that telomere length varied in cohort participants, who ranged in age from 18 to 90 years.

A growing body of literature has already linked shorter telomere length with various age-related diseases and with earlier mortality.

Interestingly, telomere length appears to be modifiable, Mr. Lapham observed. Studies in which subjects have participated in meditation camps, for example, showed that telomeres lengthened over time in response to diminished levels of stress. Physical activity has also been associated with the elongation of telomeres.

"The beauty of all of this is all the other factors you can analyze at the same time — the genetic, the environmental, all the data — to gain a better understanding of what the role of telomeres is in health and in disease, and how they work over time," said Cathy Schaefer, PhD, executive director of the Kaiser Permanente RPGEH.

Overall, 14% of the cohort is 80 years and older, Dr. Schaefer noted, which gives researches a "huge opportunity" to study factors other than genetics that might promote longer telomeres.

Longitudinal Information

Dr. Schaefer explained that a "really unique aspect" of this project is the amount of the longitudinal information researchers have at hand. "In a lot of situations where you are doing genome-wide association studies of unrelated individuals, you are essentially doing a cross-sectional study," she said. In other words, researchers are looking at individuals with disease and those without, and are trying to see if there is an association between genetic variants and disease occurrence.

In contradistinction, the RPGEH team has EMRs going back approximately 15 years, which contain multiple clinical, laboratory, radiology, pharmacy, and other health data on all participants, and which are continuously updated as the cohort ages. Furthermore, investigators have access to rich geographic information system databases that will allow them to map participants to environmental data, such as air pollution and healthy and unhealthy features in their surrounding environment.

"People often have rich genetic data but no environmental data, so you really can't ask questions about how the environment interacts with genes to produce certain outcomes, and you don't have information about behavioral or historic factors either, so you can't really ask how diseases come about and what is involved in healthy aging," Dr. Schaefer said. "What makes this project significant is that the group of people we are studying is really quite representative of the general population, so a lot of what we find can be generalized to the population as a whole. In addition, our database will just get richer and richer over time because we will be adding information as individuals age and their health changes over time."

Mr. Lapham and Dr. Schaefer have disclosed no relevant financial relationships.

12th International Congress of Human Genetics (ICHG) and the 61st American Society of Human Genetics (ASHG) Annual Meeting: Abstracts 624W, 3, 94, 1349T, 503T, 613T, 665T, 638T, 616F. Presented October 12, 13, and 14, 2011.