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Does Tiny Island in Pacific Ocean Hold Pharmacogenomics Keys to Obesity?

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Can 2,200 men and women living on an island in the middle of the Pacific Ocean help researchers in the United States pinpoint the genetic roots of obesity, diabetes, hypertension, and hypercholesterolemia?

A group of researchers from Rockefeller University, the Broad Institute, and Affymetrix hopes so, and for the next six months will be performing one of the largest genome-wide association studies in order to identify mutations linked to these conditions.

The program is also believed to be one of the first big tests for Affymetrix’s new GeneChip mapping 100K array set, which promises to play a large role in pharmacogenomics studies when it is formally launched later this month.

“We’ve been wanting to do this experiment for a long time,” Jeff Friedman, director of the Starr Center for Human Genetics at Rockefeller University, said in a statement this week.

Whole-genome-association trials have been around for years — though time-consuming and expensive, they play a significant role in pharmacogenomics research around the world. But the nature of this program is unique. Friedman’s team, which also includes Jan Breslow and Markus Stoffel at Rockefeller, and David Altshuler at Broad, will try to identify mutations linked to obesity in approximately 2,200 inhabitants of an island called Kosrae, located 2,500 miles off the coast of Hawaii.

Iceland in the Pacific?

The researchers are hoping that the population of this island, about two-thirds the size of Washington, DC, is homogenous enough to provide an accurate glimpse of the genetic underpinnings of obesity and its ancillary sequelae, such as diabetes, hypertension, and hypercholesterolemia.

Kosrae, pronounced KO-shray, was founded around 1,000 years ago by 50 Polynesians. Later, in the mid- to late-19th century, Caucasian whalers settled on the island. Today, many Kosraeans can trace their ancestry to both groups, according to Rockefeller.

Kosraeans were considered “ideal” for this research because of the more recent “Westernization” of their lifestyles. “For most of their … history, Kosraeans were active,” according to Rockefeller. But in the years following World War II, after many shipments of aid from the United States, “most began leading a sedentary lifestyle while eating foods with high salt and fat contents.” As a result, a “disproportionate percentage” of people on the island have developed obesity, diabetes, hypertension, and hypercholesterolemia — collectively known as Metabolic Syndrome, or Syndrome X.

“Because all four conditions simultaneously can affect the same individual or many family members, a common set of flawed genes may trigger the syndrome,” Rockefeller said on its website. The goal of the program, then, is to determine “why some people develop these diseases, while others ... do not.”

Results of this research might also interest big pharma, which sees obesity, diabetes, hypertension, and hypercholesterolemia as enormous — and growing — markets.

Indeed, according to the Atlanta-based Centers for Disease Control and Prevention, obesity in the United States more than doubled between 1971 and 2001, to 31 percent of the US adult population from 15 percent in 1971. Diabetes, meantime, is the fifth-deadliest disease in the United States, costing the health-care system $132 billion in 2002, or one out of every 10 health-care dollars spent in the United States, according to the American Diabetes Association.

Hypertension, on the other hand, affects one-sixth of the US population aged six and older, and was responsible for almost 45,000 deaths in 2000, according to the American Heart Association. And familial hypercholesterolemia affects about 1 in 500 people in the United States, and is an “important cause” of premature coronary heart disease and other cardiovascular events, according to the New England Journal of Medicine.

To get a foothold into the genetic component of these conditions in the Kosrae population, Friedman and colleagues had previously performed epidemiological and genetics studies on more than 90 percent of the island’s adult population, or 2,188 individuals.

For each Metabolic Syndrome disorder, Friedman, who has been studying obesity in Kosraeans for the past 10 years, will analyze DNA from volunteers on the island in the hopes of identifying genes involved in each disease, as well as to verify previous findings of candidate genes from research with animal models or human patients in the United States.

Affy’s Showcase

Rockefeller and Broad researchers will genotype samples collected on the island using the SNPs from Affy’s 100K array, plus around 100,000 additional SNPs that “may be relevant” for the Kosraean population, according to project organizers. About half of the roughly 115,000 SNPs found on the 100K two-array set are from public databases, while the other half are from SNPs identified by Affy spinout Perlegen Sciences.

For Affy, which is proving its technology to Rockefeller and Broad researchers for an undisclosed price, the program on Kosrae will help it convince other researchers that its 100K array has the resolution to make such large-scale genome-wide SNP-genotyping projects more affordable and practical. In fact, Friedman said it was the availability of the 100K array that enabled him to begin the genotyping and SNP-analysis portion of the program.

Greg Yap, senior marketing director at Affymetrix, said the portion of the study that generates data through genotyping will take less than six months. He said the data analysis, which will be done by Altshuler’s lab at the Broad Institute, will take “some time.”

Santa Clara, Calif.-based Affymetrix narrowly released the 100K array in December 2003. The product, which is slated for general launch later this month, is intended to become a linchpin in the firm’s plan to enter the SNP-analysis market. According to Affy, 27 undisclosed academic labs and drug makers are currently early-access customers.

In the short term, Affy hopes the move will place it at the back of a queue of highly competitive platform companies — Illumina, Sequenom, and ABI — intent on holding onto a finite customer base.

The 100K array “meet[s] the growing customer demand for powerful SNP genotyping and resequencing solutions in basic research, clinical research and development, drug discovery, and pharmacogenomics,” Yap said in a press release last July. At that time, the company introduced the Mapping 10K array for whole genome SNP analysis. This product, which was beta tested at around 50 labs for nine months, enables researchers to perform benchtop-based whole-genome SNP analysis using a single primer pair that can examine 10,000 SNPs in a sample assay of 250 ng of DNA.

Affy is betting that the 100K tool, which it had dubbed Centurion, will target the full-genome-association market within big biopharma and academia (the 10K product is primarily sold to the genetic-linkage market). The Rockefeller study, then, is an important trial run for a product that Affy hopes will be embraced by drug makers eager to stratify trial cohorts, revive failed drugs, and expand drug labeling. “These are all areas that people have expressed interest in on the clinical side,” Yap said last fall.

Affy has yet to organize a pricing schedule for the 100K product, and the company is still finalizing the 100K beta customers. Yap said the arrays have brought to per-SNP genotyping costs to “under 1 cent” including arrays and reagents. He added that Affy “is continuing to bring genotyping costs down.”

David Kwiatkowski, director of the genotyping core at Harvard-Partners Genome Center, said Affy officials last fall told him the informal price for the 100K is currently around $1,000 per chip.

Edvin Munk, manager of product marketing at Sequenom, said last fall when the 100K was released to its beta customers that he does not see the 100K array as a dangerous competitor. “The 100K … is still inflexible, but you would be able to do a quick scan of the genome. And I think that probably would be a market for people who have the [GeneChip] scanners already.”

Munk said that Affy’s SNP array might be better suited to “quickly looking at the genome, and doing some rough scans, but in the end I would always predict that researchers would need some other tools to do the fine mapping.”

— KL

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