"This is a stunner," said Francis Collins, M.D., Ph.D., director of the National Human Genome Research Institute. "It seems like this one place carries all of that weight for two very common and very dangerous diseases."

Dr. Collins, one of the senior researchers involved with the diabetes studies, commented,  "Not only did they find a variation that is associated with heart disease, but in the very same place, where a week before, three different groups found the same association with a different disease," Dr. Collins said.

The region in question lies near two genes known as CDKN2A and CDKN2B genes on chromosome nine, according to Ruth McPherson, M.D., Ph.D., of the University of Ottawa (Ontario) Heart Institute.

But, she and colleagues said, the genetic variation they found is not associated with established coronary heart disease risk factors such as plasma lipoproteins, hypertension, or diabetes.

The finding -- like all genome-wide association scanning -- is based on comparing the genes of people with and without the disease of interest, in a case-control fashion using microarray technology.

In this case, Dr. McPherson and colleagues analyzed the genomes of 322 people with severe early coronary heart disease taking part in the Ottawa Heart Study, and compared them with those of 312 healthy controls.

Variations identified in that analysis were then studied in an independent sample of 311 cases and 326 controls from Ottawa and the 11,478-participant Atherosclerosis Risk in Communities study in the U.S. The research narrowed candidate variations down to two single nucleotide polymorphisms (SNPs) within 20 kilobases of each other on chromosome nine.
Finally, the researchers studied the variations in three more independent groups -- one from Copenhagen, one from Dallas, and a thirds set from the Ottawa Heart Study.

The analysis showed that roughly 25% of Caucasians have two copies of the so-called risk allele, which was associated with between a 30% and 40% increased risk of early coronary heart disease.

About half of all Caucasians have one copy of the allele, and they have between a 15% and 30% increase in risk, Dr. McPherson and colleagues said.

The Icelandic study, led by Kari Stefansson, M.D., of deCODE genetics, paralleled the Canada-U.S. probe, except that the researchers chose myocardial infarction as their target. Starting with 1,097 Icelanders who had early-onset MI and 6,728 controls who had no history of coronary disease, Dr. Stefansson and colleagues found several suspect SNPs.

They repeated the analysis using an independent set of Icelanders, as well as Caucasian case-control cohorts in Philadelphia, Atlanta, and Durham, N.C., and narrowed the suspects down to three SNPs on chromosome nine.

Again, the Icelandic researchers found that 21% of Caucasians carry two copies of the risk allele (homozygous), which confers about a 64% increase in risk of MI, while those with one copy (heterozygous) face about a 26% increase in risk.
Neither group was able to say exactly how the suspect regions increase risk, especially because no known genes reside in the area. One possibility, Dr. McPherson and colleagues said, is that the region contains a regulatory element that governs genes some distance away.

Interestingly, neither group found that their heart disease signal was associated with diabetes. In the Canada-U.S. study, for example, those with diabetes were explicitly excluded.

Sciencexpress: McPherson R et al. "A Common Allele on Chromosome 9 Associated with Coronary Heart Disease." Science 2007; 10.1126/science.1142447.

Sciencexpress: Helgadottir A et al. "A Common Variant on Chromosome 9p21 Affects the Risk of Myocardial Infarction." Science 2007; 10.1126/science.1142842.