Gene Scan Finds Links to Coronary Disease

LEICESTER, England, July 18 -- An increased risk of coronary artery disease has been linked -- for the third time in as many months -- to a region on chromosome nine.

Using the increasingly common method of genome-wide association scanning, researchers here and in Germany found that a common genetic variation dubbed rs1333049 is associated with about a 36% increase in risk for each copy in a person's genome.

In two large case-control studies, about 22% of participants had two copies and 50% had one, according to Nilesh Samani, F.Med.Sci., of the University of Leicester and colleagues.

The same variation was linked to coronary artery disease in two studies published in May in Science. (See Common Genetic Variation Increases Heart Disease Risk)

The new study is one of a trilogy published online by the New England Journal of Medicine and Nature Genetics, all of which used genome-wide association scanning to find genetic links to diseases.

In genome-wide association scanning, researchers take advantage of the data on genetic variation -- so-called single nucleotide polymorphisms, or SNPs -- amassed by the Human Genome Project and the international HapMap collaboration.

Then, using microarrays that recognize up to 500,000 SNPs, they look for polymorphisms that are more common in those with a disease than in healthy controls.

In this case, Dr. Samani and colleagues began with a cohort of 1,926 volunteers with coronary artery disease and 2,938 controls (the Wellcome Trust Case Control Consortium).

The case volunteers were selected because they either had a myocardial infarction or coronary revascularization before the age of 66, as well as a strong family history of coronary artery disease.

Genome-wide association scanning isolated nine genetic variants that were highly associated with disease. They had a significance of P< 1.2X10^-5 and a false-positive report probability of less than 50%.

Dr. Samani and colleagues then turned to another case-control cohort, the German Myocardial Infarction Family Study, to replicate their findings. In this cohort, the 875 cases had had a myocardial infarction before 60 and at least one first-degree relative with premature coronary artery disease. There were 1,644 healthy controls.

In the replication analysis, only three variants retained their significance. Specifically:

• The rs1333049 region on chromosome nine was significantly associated with disease at P< 1.80X10^-14 in the British cohort and P=3.40X10^-6 in the German study.
• A variant on chromosome six, dubbed rs6922269, and a variant on chromosome two, dubbed rs2943634, were also significantly associated with disease in the German study, at P=2.90X10^-8 and P=1.61X10^-7, respectively.

A combined analysis of the two studies found four other variants that may be associated with coronary artery disease, but the researchers said the finding should be treated cautiously until the data have been replicated in another cohort.

The most compelling evidence for an association with disease concerns the region on chromosome nine, Dr. Samani and colleagues said.

"The evidence of association is strong, the risk variant is common, and each copy of the allele substantially increases the probability of the disease," they said.

The replication of the earlier Science studies also increases their confidence in the result, the researchers said.

But exactly how the genetic variation plays a role in heart disease remains unclear, although the region contains two genes, CDKN2A and CDKN2B, which may be involved in the pathogenesis of atherosclerosis, the researchers noted.

Indeed, finding genetic associations in this way is only the first step toward clinical application, according to Anthony Rosenzweig, M.D., of Beth Israel Deaconess Medical Center in Boston and the Harvard Stem Cell Institute, in an accompanying editorial. He wrote that the "work is still years from enabling personalized coronary care or elucidating new mechanisms."

Nevertheless, the study is an important proof of principle, he said, that now needs to be extended to other populations -- both the British and German studies included mainly people of European descent -- and should spark research into exactly how the genetic variation translates into disease.

Although the New England Journal of Medicine usually concentrates on research with a clinical focus, these three studies were published because they "represent an important advance in medicine," according to editor Jeffrey Drazen, M.D. and deputy editor Elizabeth Phimister, Ph.D.

"The onus now lies on us to explain how variation in the function of these genes leads to clinical disease," the editors said.

But once that understanding has been achieved - although it will not be easy - "we should have the keys that will lead us to eventual improvements in patient care," they said.