A large team of scientists from the US and Europe examining data from four studies found that millions of people have a genetic variant that makes them more susceptible to ischemic stroke, with about 20 per cent of white people and 10 per cent of black people having at least one copy of the gene, with each copy raising the risk by 30 per cent.

The genomewide association study, which is published online in the 15 April issue of the New England Journal of Medicine, NEJM, used data from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, which comprises four large cohorts from the Atherosclerosis Risk in Communities (ARIC) study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

Ischemic stroke is caused by blockage of blood to the brain. It accounts for about 90 percent of all strokes, which afflicts nearly 150,000 Americans a year, making it the third leading cause of death. Stroke survivors are often left with permanent stroke-related disabilities.

Although previous studies have looked at links between genetic factors and stroke risk, the researchers wrote that the “genes underlying the risk of stroke in the general population remain undetermined.”

One of the study’s lead authors and principal investigator of the ARIC study, the largest in the CHARGE Consortium, is Dr Eric Boerwinkle, who is Kozmetsky Family Chair in Human Genetics at the University of Texas Health Science Center, where many of the other investigators are based. Boerwinkle told the press that:

“This is the first study to identify a common genetic variant influencing the risk of stroke in the United States.”

The researchers hope their discovery leads to new ways to detect people at increased risk of stroke before symptoms appear, and new treatments that target the molecular processes that underlie stroke risk.

“We formed a consortium of the largest studies to permit rapid replication,” said Boerwinkle, explaining that:

“If you only have one study, there is a chance of a false positive. Here we’re doing millions of statistical tests and replication is necessary to rule out false positives.”

The CHARGE consortium generated a main sample of 19,602 participants and three replication samples, a prospectively evaluated cohort of 2,430 black participants in the ARIC study, a second smaller, prospectively evaluated cohort of 574 black participants in the Cardiovascular Health Study, and a case-control sample of 4,265 self-reported Caucasian (white) participants from the Rotterdam Study.

There are about 3 billion DNA base pairs in the human genome, which is a bit like a map of all our DNA. Much of the map is common to all humans, but individuals are distinguished by differences that occur now and then in the DNA sequence, in clumps of DNA called single nucleotide polymorphisms (SNPs, or “snips” for short, sometimes also referred to as gene variants). Snips are like signposts, and researchers use them to pinpoint the location of disease genes in the genome.

In this study, the researchers found strong links between two particular snips or gene variants and increased stroke risk by comparing the genomes of 1,544 CHARGE participants who developed stroke with the genomes of 18,058 who did not. They then replicated these findings in separate studies of black and white participants. The variant was not associated with increased risk for non-ischemic stroke, they said.

They found the variant on chromosome 12 near a gene called NINJ2 which is known to be involved with brain injury repair, and not far from another called WNK1, which is linked to blood pressure control.

The researchers said more research is needed to establish for certain if NINJ2 is the real culprit.

Boerwinkle took the opportunity in the press statement to remind people that one’s risk of stroke is a combination of genetic and environmental factors. Even though the variant they found is common, the effect it has on stroke risk is modest, and whether you have it or not, you can still make a difference by reducing your controllable risk factors, such as stopping smoking and reducing your blood pressure if it is too high.

ARIC is a prospective epidemiologic study conducted in four U.S. communities and sponsored by the National Heart, Lung and Blood Institute (NHLBI). The Cardiovascular Health Study, also funded by the NHLBI, is an observational study of risk factors for cardiovascular disease in adults 65 or older. The Framingham Heart Study began in 1948 as a longitudinal investigation of cardiovascular disease, and the Rotterdam Study is a prospective cohort study set up in 1990 in the Netherlands.

“Genomewide Association Studies of Stroke.”
Ikram, M. Arfan, Seshadri, Sudha, Bis, Joshua C., Fornage, Myriam, DeStefano, Anita L., Aulchenko, Yurii S., Debette, Stephanie, Lumley, Thomas, Folsom, Aaron R., van den Herik, Evita G., Bos, Michiel J., Beiser, Alexa, Cushman, Mary, Launer, Lenore J., Shahar, Eyal, Struchalin, Maksim, Du, Yangchun, Glazer, Nicole L., Rosamond, Wayne D., Rivadeneira, Fernando, Kelly-Hayes, Margaret, Lopez, Oscar L., Coresh, Josef, Hofman, Albert, DeCarli, Charles, Heckbert, Susan R., Koudstaal, Peter J., Yang, Qiong, Smith, Nicholas L., Kase, Carlos S., Rice, Kenneth, Haritunians, Talin, Roks, Gerwin, de Kort, Paul L.M., Taylor, Kent D., de Lau, Lonneke M., Oostra, Ben A., Uitterlinden, Andre G., Rotter, Jerome I., Boerwinkle, Eric, Psaty, Bruce M., Mosley, Thomas H., van Duijn, Cornelia M., Breteler, Monique M.B., Longstreth, W.T., Jr., Wolf, Philip A.
N Engl J Med Published online 15 April, 2009
DOI: 10.1056/NEJMoa0900094

Sources: NEJM, University of Texas Health Science Center at Houston.

Written by: Catharine Paddock, PhD