Scientists have identified a previously unknown connection between two genetic variants and an increased risk of stroke, providing strong evidence for the existence of specific genes that help explain the genetic component of stroke. The research was funded by the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health and by several other NIH institutes and centres.

The analysis of over 19,000 participants is published online on April 15, 2009, by the New England Journal of Medicine and will appear in print on April 23, 2009.

The genetic variants were discovered by analyzing the genomes of individuals from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. This extensive resource includes participants from the Framingham Heart Study, Atherosclerosis Risk in Communities study, Cardiovascular Health Study and Rotterdam Study.

"This study, which integrates longstanding observational trials such as Framingham with cutting edge genomic technologies, moves us closer to the era of personalized medicine," said NHLBI Director Elizabeth G. Nabel, M.D. "As we learn more about the role that an individual's unique genetic makeup plays in their overall health, we will ultimately be able to tailor care to better diagnose, prevent, and treat conditions such as stroke."

Stroke is the third leading cause of death in the United States and causes serious long-term disabilities for many Americans.

The research team included Sudha Seshadri, M.D., associate professor of neurology, and Philip A. Wolf, M.D., principal investigator of the Framingham Heart Study and professor of neurology, Boston University School of Medicine, and involved investigators from numerous universities. Supported by a grant from the National Institute of Neurological Disorders and Stroke (NINDS), Dr. Wolf has studied the risk factors for stroke in the Framingham Heart Study over the past three decades.

The researchers discovered that two previously unsuspected common genetic variants or single-nucleotide polymorphisms (SNPs, pronounced 'snips') were consistently associated with total stroke (all types) and ischemic stroke in white persons. The SNPs were located on chromosome 12p13 near the gene NINJ2, which encodes ninjurin2, a member of the ninjurin nerve-injury-induced protein family.

"Consistent with the discoveries from genome-wide association studies in many other common disorders, the risk of stroke associated with these SNPs is not sufficiently high to make an individual change their stroke prevention plan. However, the results will lead scientists to direct their attention to new, important biologic mechanisms and hopefully new treatments to prevent stroke," noted Walter Koroshetz, M.D., deputy director of NINDS.

The association of one of the genetic variants was replicated in two independent samples: North American black persons and Dutch white persons. The association held when the analyses were adjusted for systolic blood pressure, hypertension, diabetes, atrial fibrillation, and current smoking.

"This impressive report shows how the power of genome-wide association studies can be enhanced by pooling data from large, population-based studies that follow participants over long periods of time. It also underscores the value of replicating initial results in populations with different demographics," said National Human Genome Research Institute Acting Director Alan E. Guttmacher, M.D.

Genome-wide association studies (GWAS) are a relatively new tool that allow researchers to rapidly scan the complete set of DNA (a genome) of many individuals in order to find genetic variations, or misspellings, associated with a particular disease or condition. This technique has revealed numerous relationships between genetic variations and conditions such as type 2 diabetes, obesity, and heart disorders. GWAS are possible due to the completion of the human genome in 2003 and the International HapMap Project in 2005, the advent of powerful information technology, and the participation of thousands of study volunteers whose confidentiality is safeguarded.

"Discovering genes for stroke has been a challenge in part because there are many different types of stroke. These results provide strong evidence for a previously unknown gene that may predispose to stroke and suggests that more genes will be discovered -- improving our chances of reducing the toll from this important public health problem," said Christopher O'Donnell, M.D., M.P.H., senior advisor to the NHLBI Director for genome research and associate director of the Framingham Heart Study.

There are two major types of stroke. The most common kind, ischemic stroke, is caused by a blood clot that blocks a blood vessel in the brain. The second type, hemorrhagic stroke, is caused by a blood vessel that breaks and bleeds into or around the brain. Stroke causes permanent brain injury. Stroke survivors suffer from disability that varies from mild to extremely severe.

The research was funded by NHLBI grants and contracts and was also supported by the National Human Genome Research Institute (NHGRI), National Center for Research Resources (NCRR), National Institute on Aging (NIA), National Institute of Diabetes and Digestive and Kidney Disorders (NIDDK), National Institute of Neurological Disorders and Stroke (NINDS), and the NIH Roadmap.