Scientists 1 Step Closer to Identifying Genes for Intracranial Aneurysm

Caroline Cassels

February 27, 2008

February 27, 2008 (New Orleans, Louisiana) — Scientists have found 2 chromosomal regions that may harbor genes responsible for increasing intracranial aneurysm (IA) risk.

Results from the Familial Intracranial Aneurysm study, presented here in a late-breaking science session at the American Stroke Association International Stroke Conference 2008, demonstrated "modest evidence" that regions on chromosomes 7 and 11 may harbor genes important in increasing genetic IA risk.

According to study investigator Tatiana Foroud, PhD, from the Indiana University School of Medicine, in Indianapolis, it is well-known that family history plays a role in IA risk. Individuals with 1 first-degree relative have a 2-fold increased risk for IA, while those with 2 first-degree relatives have about a 4-fold increased risk.

The ultimate long-term goal of the current study, she said, is to identify genes responsible for the condition. First, however, investigators sought to identify chromosomal regions in which genes contributing to the risk for IA are likely to be located.

"This is a critical first step if you want to find genes. Right now we identify individuals at increased risk of intracranial aneurysm through family history and use of magnetic resonance angiography (MRA). The ultimate goal is to have a genetic test that could identify high-risk individuals and then implement targeted screening," she said.

Largest Familial Sample

The study included 1895 subjects from 333 families recruited by an international consortium of 25 centers in the United States, Canada, New Zealand, and Australia, representing the largest linkage study of IA reported to date.

Researchers focused on individuals with IA who had multiple family members with ruptured or unruptured IA. Following a rigorous protocol that involved reviewing all available medical records and imaging data, possible IA subjects were classified as definite, probable, possible, or not a case.

A 6000–single nucleotide polymorphism (SNP) screen was then performed in 2 independent study groups — 705 individuals in the "narrow" group (defined as a definite IA) and 866 in the "broad" group (defined as definite or probable cases).

Three types of statistical analysis were performed to identify chromosomal regions that might harbor a gene that increases the risk for IA — 1 of which attempted to identify genes that have the greatest impact on families with the highest rates of smoking.

Gene by Smoking Interaction

"We found there is a region of chromosome 7 that probably has an important effect in about the top third of our families that have the heaviest rates of smoking. This region is probably not important in all our families, but it is strong evidence of a gene by smoking interaction, and it is a region we would not have found if we had not included smoking in our analysis," said Dr. Foroud.

The study also looked for evidence of a common genetic etiology among individuals with both aortic and intracranial aneurysms. "We found there is a region on chromosome 11 that has been reported in studies of aortic aneurysms — both abdominal and thoracic — and we were able to replicate this finding. So for a subset of about 29 families that have both intracranial and aortic aneurysms, there is a likelihood there could be a gene in this region that contributes to both," said Dr. Foroud.

It is unlikely, she added, there is a single gene that increases IA risk. "This is a very complex disease, and many genes are likely to be important its etiology. This will present its own challenges in terms of screening, but this is an important first step that will allow us to design future studies that will build on this information and allow us to more effectively find genes."

International Stroke Conference 2008:Abstract LB 6. Presented February 22, 2008.

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