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Familial Intracranial Aneurysm (FIA) Study II

PI: Joseph P. Broderick, MD
Sponsor: NIH/NINDS
Study No.: RO1 NS39512

What Is the FIA II Study?

The Familial Intracranial Aneurysm Study, also known as the FIA study, is a collaborative research effort of neurologists and neurosurgeons throughout the United States, Canada, Australia, and New Zealand. These researchers are studying genetic and other risk factors which may be important in the development of intracranial aneurysms. This study was sponsored by the National Institutes of Health and initially involved 475 families with multiple affected family members throughout North America, Australia and New Zealand. In phase II enrollment was completed on an additional 99 families and 1896 sporadic (without a family history) intracranial aneurysm subjects were enrolled. The study officially ended in 2012.

End of Study Findings for the FIA Study (Phases I & II)

In the first phase of the Familial Intracranial Aneurysm (FIA) Study we conducted a genome screen to identify at risk genes in 333 families. The data suggests it is unlikely a single gene with a strong effect is responsible for intracranial aneurysms in families. Rather it is likely that multiple genes of smaller or modest effect and environmental risk factors contribute to the susceptibility for intracranial aneurysms.

During Phase I there were other significant including the results of screening first degree relatives (parents, siblings, and children) of a person diagnosed with an intracranial aneurysm, it was found that 19.1% of the participants who have a study Magnetic Resonance Angiogram (MRA) had a previously undiagnosed aneurysm. Those diagnosed with an aneurysm were over the age of 30 years, female or have a history of smoking and/or high blood pressure. These findings provide guidance to health care professionals for screen high-risk individuals based on family and medical history.

113 subjects were diagnosed with an un-ruptured aneurysm during the course of their participation in the FIA study. The majority of these aneurysms, all but five, where classified as small less than 7 millimeters. However, the observed annual ruptured rate was determined to be 1.2 percent. That is approximately 17 higher than the annual rupture rate for subjects with an un-ruptured intracranial aneurysm (IA) of similar size and no family history of IA. This information is important in determining the management of an IA in a person with a family history.

Additionally previous studies have suggests IAs occur at younger ages in subsequent generations of families with at least one case of ruptured aneurysms. However the FIA study found that when accounting for similar length of follow-up in both generations, IAs actually tend to occur at an older age. Ruptured aneurysms were identified in the second generation 50% less often than the older generation of the family, but the FIS study findings suggest that the second generation will “catch up” in the number of aneurysms ruptures as that generation ages.

After following the FIA study participants with yearly phone calls for 3 years, it was found that participants had significantly decreased their smoking rate, in both those with a diagnosis of IA, and to a lesser degree those without a known aneurysm. This demonstrates that high-risk individuals can change their behavior to reduce their risk of a potentially life-threatening condition. Health care professionals should provide more aggressive risk factor education and smoking cessation strategies in this high risk group.

In addition to reporting brain aneurysms, families also reported aneurysms elsewhere in the body including the chest and abdomen. The genome screen was completed in 29 of these families and the findings suggest that common genes may be responsible for both brain and abdominal aortic aneurysms. The two chromosomes involved include chromosome 11 (which has previously been reported in abdominal aortic aneurysms) and chromosome 6. The identification of the actual genes involved could one day allow a genetic screening test for families.

Late in phase I and at the beginning of phase II we compared the DNA from one person with an IA from each family and from subjects with and IA without a family history to controls (people without an IA) by using genome-wide association study (GWAS). We replicated previously reported findings on chromosomes 9 and 8.

During phase II we also compared the location and number of IAs in FIA subjects to non-familial subjects in the International Study of Intracranial Un-ruptured Aneurysms (ISUIA). Subjects with multiple aneurysms were more common in the FIA study. FIA subjects also had a higher proportion of IAs located in the middle cerebral artery, whereas ISUIA subjects had a higher proportion of posterior communicating artery IAs. The FIA study found that aneurysm location is hereditable indicating that even the location of aneurysms has a genetic component.

The FIA study has proved invaluable information and resources that will allow future research into the effects of genetics and environmental factors on aneurysm formation and rupture to continue. This work would not have possible without the participation of our subjects, the hard work of the study investigators and the collaboration of other experts in this field.

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