Abstract
BackgroundSubarachnoid hemorrhage (SAH) due to ruptured intracranial aneurysms (IAs) occurs in about 20,000 people per year in the U.S. annually and nearly half of the affected persons are dead within the first 30 days. Survivors of ruptured IAs are often left with substantial disability. Thus, primary prevention of aneurysm formation and rupture is of paramount importance. Prior studies indicate that genetic factors are important in the formation and rupture of IAs. The long-term goal of the Familial Intracranial Aneurysm (FIA) Study is to identify genes that underlie the development and rupture of intracranial aneurysms (IA).Methods/DesignThe FIA Study includes 26 clinical centers which have extensive experience in the clinical management and imaging of intracerebral aneurysms. 475 families with affected sib pairs or with multiple affected relatives will be enrolled through retrospective and prospective screening of potential subjects with an IA. After giving informed consent, the proband or their spokesperson invites other family members to participate. Each participant is interviewed using a standardized questionnaire which covers medical history, social history and demographic information. In addition blood is drawn from each participant for DNA isolation and immortalization of lymphocytes. High- risk family members without a previously diagnosed IA undergo magnetic resonance angiography (MRA) to identify asymptomatic unruptured aneurysms. A 10 cM genome screen will be performed to identify FIA susceptibility loci. Due to the significant mortality of affected individuals, novel approaches are employed to reconstruct the genotype of critical deceased individuals. These include the intensive recruitment of the spouse and children of deceased, affected individuals.DiscussionA successful, adequately-powered genetic linkage study of IA is challenging given the very high, early mortality of ruptured IA. Design features in the FIA Study that address this challenge include recruitment at a large number of highly active clinical centers, comprehensive screening and recruitment techniques, non-invasive vascular imaging of high-risk subjects, genome reconstruction of dead affected individuals using marker data from closely related family members, and inclusion of environmental covariates in the statistical analysis.
Highlights
Subarachnoid hemorrhage (SAH) due to ruptured intracranial aneurysms (IAs) occurs in about 20,000 people per year in the U.S annually and nearly half of the affected persons are dead within the first 30 days
A successful, adequately-powered genetic linkage study of IA is challenging given the very high early mortality of ruptured IA. Other diseases such as lung cancer have a high associated mortality but patients survive months and even years after diagnosis whereas 40% of patients with a ruptured IA die within the first month
This clinical reality necessitates very aggressive recruitment of potential probands who have a ruptured IA within the first week or so after admission to the hospital
Summary
A successful, adequately-powered genetic linkage study of IA is challenging given the very high early mortality of ruptured IA. Major advances in non-invasive imaging of cerebral arteries over the past 10 years have dramatically changed the approach to IAs and have resulted in identification of additional affected individuals in genetic linkage studies of IA with an increase in study power [31,33,56]. Only those patients with aneurysms that are 5 mm or larger on MRA or CT angiography undergo subsequent intra-arterial angiography To address this issue of phenotyping using MRA or CT angiography, we have required high-quality methods for MRA imaging at the clinical centers and have developed a rigorous protocol for centralized identification of MRA by highly experienced neuroradiologists. Our modeling of various pedigree structures indicates that reconstruction of the most probable genotype of a dead affected can be determined by including the spouse and children Another important aspect of IA genetic studies is the critical need to consider environmental covariates in disease risk. The FIA Study has excellent power to detect genes associated with the development of rupture of IA and has a unique opportunity to understand the complex interrelationships between genes and environment that lead frequently to a deadly outcome
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