DNA Sequence Variant Linked to Intracranial Aneurysms

Sequence variants contributing to common diseases, including myocardial infarction, coronary artery disease, and type 2 diabetes mellitus, have been recently identified through genome-wide association studies. In one of the largest genome-wide association studies published to date (Nat Genet 40:217–224, 2008), groups from Iceland, Belgium, Canada, the United States, the United Kingdom, New Zealand, The Netherlands, Finland, Italy, Sweden, and Denmark pooled available genetic materials to test whether a link exists between two common genotype sequence variants and the risk of coronary artery disease, myocardial infarction, stroke, abdominal aortic aneurysms (AAAs), peripheral arterial disease, type 2 diabetes, and intracranial aneurysms. After sequencing two key regions of DNA in 22,764 individuals, Helgadottir et al. confirmed a previously described gene locus of rs10811661-T on chromosome 9p21 in association with intracranial aneurysms, AAAs, and type 2 diabetes. More specifically, patients with intracranial aneurysms, AAAs, and type 2 diabetes were 1.29, 1.31, and 1.30 times more likely to have the sequence alteration, respectively. These results add to the evidence supporting a role of the sequence variant tagged by rs10757278-G in vascular diseases that are characterized by abnormal vascular remodeling, thereby providing insight into its pathophysiological role. Although it is well established that genetic factors play an important role in aneurysm etiology, these results are the first to demonstrate an association of a common sequence variant with intracranial aneurysms and AAAs that replicate among populations.FIGUREApproximately 21% of individuals in the general population are homozygous for this variant, and their attributable risk is estimated to be about 26% for both AAAs and intracranial aneurysms. The exact link between this genetic alteration and the expression of these conditions remains unclear. Of the arterial diseases, the most prevalent is atherosclerosis, characterized by accumulation of lipids, inflammatory cells, calcium, and necrosis within the walls of large- and medium-sized arteries. Degenerative changes of the arterial wall may also cause localized dilatation, or aneurysm, of the artery. Although atherosclerotic changes are found in the majority of AAAs, intracranial aneurysms are not associated as often with these histological criteria. Intracranial aneurysms, usually located at arterial bifurcations, typically have a thin media or none at all, and the internal elastic lamina is either absent or severely fragmented. Although the pathophysiology of intracranial aneurysm formation seems to be different from that of AAA, there are a number of overlapping risk factors including smoking, hypertension, excessive alcohol, family history, and, as this study demonstrates, a genetic variant. It is unclear how these sequence alterations affect DNA transcription, translation, or protein synthesis and how this affects intracranial aneurysm development. These sequence variants are in proximity to genes known to play critical roles in cell proliferation, aging, senescence, and apoptosis. Despite the promising results, inherent limitations may deter the application of these genetic tests into current patient management. In the case of aneurysms, it is difficult to determine within families whether a sibling is not affected, as aneurysms develop throughout life. This problem can be avoided by increasing the numbers of analyzed pairs, but solving it may be difficult, as intracranial aneurysms tend to have a late onset, a relatively low prevalence, and a high incidence of fatality after rupture. Different populations and ethnic groups may have various risks for aneurysm formation and rupture with potentially distinctive genetic determinants. This genetic heterogeneity may also play a role within families, as genetic variants may be rare, making them difficult to detect. It is important to note that patients with both asymptomatic and symptomatic diseases were enrolled, and the inclusion criteria varied greatly between groups in different countries. Hence, the genetic loci may link to increased susceptibility to aneurysm formation, symptomatic aneurysm progression, or both. Ongoing research by other groups, including the Familial Intracranial Aneurysm Study may identify other genetic loci associated with familial clustering of intracranial aneurysms or linking cerebral aneurysms to smoking and other risk factors. Such genetic heterogeneity will necessarily underlie a complex disease pathway for cerebral aneurysms, reflecting the well-recognized clinical heterogeneity. Despite the limitations involved in genetic analysis, this study may ultimately provide diagnostic tools for identifying individuals at increased risk for aneurysm formation and relatives of affected families who do not carry the disease trait may be reassured. If aneurysm rupture were associated with specific genetic determinants, identification of these variants would provide a tool for selecting patients at higher risk of future rupture. Knowledge regarding the various molecular pathways involved may provide insight into aneurysm etiology and open new doors for innovative diagnostic strategies and therapeutic manipulations. RICARDO J. KOMOTAR, MD ROBERT M. STARKE, BA E. SANDER CONNOLLY, JR, MD CLINICAL RESEARCH

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