Rouleau, Guy Armand

Background Higher mortality for patients with aneurysmal subarachnoid haemorrhage has been reported. Aims In families with intracranial aneurysms, we sought to determine whether mortality among subjects with intracranial aneurysm (affected) was higher and related to rupture, compared with unaffected family members. Methods Subjects enrolled in the Familial Intracranial Aneurysm protocol were contacted yearly and their status was obtained. If reported to be deceased, the cause of death was verified by available records. A Cox proportional hazards model was utilized to compare mortality rates. Results Of the 2794 subjects, 1073 were affected and 1721 were unaffected. There were 8525 person-years of follow-up (mean 3·05 ± 1·73 years) and 85 deaths. Age at study entry for the affected (58·4 ±11·9 years) was significantly older ( P < 0·0001) than for the unaffected (52·2 ± 16·1). After adjusting for age, the overall mortality rate for the affected subjects was not significantly different from that for the unaffected (Rate Ratio [RR] 1·26, 95% confidence interval 0·82–1·93, P = 0·292). There was a strong effect modification due to age. The mortality rate ratio of the affected to the unaffected who were ≤60 years of age was RR = 3·48 (95% confidence interval: 1·59–7·63, P = 0·002), the rate for the affected subjects who were ≥60 was less than the rate for the unaffected (RR = 0·69, 95% confidence interval: 0·404–1·19, P = 0·178). The affected who had ruptures had 2·62 times the mortality rate as those without ruptures (95% confidence interval 1·43–4·80, P = 0·002). Conclusion The overall mortality was similar for the affected and unaffected subjects in this cohort. Among the affected only, those with ruptured intracranial aneurysm had a higher mortality rate than those without ruptured.

Object Familial predisposition is a recognized nonmodifiable risk factor for the formation and rupture of intracranial aneurysms (IAs). However, data regarding the characteristics of familial IAs are limited. The authors sought to describe familial IAs more fully, and to compare their characteristics with a large cohort of nonfamilial IAs. Methods The Familial Intracranial Aneurysm (FIA) study is a multicenter international study with the goal of identifying genetic and other risk factors for formation and rupture of IAs in a highly enriched population. The authors compared the FIA study cohort with the International Study of Unruptured Intracranial Aneurysms (ISUIA) cohort with regard to patient demographic data, IA location, and IA multiplicity. To improve comparability, all patients in the ISUIA who had a family history of IAs or subarachnoid hemorrhage were excluded, as well as all patients in both cohorts who had a ruptured IA prior to study entry. Results Of 983 patients enrolled in the FIA study with definite or probable IAs, 511 met the inclusion criteria for this analysis. Of the 4059 patients in the ISUIA study, 983 had a previous IA rupture and 657 of the remainder had a positive family history, leaving 2419 individuals in the analysis. Multiplicity was more common in the FIA patients (35.6% vs 27.9%, p < 0.001). The FIA patients had a higher proportion of IAs located in the middle cerebral artery (28.6% vs 24.9%), whereas ISUIA patients had a higher proportion of posterior communicating artery IAs (13.7% vs 8.2%, p = 0.016). Conclusions Heritable structural vulnerability may account for differences in IA multiplicity and location. Important investigations into the underlying genetic mechanisms of IA formation are ongoing.

Background and Purpose— The purpose of this study was to replicate the previous association of single nucleotide polymorphisms (SNPs) with risk of intracranial aneurysm (IA) and to examine the relationship of smoking with these variants and the risk of IA. Methods— White probands with an IA from families with multiple affected members were identified by 26 clinical centers located throughout North America, New Zealand, and Australia. White control subjects free of stroke and IA were selected by random digit dialing from the Greater Cincinnati population. SNPs previously associated with IA on chromosomes 2, 8, and 9 were genotyped using a TaqMan assay or were included in the Affymetrix 6.0 array that was part of a genomewide association study of 406 IA cases and 392 control subjects. Logistic regression modeling tested whether the association of replicated SNPs with IA was modulated by smoking. Results— The strongest evidence of association with IA was found with the 8q SNP rs10958409 (genotypic P =9.2×10 −5 ; allelic P =1.3×10 −5 ; OR=1.86, 95% CI: 1.40 to 2.47). We also replicated the association with both SNPs on chromosome 9p, rs1333040 and rs10757278, but were not able to replicate the previously reported association of the 2 SNPs on chromosome 2q. Statistical testing showed a multiplicative relationship between the risk alleles and smoking with regard to the risk of IA. Conclusion— Our data provide complementary evidence that the variants on chromosomes 8q and 9p are associated with IA and that the risk of IA in patients with these variants is greatly increased with cigarette smoking.

Background and Purpose— The risk of intracranial aneurysm (IA) rupture in asymptomatic members of families who have multiple affected individuals is not known. Methods— First-degree unaffected relatives of those with a familial history of IA who had a history of smoking or hypertension but no known IA were offered cerebral MR angiography (MRA) and followed yearly as part of a National Institute of Neurological Diseases and Stroke-funded study of familial IA (Familial Intracranial Aneurysm [FIA] Study). Results— A total of 2874 subjects from 542 FIA Study families were enrolled. After study enrollment, MRAs were performed in 548 FIA Study family members with no known history of IA. Of these 548 subjects, 113 subjects (20.6%) had 148 IAs by MRA of whom 5 subjects had IA ≥7 mm. Two subjects with an unruptured IA by MRA/CT angiography (3-mm and 4-mm anterior communicating artery) subsequently had rupture of their IA. This represents an annual rate of 1.2 ruptures per 100 subjects (1.2% per year; 95% CI, 0.14% to 4.3% per year). None of the 435 subjects with a negative MRA have had a ruptured IA. Survival curves between the MRA-positive and -negative cohorts were significantly different ( P =0.004). This rupture rate of unruptured IA in the FIA Study cohort of 1.2% per year is approximately 17 times higher than the rupture rate for subjects with an unruptured IA in the International Study of Unruptured Aneurysm Study with a matched distribution of IA size and location 0.069% per year. Conclusions— Small unruptured IAs in patients from FIA Study families may have a higher risk of rupture than sporadic unruptured IAs of similar size, which should be considered in the management of these patients.

Background and Purpose— Evidence supports a substantial genetic contribution to the risk of intracranial aneurysm (IA). The purpose of this study was to identify chromosomal regions likely to harbor genes that contribute to the risk of IA. Methods— Multiplex families having at least 2 individuals with “definite” or “probable” IA were ascertained through an international consortium. First-degree relatives of individuals with IA who were at increased risk of an IA because of a history of hypertension or present smoking were offered cerebral magnetic resonance angiography. A genome screen was completed using the Illumina 6K SNP system, and the resulting data from 192 families, containing 1155 genotyped individuals, were analyzed. Narrow and broad disease definitions were used when testing for linkage using multipoint model-independent methods. Ordered subset analysis was performed to test for a gene×smoking (pack-years) interaction. Results— The greatest evidence of linkage was found on chromosomes 4 (LOD=2.5; 156 cM), 7 (LOD=1.7; 183 cM), 8 (LOD=1.9; 70 cM), and 12 (LOD=1.6; 102 cM) using the broad disease definition. Using the average pack-years for the affected individuals in each family, the genes on chromosomes 4 (LOD=3.5; P =0.03), 7 (LOD=4.1; P =0.01) and 12 (LOD=3.6; P =0.02) all appear to be modulated by the degree of smoking in the affected members of the family. On chromosome 8, inclusion of smoking as a covariate did not significantly strengthen the linkage evidence, suggesting no interaction between the loci in this region and smoking. Conclusions— We have detected possible evidence of linkage to 4 chromosomal regions. There is potential evidence for a gene×smoking interaction with 3 of the loci.