Association between genetic variation on chromosome 9p21 and aneurysmal subarachnoid haemorrhage

Olsson, Sandra; Csajbok, L. Z.; Jood, Katarina; Nylén, Karin; Nellgård, Bengt; Jern, Christina

doi:10.1136/jnnp.2009.187427

Cited by 28 publications

(16 citation statements)

References 36 publications

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“…However, a similar pattern was observed with suggestive association of two SNPs (rs10217586-T and rs1333045-T) in strong LD with rs10757278 among BAVMs with aneurysms ( p=0.006) and not among BAVMs without aneurysms ( p>0.77); rs1333045 and rs10757278 have also been previously reported to be associated with aneurysmal subarachnoid haemorrhage in a Swedish population. 13 Our finding that the same 9p21 SNPs are also associated with increased risk of BAVM with coexisting arterial aneurysms suggests that BAVM-associated aneurysms share similar vascular pathology mechanisms with other aneurysmal diseases. Since both aneurysms of feeding arteries supplying BAVMs and IA in general are both subject to high-flow arterial conditions (though higher flows should be present in arteries supplying AVMs as compared to arteries not supplying AVMs), genetic variation alone may not be sufficient for aneurysm formation.…”

Section: Discussionmentioning

confidence: 61%

Common variants on 9p21.3 are associated with brain arteriovenous malformations with accompanying arterial aneurysms

Bendjilali

Nelson

Weinsheimer

et al. 2014

Journal of Neurology, Neurosurgery & Psychiatry

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Objective To investigate whether previously reported 9p21.3 single nucleotide polymorphisms (SNPs) are associated with risk of brain arteriovenous malformations (BAVMs), which often have accompanying arterial aneurysms. Common variants in the 9p21.3 locus have been reported to be associated with multiple cardiovascular phenotypes, including coronary artery disease and intracranial aneurysms (rs10757278 and rs1333040). Methods We used data from 338 BAVM cases participating in the University of California, San Francisco-Kaiser Brain AVM Study Project and 504 healthy controls to evaluate genotypes for seven common SNPs (minor allele frequency>0.05) that were imputed using 1000 Genomes Phase 1 European data (R2>0.87). Association with BAVM was tested using logistic regression adjusting for age, sex and the top three principal components of ancestry. Subgroup analysis included 205 BAVM cases with aneurysm data: (a) 74 BAVM with aneurysm vs. 504 controls, and (b) 131 BAVM without aneurysm vs. 504 controls. Results We observed suggestive association with BAVM and rs10757278-G (OR=1.23, 95% CI=0.99–1.53, P=0.064) and rs1333040-T (OR=1.27, 95% CI=1.01–1.58, P=0.04). For rs10757278-G, the association was stronger in BAVM cases with aneurysm (OR=1.52, 95% CI=1.03–2.22, P=0.032) than in BAVM without aneurysm (OR=0.98, 95% CI=0.72–1.34, P=0.91). Similar patterns of effects were observed for rs1333040 and for other SNPs in linkage disequilibrium (r2>0.8) with rs10757278. Conclusions Common 9p21.3 variants showed similar effect sizes for association with BAVM as previously reported for aneurysmal disease. The association with BAVM appears to be explained by known associations with aneurysms, suggesting that BAVM associated aneurysms share similar vascular pathology mechanisms with other aneurysm types.

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Section: Discussionmentioning

confidence: 61%

Common variants on 9p21.3 are associated with brain arteriovenous malformations with accompanying arterial aneurysms

Bendjilali

Nelson

Weinsheimer

et al. 2014

Journal of Neurology, Neurosurgery & Psychiatry

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“…Previous studies reported an association of IA, 2–6,18,19 as well as myocardial infarction, 18 large-vessel ischemic stroke subtype, 20 and aortic aneurysm, 18,21 with SNP in this region. Others 6 examined the association in multiplex families as well as sporadic IA and found consistent evidence of association with rs1333040 (allele T), located in intron 12 of CDKN2BAS and having limited linkage disequilibrium spanning introns 7 through 15 of CDKN2BAS .…”

Section: Discussionmentioning

confidence: 84%

Genome-Wide Association Study of Intracranial Aneurysms Confirms Role of Anril and SOX17 in Disease Risk

Foroud¹,

Koller²,

Lai³

et al. 2012

Stroke

111

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Background Genome-wide association studies have identified novel genetic factors that contribute to intracranial aneurysm (IA) susceptibility. We sought to confirm previously reported loci, to identify novel risk factors, and to evaluate the contribution of these factors to familial and sporadic IA. Method We utilized 2 complementary samples, one recruited on the basis of a dense family history of IA (discovery sample 1: 388 IA cases and 397 controls) and the other without regard to family history (discovery sample 2: 1095 IA cases and 1286 controls). Imputation was used to generate a common set of single nucleotide polymorphisms (SNP) across samples, and a logistic regression model was used to test for association in each sample. Results from each sample were then combined in a meta-analysis. Results There was only modest overlap in the association results obtained in the 2 samples. In neither sample did results reach genome-wide significance. However, the meta-analysis yielded genome-wide significance for SNP on chromosome 9p (CDKN2BAS; rs6475606; P=3.6×10−8) and provided further evidence to support the previously reported association of IA with SNP in SOX17 on chromosome 8q (rs1072737; P=8.7×10−5). Analyses suggest that the effect of smoking acts multiplicatively with the SNP genotype, and smoking has a greater effect on risk than SNP genotype. Conclusion In addition to replicating several previously reported loci, we provide further evidence that the association on chromosome 9p is attributable to variants in CDKN2BAS (also known as ANRIL, an antisense noncoding RNA).

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“…21 Moreover, p14 levels correlate with ANRIL activity and modulate MMP-3 levels, which may influence extracellular matrix repair. 21 In the most recent GWAS 14 in a Caucasian population of familial and sporadic IA, 6 SNPs, also located in the 9p21.3 region, were associated with IA; one of these (rs6475606) achieved GWAS-level statistical significance (OR 1.34; p 5 4.29 3 10 207 ) for association with sporadic and familial IAs. Association with the rs1333040 SNP was also confirmed in this study, 14 further strengthening association of this locus with IA.…”

Section: Genetic Variants Associated With Ias Identified By Gwasmentioning

confidence: 99%

Genetic risk factors for intracranial aneurysms

et al. 2013

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A meta-analysis in more than 116,000 individuals ABSTRACT Objective: There is an urgent need to identify risk factors for sporadic intracranial aneurysm (IA) development and rupture. A genetic component has long been recognized, but firm conclusions have been elusive given the generally small sample sizes and lack of replication. Genome-wide association studies have overcome some limitations, but the number of robust genetic risk factors for IA remains uncertain. Methods:We conducted a comprehensive systematic review and meta-analysis of all genetic association studies (including genome-wide association studies) of sporadic IA, conducted according to Strengthening the Reporting of Genetic Association Studies and Human Genome Epidemiology Network guidelines. We tested the robustness of associations using random-effects and sensitivity analyses.Results: Sixty-one studies including 32,887 IA cases and 83,683 controls were included. We identified 19 single nucleotide polymorphisms associated with IA. The strongest associations, robust to sensitivity analyses for statistical heterogeneity and ethnicity, were found for the following single nucleotide polymorphisms: on chromosome 9 within the cyclin-dependent kinase inhibitor 2B antisense inhibitor gene (rs10757278: odds ratio [OR] 1.29; 95% confidence interval [CI] 1.21-1.38; and rs1333040: OR 1.24; 95% CI 1.20-1.29), on chromosome 8 near the SOX17 transcription regulator gene (rs9298506: OR 1.21; 95% CI 1.15-1.27; and rs10958409: OR 1.19; 95% CI 1.13-1.26), and on chromosome 4 near the endothelin receptor A gene (rs6841581: OR 1.22; 95% CI 1.14-1.31). Conclusions:Our comprehensive meta-analysis confirms a substantial genetic contribution to sporadic IA, implicating multiple pathophysiologic pathways, mainly relating to vascular endothelial maintenance. However, the limited data for IA compared with other complex diseases necessitates large-scale replication studies in a full spectrum of populations, with investigation of how genetic variants relate to phenotype (e.g., IA size, location, and rupture status). Neurology â 2013;80:2154-2165 GLOSSARY ACE 5 angiotensin-converting enzyme; ANRIL 5 antisense noncoding RNA in the INK4 locus; CI 5 confidence interval; CGAS 5 candidate gene association study; EDNRA 5 endothelin receptor type A; GWAS 5 genome-wide association studies; IA 5 intracranial aneurysm; IL 5 interleukin; LD 5 linkage disequilibrium; MMP 5 matrix metalloproteinase; OR 5 odds ratio; SAH 5 subarachnoid hemorrhage; SNP 5 single nucleotide polymorphism.Intracranial aneurysms (IAs) are present in 2%-5% of the general population; approximately 0.7%-1.9% of cases rupture, causing subarachnoid hemorrhage (SAH).1 The annual incidence of SAH is 8-9 in 100,000, yet because of the high risk of death or severe disability 2 and younger age at onset compared with other stroke types (40-65 years), 3 SAH has a disproportionately large socioeconomic impact.SAH has been associated with common modifiable risk factors, including hypertension, smoking, and alcohol intake. [4][...

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Association between genetic variation on chromosome 9p21 and aneurysmal subarachnoid haemorrhage

Cited by 28 publications

References 36 publications

Common variants on 9p21.3 are associated with brain arteriovenous malformations with accompanying arterial aneurysms

Common variants on 9p21.3 are associated with brain arteriovenous malformations with accompanying arterial aneurysms

Genome-Wide Association Study of Intracranial Aneurysms Confirms Role of Anril and SOX17 in Disease Risk

Genetic risk factors for intracranial aneurysms

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