Confirmation of an Association of Single-Nucleotide Polymorphism rs1333040 on 9p21 With Familial and Sporadic Intracranial Aneurysms in Japanese Patients

Hashikata, Hirokuni; Liu, Wanyang; Inoue, Kazuhiro; Mineharu, Yohei; Yamada, Shigeki; Nanayakkara, Shanika; Matsuura, Nobuki; Hitomi, Toshiaki; Takagi, Yasushi; Hashimoto, Nobuo; Miyamoto, Susumu; Koizumi, Akio

doi:10.1161/strokeaha.109.576694

Cited by 36 publications

(33 citation statements)

References 29 publications

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“…3,4 Interestingly, this association holds true for different forms of aneurysms, including abdominal aortic aneurysm and intracranial aneurysms. 3,[5][6][7] These observations highly suggest common pathogenic mechanisms for apparently distinct forms of aneurysms.…”

Section: Clinical Perspective On P 805mentioning

confidence: 89%

Deletion of Chromosome 9p21 Noncoding Cardiovascular Risk Interval in Mice Alters Smad2 Signaling and Promotes Vascular Aneurysm

Loinard

Basatemur

Masters

et al. 2014

Circ Cardiovasc Genet

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Background— Vascular aneurysm is an abnormal local dilatation of an artery that can lead to vessel rupture and sudden death. The only treatment involves surgical or endovascular repair or exclusion. There is currently no approved medical therapy for this condition. Recent data established a strong association between genetic variants in the 9p21 chromosomal region in humans and the presence of cardiovascular diseases, including aneurysms. However, the mechanisms linking this 9p21 DNA variant to cardiovascular risk are still unknown. Methods and Results— Here, we show that deletion of the orthologous 70-kb noncoding interval on mouse chromosome 4 (chr4 Δ70kb/Δ70kb mice) is associated with reduced aortic expression of cyclin-dependent kinase inhibitor genes p19Arf and p15Inkb . Vascular smooth muscle cells from chr4 Δ70kb/Δ70kb mice show reduced transforming growth factor-β–dependent canonical Smad2 signaling but increased cyclin-dependent kinase–dependent Smad2 phosphorylation at linker sites, a phenotype previously associated with tumor growth and consistent with the mechanistic link between reduced canonical transforming growth factor-β signaling and susceptibility to vascular diseases. We also show that targeted deletion of the 9p21 risk interval promotes susceptibility to aneurysm development and rupture when mice are subjected to a validated model of aneurysm formation. The vascular disease of chr4 Δ70kb/Δ70kb mice is prevented by treatment with a cyclin-dependent kinase inhibitor. Conclusions— The results establish a direct mechanistic link between 9p21 noncoding risk interval and susceptibility to aneurysm and may have important implications for the understanding and treatment of vascular diseases.

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Section: Clinical Perspective On P 805mentioning

confidence: 89%

Deletion of Chromosome 9p21 Noncoding Cardiovascular Risk Interval in Mice Alters Smad2 Signaling and Promotes Vascular Aneurysm

Loinard

Basatemur

Masters

et al. 2014

Circ Cardiovasc Genet

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“…Moreover, the observed association of rs10757278 with IA may arise from moderate LD with the known IA risk variant rs1333040 SNP (r 5 0.59), from which it is approximately 41 kbp upstream. 20 However, these 2 SNPs were not in strong LD in a Japanese population, raising the possibility of a smaller LD block associated with IA. In a Japanese study, 19 haplotype…”

Section: Genetic Variants Associated With Ias Identified By Gwasmentioning

confidence: 94%

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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“…Although several common variants were identified to be associated with the increased risk of IA development through candidate gene approaches [12][13][14][15][16] and genome-wide association studies, 17,18 only few associations were consistently replicated. 19,20 These might be because of the lack of statistical power of the study or differences in the allele frequencies across different populations. With the rationale of limited reports on the susceptibility loci for IA among Asia populations, we conducted a case-control association study using a total of 2050 IA patients and 1835 control samples, and screened a total of 45 single-nucleotide polymorphisms (SNPs) in 24 genes, which have been considered as potential genetics risk factors to IA pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Impact of LIMK1, MMP2 and TNF-α variations for intracranial aneurysm in Japanese population

et al. 2011

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Genetic factors are known to have an important role in intracranial aneurysm (IA) pathogenesis. The purpose of this study is to identify single-nucleotide polymorphisms (SNPs) that are associated with IA in Japanese population. A total of 2050 IA patients and 1835 controls recruited in Biobank Japan, The University of Tokyo were used in this study. In all, 45 SNPs in 24 genes encoding proteins, which have been considered to be possible risk factors to IA pathogenesis, were genotyped using multiplex PCR-invader assay. Association analysis was evaluated by logistic regression analysis before and after adjustment of age, smoking and hypertension status. This case-control association study revealed a SNP, rs6460071 located on LIMK1 gene (P¼0.00069) to be significantly associated with increased risk of IA. In addition, two SNPs, rs243847 (P¼0.00086) and rs243865 (P¼0.00090), on matrix metallopeptidase 2 (MMP2) gene and one SNP rs1799724 (P¼0.0026) on tumor necrosis factor-a (TNF-a) gene, are marginally associated with IA in male-and female-specific manner, respectively. In conclusion, a large-scale case-control association study was conducted to verify genetic variations associated with IA in Japanese population. This study gave insights on the importance of stratified analysis between genders, and suggested that the underlying mechanism of IA pathogenesis might differ between females and males.

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Confirmation of an Association of Single-Nucleotide Polymorphism rs1333040 on 9p21 With Familial and Sporadic Intracranial Aneurysms in Japanese Patients

Cited by 36 publications

References 29 publications

Deletion of Chromosome 9p21 Noncoding Cardiovascular Risk Interval in Mice Alters Smad2 Signaling and Promotes Vascular Aneurysm

Deletion of Chromosome 9p21 Noncoding Cardiovascular Risk Interval in Mice Alters Smad2 Signaling and Promotes Vascular Aneurysm

Genetic risk factors for intracranial aneurysms

Impact of LIMK1, MMP2 and TNF-α variations for intracranial aneurysm in Japanese population

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