Association analysis of common variants of ELN, NOS2A, APOE and ACE2 to intracranial aneurysm

Department of Health and Environmental Sciences, Kyoto University, Kioto, Kyōto, Japan
Stroke (Impact Factor: 5.72). 06/2006; 37(5):1189-94. DOI: 10.1161/01.STR.0000217408.91389.4d
Source: PubMed


Previous studies have shown positive evidence of linkage of the intracranial aneurysm (IA) at chromosome 7q11, 17cen, 19q13, and Xp22. These regions contain elastin (ELN), nitric oxide synthetase 2A (NOS2A), apolipoprotein E (APOE), and angiotensin-I converting enzyme 2 (ACE2), which are considered to be promising candidate genes for IA. We aimed to examine the association of single-nucleotide polymorphisms (SNPs) with IA in these candidate genes.
To identify polymorphisms in NOS2A and ACE2, all exons and exon-intron boundaries were screened by direct sequencing in 30 randomly selected controls. The program tagSNPs was used to select an optimal set of haplotype-tagging SNPs. For ELN and APOE, SNPs were selected from previous reports. These selected SNPs were then genotyped in 362 cases with IA and 332 residential area matched controls. THESIAS software was used to investigate the association of alleles and haplotypes with IA by adjusting with covariates.
We genotyped 8 SNPs in ELN, 8 SNPs in NOS2A, 3 epsilon alleles in APOE and 1 SNP in ACE2. No alleles or haplotypes of 4 candidate genes revealed any significant association with IA.
Investigated polymorphisms in this study were not associated with IA.

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Available from: Shigeki Yamada
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    • "(Ruigrok et al. 2006a), the versican gene (CSPG2) at 5q14.3 (Ruigrok et al. 2006b), elastin (ELN) and LIM domain kinase 1 (LIMK1) genes at 7q11 (Onda et al. 2001; Akagawa et al. 2006), collagen alpha 2(I) (COL1A2) at 7q22 (Yoneyama et al. 2004), tumor necrosis factor receptor, superfamily member 13B (TNFRSF13B) at 17cen (Inoue et al. 2006), and kallikrein at 19q13 (Weinsheimer et al. 2007) have been proposed as susceptibility genes for IA. However, there has been a failure to replicate the linkage to 7q11 and the association of ELN polymorphisms with IA in several studies (Berthelemy-Okazaki et al. 2005; Hofer et al. 2003; Krex et al. 2004; Mineharu et al. 2006; Yamada et al. 2003b), and linkage to 17cen also could not be replicated in a study of the same ethnic group (Krischek et al. 2006). Further studies are warranted to replicate the previously reported IA loci. "
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    ABSTRACT: Previous linkage analyses of intracranial aneurysm (IA) have proposed several genetic susceptibility loci; however, some loci remain contradictory. The objective of this study was to confirm these loci in a Japanese population using allelic and haplotype association analyses. We set high-density single nucleotide polymorphism markers in previously suggested IA loci and conducted an association analysis in 29 cases and 35 controls from a small community in Akita, Japan. Genotyping was carried out using the GeneChip 10 K mapping array, and the association analysis was performed using GeneSpring GT2 software. The result was confirmed in a replication cohort consisting of 237 cases and 253 controls from all over Japan. Only one variant, rs767603, at chromosome 14q23, was significantly associated with IA, both in allelic analysis (p=0.00017, Bonferroni-corrected p=0.021) and haplotype analysis (p=0.00178, Bonferroni-corrected p=0.048). This association was confirmed in the replication cohort (p=0.0046 for allelic association, p=0.0060 for haplotype association). Our findings confirm 14q23 to be a susceptibility locus for intracranial aneurysm.
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    ABSTRACT: In der vorliegenden Arbeit untersuchten wir an einer europäischen Population ausgewählte Polymorphismen zweier Gene auf eine Assoziation zu IA. Beide Gene FIGF und ACE2 sind lokalisiert auf Chromosom Xp22 und stellen damit positionelle Kandidatengene dar, aber auch funktionell sind sie von Interesse, da sie v.a. in Prozesse des Gefäßwachstums (FIGF) und der Blutdruckregulierung (ACE2) involviert sind; Vorgänge also, die möglicherweise in die pathophysiologische Erklärung der IA Entstehung mit hineinspielen. In keinem der insgesamt neun analysierten Polymorphismen konnten wir jedoch eine signifikante Assoziation zu IA finden. Auch eine Analyse möglicher intra- und intergenetischer Haplotypen aller untersuchten Varianten erbrachte kein signifikantes Ergebnis.
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