Association of a Genetic Variant in the &lt;i&gt;ALOX5AP&lt;/i&gt; with Higher Risk of Ischemic Stroke: A Case-Control, Meta-Analysis and Functional Study

Domingues‐Montanari, Sophie; Fernández‐Cadenas, Israel; Río-Espínola, Alberto Del; Corbeto, Natália; Krug, Tiago; Manso, Helena; Gouveia, Luís F.; Sobral, João; Mendioroz, Maite; Fernández-Morales, Jèssica; Alvarez-Sabin, José; Ribó, Marc; Rubiera, Marta; Obach, Vı́ctor; Martí‐Fàbregas, Joan; Freijó, Marimar; Serena, J; Ferro, José M.; Vicente, Astrid M.; Oliveira, Sofia A.; Montaner, Joan

doi:10.1159/000302738

Cited by 49 publications

(31 citation statements)

References 63 publications

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“…[1][2][3][4][5][6][7][8][9][10][11][12][13][24][25][26] The meta-analysis thus involved a total of 20 populations from 17 publications when our current study was included.…”

Section: Meta-analysismentioning

confidence: 99%

A large-sample assessment of possible association between ischaemic stroke and rs12188950 in the PDE4D gene

et al. 2012

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Previous reports have shown ambiguous findings regarding the possible associations between ischaemic stroke (IS) and single nucleotide polymorphisms (SNPs) in the phosphodiesterase 4D (PDE4D) gene region. The SNP rs12188950 (or SNP45) has often been studied in this context. We performed a multi-centre study involving a large sample of 2599 IS patients and 2093 control subjects from the south and west regions of Sweden to replicate previous studies regarding IS risk and rs12188950. Subjects from Lund Stroke Register (LSR), Malmö Diet and Cancer Study (MDC) and Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS) were enroled. Subgroups of participants with hypertension and participants o55 years of age, as well as the TOAST subgroups large vessel disease, small vessel disease and cardioembolism, were also assessed. Univariate odds ratios (ORs) and ORs controlling for hypertension, diabetes and current smoking were calculated. We additionally performed a meta-analysis including 10 500 patients and 10 102 control subjects from 17 publications (including the present study). When assessing pooled data from LSR, MDC and SAHLSIS we obtained no association between IS and rs12188950 for all participants (OR¼0.93; 95% confidence interval (CI): 0.83-1.05). Significant associations were not found for hypertensive participants or participants with age o55, or when separately evaluating patients from the three different TOAST subgroups. The meta-analysis showed no significant overall estimate (OR¼0.96; 95% CI: 0.89-1.04) with significant heterogeneity for random effect (P¼0.042). No effect from rs12188950 on IS was found from either our pooled multi-centre data or the performed meta-analysis. We did not find any association between the examined subgroups and rs12188950 either.

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“…[1][2][3][4][5][6][7][8][9][10][11][12][13][24][25][26] The meta-analysis thus involved a total of 20 populations from 17 publications when our current study was included.…”

Section: Meta-analysismentioning

confidence: 99%

A large-sample assessment of possible association between ischaemic stroke and rs12188950 in the PDE4D gene

et al. 2012

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“…No variants in the coding sequence of the ALOX5AP gene that lead to amino acid substitution have been found [24]. Domingues-Montanari et al [20] found that SG13S114 SNP genotypes modulate the mRNA level of the ALOX5AP gene and that mRNA levels were higher in ischemic stroke cases than in controls. Helgadottir et al [7] found that LTB 4 generation by neutrophils stimulated with ionomycin was greater in individuals with myocardial infarction than in controls.…”

Section: Discussionmentioning

confidence: 99%

“…Another SNPs-based ALOX5AP haplotype (Hap B) showed a significant association with MI in a British cohort [7]. Replications of these findings have been conducted in various populations [8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23] and the results are controversial [24]. …”

Section: Introductionmentioning

confidence: 99%

“…No variants in the coding sequence of the ALOX5AP gene that lead to amino acid substitution have been found [24]. Previous studies indicated that the ALOX5AP gene expression level and its downstream LTB 4 synthesis activity were greater in patients with MI or IS than controls [7,20]. These phenomena highly suggest that there might be some unidentified variants in the regulatory regions of gene expression, such as the promoter region, which underline the potential risk conferred by the ALOX5AP gene.…”

Section: Introductionmentioning

confidence: 99%

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Genetic Variants in the Promoter Region of the <i>ALOX5AP</i> Gene and Susceptibility of Ischemic Stroke

Jia

et al. 2011

Cerebrovasc Dis

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Background: Despite accumulating evidence supporting the association between variants of the ALOX5AP gene and atherosclerotic vascular events, the precise mechanism is still unclear. No variants in the coding sequence that lead to amino acid substitution have been found. We investigated genetic variants in the promoter region of the ALOX5AP gene and the association with ischemic stroke in a north Chinese Han population. Methods: 505 cases of ischemic stroke and 500 age- and gender-matched controls of the north Chinese Han population were enrolled. Genetic variants in the promoter region of the ALOX5AP gene were identified by polymerase chain reaction and DNA sequencing. 40 cases and 40 controls were randomly selected and compared for serum leukotriene B₄ (LTB₄) concentration. The effect on ischemic stroke was evaluated by logistic regression. Results: Three genetic variants were identified, including a mutation (–519 G > A), an insertion and deletion polymorphisms (–581_582 Ins A) and a single nuclear polymorphisms (–946 A > G). Association study showed that the II genotype of –581_582 Ins A was significantly associated with ischemic stroke of a large artery atherosclerosis (OR = 3.50, 95% CI = 1.93–6.36, p = 0.0002) and undetermined etiology (OR = 3.66, 95% CI = 1.92–6.94, p = 0.0006). No significant association was found between the –519 GA genotype (OR = 0.35, 95% CI = 0.02–5.88, p = 0.46), –946 AG genotype (OR = 1.35, 95% CI = 0.85–2.16, p = 0.21) and ischemic stroke. There was no significant difference in serum LTB₄ concentration between cases (n = 40) and controls (n = 40) (log serum LTB₄ of cases vs. controls: 2.67 ± 0.14 vs. 2.73 ± 0.18 pg/ml, p = 0.10). However, the serum LTB₄ concentration was significantly higher in participants with the II genotype of –581_582 Ins A (n = 12) than that of participants with the DD genotype (n = 68) (log serum LTB₄ of participants with II genotype vs. DD genotype: 2.82 ± 0.18 vs. 2.68 ± 0.15 pg/ml, p = 0.01). Conclusion: The –581_582 Ins A polymorphism might be a novel genetic risk factor for ischemic stroke in a north Chinese Han population. Further studies on molecular mechanism are warranted.

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“…Recently, 2 ethnic specific metaanalyses were published. Domingues-Monatanari et al [18] (2010) reported that none of the SNPs in the PDE4D gene was associated with ischemic stroke in the Iberian population. However, Xu et al [19] (2010) found an association between SNP83 and ischemic cerebral infarction in Asian populations.…”

mentioning

confidence: 99%

Meta-Analysis of Homogeneous Subgroups Reveals Association between <i>PDE4D</i> Gene Variants and Ischemic Stroke

Yoon¹,

Park²,

Kang³

et al. 2011

Neuroepidemiology

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Background: An Icelandic study showed a significant positive association between phosphodiesterase 4D (PDE4D) gene variants and stroke. However, subsequent studies reported conflicting results, possibly due to small sample sizes and the heterogeneity of the studies. Method: We performed a meta-analysis on 6 SNPs of the PDE4D gene to investigate the association between this gene and ischemic stroke by integrating the results of previous studies, comprising 11,834 cases and 15,233 controls. A pooled genotypic odds ratio (OR) for each SNP was determined under 3 genetic models (i.e. dominant, recessive, and codominant) using both fixed- and random-effects models with consideration for heterogeneity and publication bias across studies. Results: Among the SNPs included in this study, SNP56 (rs702553) showed the most significant association with ischemic stroke in a meta-analysis comprised of 7 homogenous studies. The overall OR of the TT genotype compared to the AA genotype was 1.29 (95% CI 1.03–1.61; p = 0.022). For SNP83 (rs966221), a protective effect of the ancestral allele T was observed only in Asian populations (ORTT 0.79, 95% CI 0.69–0.90; p = 0.0005). This meta-analysis revealed a significant association of PDE4D gene variants with the risk of ischemic stroke, and further investigations are warranted to evaluate possible ethnic-specific effects.

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Association of a Genetic Variant in the <i>ALOX5AP</i> with Higher Risk of Ischemic Stroke: A Case-Control, Meta-Analysis and Functional Study

Cited by 49 publications

References 63 publications

A large-sample assessment of possible association between ischaemic stroke and rs12188950 in the PDE4D gene

A large-sample assessment of possible association between ischaemic stroke and rs12188950 in the PDE4D gene

Genetic Variants in the Promoter Region of the <i>ALOX5AP</i> Gene and Susceptibility of Ischemic Stroke

Meta-Analysis of Homogeneous Subgroups Reveals Association between <i>PDE4D</i> Gene Variants and Ischemic Stroke

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