<i>ALOX5AP</i>
            Gene and the
            <i>PDE4D</i>
            Gene in a Central European Population of Stroke Patients

Lõhmussaar, Elin; Gschwendtner, Andreas; Mueller, Jakob C.; Org, Tõnis; Wichmann, Erich; Hamann, Gerhard F.; Meitinger, Thomas; Dichgans, Martin

doi:10.1161/01.str.0000157587.59821.87

Cited by 165 publications

(145 citation statements)

References 19 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%

“…2 However, a meta-analysis in our previous publication in 2008 showed ambiguous results concerning the possible association between IS risk and variants in rs12188950. [3][4][5][6][7][8][9][10][11][12] We were aware of three replicating studies, that showed significant allelic association with IS by detecting and examining haplotype blocks located at the 5¢ end region of the PDE4D gene. 4,13,14 Moreover, a meta-analysis including four studies indicated significantly increased IS risk when considering an at-risk haplotype, including rs12188950.…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

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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“…However, results were controversial and conflicting, even suggesting the possibility of spurious associations. In particular, whereas no association with PDE4D SNPs and risk of stroke was found in several European populations, 12,28,23 evidence of a significant positive association was reported in studies conducted in other cohorts from Europe, 24 North America, 25 Australia, 26 and Asia. 16 It is of interest that two studies on the US populations 18,27 have shown a potential role of hypertension in directing the effect of PDE4D gene.…”

Section: Discussionmentioning

confidence: 88%

Phosphodiesterase 4D and 5-lipoxygenase activating protein genes and risk of ischemic stroke in Sardinians

et al. 2009

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Genetic factors contribute to the risk of ischemic stroke (IS). The phosphodiesterase-4D (PDE4D) and the 5-lipoxygenase activating protein (ALOX5AP) genes were identified as contributors to stroke in an Icelandic population. In an attempt to better define the contributory role of PDE4D and ALOX5AP genes to the risk of IS in humans, we carried out the present association study in a well-characterized, earlier published, genetically homogenous population from the island of Sardinia, Italy. In this cohort, including 294 cases and 235 controls, age, hypertension, hypercholesterolemia, and atrial fibrillation represent risk factors for IS. The PDE4D gene was evaluated by four single nucleotide polymorphisms (SNP32, SNP45, SNP83, SNP87) and by the microsatellite AC008818-1; the ALOX5AP gene was characterized by three SNPs (SG13S32, SG13S89, ALO2A). The results of our study provide no evidence of association between any single PDE4D and ALOX5AP gene variant with the risk of IS in the Sardinian cohort. Haplotype analysis, including that constructed with allele 0 of microsatellite AC008818-1 and SNP45 of the PDE4D gene, was also negative. In conclusion, we found no evidence of association between PDE4D and ALOX5AP genes and the risk of IS in a genetically homogenous population from Sardinia.

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“…Leukotrienes are arachidonic acid derivatives long known for their inflammatory properties and their involvement with a number of complex human diseases, most particularly asthma. Several genetic linkage and associations studies as well as gene expression studies have shown an association of the leukotriene biosynthesis pathway to CAD (Dwyer et al, 2004, Helgadottir et al, 2004, 2005b,a, Lohmussaar et al, 2005, Shah et al, 2008. Helgadottir et al (2004) identified a four-SNP haplotype (HapA) spanning the ALOX5AP gene that conferred a nearly two times greater risk of MI and stroke in a case-control cohort.…”

Section: Introductionmentioning

confidence: 99%

Assessment of LD Matrix Measures for the Analysis of Biological Pathway Association

Crosslin¹,

Qin²,

Hauser³

2010

Statistical Applications in Genetics and Molecular Biology

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Complex diseases will have multiple functional sites, and it will be invaluable to understand the cross-locus interaction in terms of linkage disequilibrium (LD) between those sites (epistasis) in addition to the haplotype-LD effects. We investigated the statistical properties of a class of matrix-based statistics to assess this epistasis. These statistical methods include two LD contrast tests (Zaykin et al., 2006) and partial least squares regression . To estimate Type 1 error rates and power, we simulated multiple two-variant disease models using the SIMLA software package. SIMLA allows for the joint action of up to two disease genes in the simulated data with all possible multiplicative interaction effects between them. Our goal was to detect an interaction between multiple disease-causing variants by means of their linkage disequilibrium (LD) patterns with other markers. We measured the effects of marginal disease effect size, haplotype LD, disease prevalence and minor allele frequency have on cross-locus interaction (epistasis).In the setting of strong allele effects and strong interaction, the correlation between the two disease genes was weak (r = 0.2). In a complex system with multiple correlations (both marginal and interaction), it was difficult to determine the source of a significant result. Despite these complications, the partial least squares and modified LD contrast methods maintained adequate power to detect the epistatic effects; however, for many of the analyses we often could not separate interaction from a strong marginal effect. While we did not exhaust the entire parameter space of possible models, we do provide guidance on the effects that population parameters have on cross-locus interaction.

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ALOX5AP Gene and the PDE4D Gene in a Central European Population of Stroke Patients

Cited by 165 publications

References 19 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

Phosphodiesterase 4D and 5-lipoxygenase activating protein genes and risk of ischemic stroke in Sardinians

Assessment of LD Matrix Measures for the Analysis of Biological Pathway Association

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