Ischaemic stroke in hypertensive patients is associated with variations in the PDE4D genome region

Lövkvist, Håkan; Smith, J Gustav; Luthman, Holger; Höglund, Peter; Norrving, Bo; Kristoffersson, Ulf; Jönsson, Ann-Cathrin; Lindgren, Arne

doi:10.1038/ejhg.2008.62

Cited by 25 publications

(31 citation statements)

References 26 publications

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Section: Introductionmentioning

confidence: 88%

“…1,2 Our previous study also showed a significant inhibiting effect of rs12188950 minor (T) allele on IS among subjects with hypertension. 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.…”

Section: Introductionmentioning

confidence: 88%

“…2,16-21 Briefly, LSR is a prospective, consecutive epidemiological study from which we have included 920 patients with first-ever stroke from the local catchment area of Skåne University Hospital in Lund, and 566 control subjects from the same geographical area, selected randomly after stratification by age and sex to match the patient group (when including intracranial bleedings as well as cerebral infarctions). 2,17 The LSR data was collected between March 2001 and August 2007. In a previous study by us from 2008 we assessed 932 IS patients and 396 control subjects from LSR.…”

Section: Study Population and Sample Characteristicsmentioning

confidence: 99%

“…In a previous study by us from 2008 we assessed 932 IS patients and 396 control subjects from LSR. 2 In order to perform a replication being independent of assessments made previously, we did not include any of these participants in the current study. However, the results from 2008 were included as a separate study/population in our meta-analysis.…”

Section: Study Population and Sample Characteristicsmentioning

confidence: 99%

“…[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%

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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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Section: Introductionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 88%

Section: Study Population and Sample Characteristicsmentioning

confidence: 99%

Section: Study Population and Sample Characteristicsmentioning

confidence: 99%

“…[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%

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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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Bayesian semiparametric meta-analysis for genetic association studies

et al. 2011

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We present a Bayesian semiparametric model for the meta-analysis of candidate gene studies with a binary outcome. Such studies often report results from association tests for different, possibly study-specific and non-overlapping genetic markers in the same genetic region. Meta-analyses of the results at each marker in isolation are seldom appropriate as they ignore the correlation that may exist between markers due to linkage disequilibrium (LD) and cannot assess the relative importance of variants at each marker. Also such marker-wise meta-analyses are restricted to only those studies that have typed the marker in question, with a potential loss of power. A better strategy is one which incorporates information about the LD between markers so that any combined estimate of the effect of each variant is corrected for the effect of other variants, as in multiple regression. Here we develop a Bayesian semiparametric model which models the observed genotype group frequencies conditional to the case/control status and uses pairwise LD measurements between markers as prior information to make posterior inference on adjusted effects. The approach allows borrowing of strength across studies and across markers. The analysis is based on a mixture of Dirichlet processes model as the underlying semiparametric model. Full posterior inference is performed through Markov chain Monte Carlo algorithms. The approach is demonstrated on simulated and real data.

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Meta-analysis of association between variation in the PDE4D gene and ischemic cerebral infarction risk in Asian populations

et al. 2010

Neurogenetics

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Phosphodiesterase 4D (PDE4D) was found to be associated with increased risk of ischemic stroke by Iceland researchers in 2003. Replication studies have produced conflicting results. A recent meta-analysis reported that no genetic variant of PDE4D demonstrated a reproducible association with ischemic stroke, especially when analyzed with respect to white subjects exclusively. In this study, we aimed to determine the association between PDE4D and ischemic infarction risk in Asian populations. After collecting all case-control studies in English or Chinese related to the association between PDE4D and ischemic infarction in Asian people, strict selection criteria and exclusion criteria were determined, and a fixed or random effects model was used on the basis of heterogeneity. To measure the strength of the genetic association, a pooled odds ratio (OR) and 95% confidence interval (CI) were calculated for each gene variant. Publication bias was evaluated. None of the Asian subjects were heterozygous for SNP 45 or SNP 41. Only seven studies involving SNP 83 and SNP 87 had sufficient data to allow inclusion into meta-analyses. Statistically significant associations with ischemic infarction in the Asian populations were determined for SNP 83 C allele (OR, 1.22; 95% CI, 1.03-1.43) and SNP 83 CC genotype (OR, 1.42; 95% CI, 1.14-1.77), but not for SNP 83 CC + CT genotypes or SNP 87. PDE4D was associated with ischemic infarction risk in Asian people, and SNP 83 was an important biomarker.

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Ischaemic stroke in hypertensive patients is associated with variations in the PDE4D genome region

Cited by 25 publications

References 26 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

Bayesian semiparametric meta-analysis for genetic association studies

Meta-analysis of association between variation in the PDE4D gene and ischemic cerebral infarction risk in Asian populations

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