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

Abstract

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.

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

“…A previously published meta-analysis, with similarities to ours regarding selection of publication, presented a significant overall OR¼1.29 (P¼0.05) after removal of publications causing heterogeneity. 27 The slightly significant heterogeneity test (P¼0.042) suggests a nonrandom effect explaining the difference between the ORs among the 20 compared populations in our meta-analysis. Figure 1 visualises this ambiguity regarding the OR estimates.…”

Association of SNP41, SNP56 and a novel SNP in PDE4D gene with stroke and its subtypes

“…However, other studies failed to establish an association Kuhlenbaumer et al, 2006;Matsushita et al, 2009;Staton et al, 2006;Sun et al, 2009). A recent meta-analysis by Yoon et al found the most significant association of SNP56 with ischemic stroke (Yoon et al, 2011). They integrated the results of previous studies, comprising 11,834 cases and 15,233 controls.…”

“…Cohorts of different ethnicities have been studied. A detailed account of all these follow-up studies has already been reviewed Yoon et al, 2011). Inflammation has emerged as a key factor in the development of atherosclerotic lesions and in the progression to mature atheroma (Quarta et al, 2009).…”

“…Number of subsequent studies tried to replicate this association in different populations but the results were conflicting Yoon et al, 2011). PDE4D gene encodes for an enzyme that selectively degrades cAMP.…”

“…SNP41 (rs12153798), SNP45 (rs12188950), one microsatellite marker (AC008818-8) and the haplotypes constructed by SNP45 and this satellite marker were reported to show the most significant association with stroke. A recent meta-analysis carried out by Yoon et al (2011) including 6 SNPs (SNP26, SNP45, SNP56, SNP83, SNP87 and SNP89) showed the most significant association of SNP56 (rs702553) with ischemic stroke (Yoon et al, 2011). We have already tested the association of SNPs 83, 32 and 87 with ischemic stroke in a South Indian population from Andhra Pradesh (Munshi et al, 2009).…”