Variation in the PDE4D gene and ischemic stroke risk: a systematic review and meta-analysis on 5200 cases and 6600 controls.

Abstract

PDE4D was identified as the first novel gene associated with ischemic stroke risk. Replication studies have produced conflicting results, but many have been small and underpowered. Meta-analysis provides a method to combine this data and determine in a larger sample size whether the association with PDE4D can be replicated. A meta-analysis of all PDE4D variants investigated in relation to ischemic stroke has been undertaken. Analysis of any variant appearing in 2 or more replication studies was included; this comprised 6 single nucleotide polymorphisms together with allele 0 of minisatellite AC008818 and the G0 haplotype. A total of 16 studies were identified, allowing examination of up to 5216 cases and 6615 controls for a single variant. Analyses were performed including all data, excluding data from the original report (providing true replication data), and for individual stroke subtypes and limited to white ethnicity. No individual single nucleotide polymorphism was associated with all ischemic stroke cases. Allele 0 of AC008818 and haplotype G0 carriers was associated with increased risk (relative risk, 1.12; 95 CI, 1.01 to 1.25; P=0.03 and relative risk, 1.18; 95% CI, 1.05 to 1.33; P=0.007), but these associations became nonsignificant after exclusion of the original study from the analysis (relative risk, 1.06; 95% CI, 0.94 to 1.20; P=0.34 and relative risk, 1.16; 95% CI, 1.00 to 1.34; P=0.06, respectively). Analyzing only whites, the majority of cases studied, did not result in a significant association for any analysis. Few robust associations were found with individual stroke subtypes. No genetic variant examined in PDE4D showed a robust and reproducible association to ischemic stroke. Any association that may exist is likely to be weak and potentially restricted to specific populations.