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

Background and Purpose - 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. Methods - 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. Results - 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. Conclusion - 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.