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

Previous Icelandic studies reported that single nucleotide polymorphisms (SNPs) in the phosphodiesterase 4D (PDE4D) region and the 5-lipoxygenase activating protein ALOX5AP were associated with ischaemic stroke, whereas other studies reported ambiguous findings. We examined 932 ischaemic stroke patients from a Swedish population-based stroke register, and 396 control subjects. We assessed possible associations between ischaemic stroke and nine preselected SNPs in the chromosome regions of the PDE4D gene, including rs12188950 (SNP45) and rs3887175 (SNP39); the ALOX5AP gene, including rs17222814 (SG13S25) and the promoter region of the MHC class II transactivator, MHC2TA. The T allele of SNP45 showed negative association with ischaemic stroke (odds ratio, OR 0.72; 95% confidence interval (CI): 0.58-0.91; P = 0.0055). Among hypertensive subjects, this influence of the T allele of SNP45, and the T allele of SNP39, were more pronounced (with OR 0.52; 95% CI: 0.37-0.73; P = 0.0001 and OR = 0.57; 95% CI: 0.41-0.79; P = 0.0007, respectively). These SNPs also interacted with hypertension with a relative excess risk due to interaction of -1.66 (P = 0.0002) for SNP45 and -1.65 (P = 0.0005) for SNP39. The P-values remained significant after correction for multiple testing. Among nonhypertensives, the A allele of SG13S25 indicated increased stroke risk (OR 1.82; 95% CI: 1.21-2.74; P = 0.0039; not significant after Bonferroni correction). SNP45 was associated with ischaemic stroke even when controlling for hypertension, diabetes, heart disease and smoking. Our meta-analysis of 13 studies (including ours) showed no overall influence of SNP45 on ischaemic stroke. However, the 13 studies may differ because of nonrandom causes, as suggested by the heterogeneity test (P = 0.042). This might support previously undetected mechanisms causing fluctuating ischaemic stroke risk.