Association of a genetic variant in the ALOX5AP with higher risk of ischemic stroke : a case-control, meta-analysis and functional study

Copyright © 2010 S. Karger AGBackground: Variants in the 5-lipoxygenase-activating protein (ALOX5AP) and phosphodiesterase 4D (PDE4D) genes have first been associated with ischemic stroke (IS) through whole-genome linkage screens. However, association studies obtained conflicting results. We aimed to investigate the contribution of selected single nucleotide polymorphisms (SNPs) in these genes for the first time in a large Iberian population. Methods: A case-control design was used to analyze one SNP in ALOX5AP and five SNPs in PDE4D in a total of 1,092 IS patients and 781 healthy controls of two different subsets from Spain and Portugal. The analysis was adjusted for confounding variables and the results were integrated in a meta-analysis of all case-control studies. In addition, ALOX5AP gene expression levels were determined in controls and IS cases. Results: A first meta-analysis of both subsets showed that the T allele of the SG13S114 SNP in ALOX5AP was a risk factor for IS after Bonferroni correction [OR = 1.22 (1.06–1.40); p = 0.006]. A second meta-analysis of white populations confirmed these results [OR = 1.18 (1.07–1.31); p = 0.001]. ALOX5AP gene expression analysis in a subset of controls and cases revealed that the SG13S114 genotypes modulate mRNA levels of ALOX5AP (p = 0.001) and mRNA levels were higher in IS cases (2.8 ± 2.4%) than in controls (1.4 ± 1.3%; p = 0.003). No association of the variants in PDE4D with IS was observed in our study. Conclusions: The ALOX5AP SG13S114 variant is an independent risk factor for IS in the Iberian population and is associated with ALOX5AP expression levels. The role of this gene in stroke merits further investigation.This study was funded by a grant from the Spanish government (Geno-tPA project FIS PJ060586), the stroke research network (RENEVAS) and the Ramón Areces Foundation. S.D.-M. is the recipient of a grant from the Ramón Areces Foundation, I.F.-C. a postdoctoral grant from the Vall d’Hebron Research Institute (IRVH), A.d.R.-E. received a grant from the Vall d’Hebron Research Institute (IRVH), M.M. received a grant for Formation in Investigation (FI05/00081), and J.F.-M. was a recipient of a grant from La Marató (Chromig Exp. 072310). This work was also supported in part by the Portuguese Fundação para a Ciência e a Tecnologia (FCT) grant PTDC/SAU-GMG/ 64426/2006, FCT fellowships (TK, HM), and the Fundação AstraZeneca/Faculdade de Medicina de Lisboa research fellowship (LG). The Neurovascular Research Laboratory takes part in the International Stroke Genetics Consortium ISGC and in the RENEVAS network