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Association of a Genetic Variant in the <i>ALOX5AP</i> with Higher Risk of Ischemic Stroke: A Case-Control, Meta-Analysis and Functional Study

2010; Karger Publishers; Volume: 29; Issue: 6 Linguagem: Inglês

10.1159/000302738

1421-9786

Sophie Domingues‐Montanari, Israel Fernández‐Cadenas, Alberto del Río-Espínola, Natália Corbeto, Tiago Krug, Helena Manso, Liliana Gouveia, João Sobral, Maite Mendióroz, Jessica Fernández‐Morales, José Álvarez‐Sabín, Marc Ribó, Marta Rubiera, Vı́ctor Obach, Joan Martí‐Fàbregas, Marimar Freijó, Joaquı́n Serena, José M. Ferro, Astrid M. Vicente, Sofia A. Oliveira, Joan Montaner,

Receptor Mechanisms and Signaling

<i>Background:</i> Variants in the 5-lipoxygenase-activating protein <i>(ALOX5AP)</i> and phosphodiesterase 4D <i>(PDE4D)</i> 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. <i>Methods:</i> A case-control design was used to analyze one SNP in <i>ALOX5AP</i> and five SNPs in <i>PDE4D</i> 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, <i>ALOX5AP </i>gene expression levels were determined in controls and IS cases. <i>Results:</i> A first meta-analysis of both subsets showed that the T allele of the SG13S114 SNP in <i>ALOX5AP</i> 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]. <i>ALOX5AP</i> gene expression analysis in a subset of controls and cases revealed that the SG13S114 genotypes modulate mRNA levels of <i>ALOX5AP </i>(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 <i>PDE4D</i> with IS was observed in our study. <i>Conclusions:</i> The <i>ALOX5AP</i> SG13S114 variant is an independent risk factor for IS in the Iberian population and is associated with <i>ALOX5A</i>P expression levels. The role of this gene in stroke merits further investigation.