Association of a Genetic Variant in the ALOX5AP with Higher Risk of Ischemic Stroke: A Case-Control, Meta-Analysis and Functional StudyDomingues-Montanari S.e · Fernández-Cadenas I.e · del Rio-Espinola A.e · Corbeto N.e · Krug T.a, b · Manso H.a, c · Gouveia L.d · Sobral J.a, c · Mendioroz M.e · Fernández-Morales J.e · Alvarez-Sabin J.e · Ribó M.e · Rubiera M.e · Obach V.f · Martí-Fàbregas J.g · Freijo M.h · Serena J.i · Ferro J.M.b, d · Vicente A.M.a, c · Oliveira S.A.a, b · Montaner J.e
aInstituto Gulbenkian de Ciência, Oeiras, bInstituto de Medicina Molecular, cInstituto Nacional de Saúde Dr. Ricardo Jorge, dServiço de Neurologia, Hospital de Santa Maria, Lisboa, Portugal; eNeurovascular Research Laboratory and Neurovascular Unit, Neurology and Medicine Departments, Universitat Autònoma de Barcelona, Vall d’Hebron Hospital, fStroke Unit, Department of Neurological Sciences, Hospital Clinic and Institut d’Investigacions Biomédiques August Pi i Sunyer, University of Barcelona, and gDepartment of Neurology, Hospital de la Santa Creu i Sant Pau, Barcelona, hDepartment of Neurology, Hospital de Basurto, Bilbao, and iDepartment of Neurology, Hospital Universitario Dr. Josep Trueta, Institut d’Investigació Biomèdica de Girona, Girona, Spain
Background: 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.
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