title: Association of a genetic variant in the ALOX5AP with higher risk of ischemic stroke: a case-control, meta-analysis and functional study.
abstract: 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.
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal.
authors.forename: Sophie
authors.initials: S
authors.lastname: Domingues-Montanari
authors.forename: Israel
authors.initials: I
authors.lastname: Fernández-Cadenas
authors.forename: Alberto
authors.initials: A
authors.lastname: del Rio-Espinola
authors.forename: Natalia
authors.initials: N
authors.lastname: Corbeto
authors.forename: Tiago
authors.initials: T
authors.lastname: Krug
authors.forename: Helena
authors.initials: H
authors.lastname: Manso
authors.forename: Liliana
authors.initials: L
authors.lastname: Gouveia
authors.forename: Joao
authors.initials: J
authors.lastname: Sobral
authors.forename: Maite
authors.initials: M
authors.lastname: Mendioroz
authors.forename: Jessica
authors.initials: J
authors.lastname: Fernández-Morales
authors.forename: José
authors.initials: J
authors.lastname: Alvarez-Sabin
authors.forename: Marc
authors.initials: M
authors.lastname: Ribó
authors.forename: Marta
authors.initials: M
authors.lastname: Rubiera
authors.forename: Victor
authors.initials: V
authors.lastname: Obach
authors.forename: Joan
authors.initials: J
authors.lastname: Martí-Fàbregas
authors.forename: Marimar
authors.initials: M
authors.lastname: Freijo
authors.forename: Joaquin
authors.initials: J
authors.lastname: Serena
authors.forename: José M
authors.initials: JM
authors.lastname: Ferro
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Vicente
authors.forename: Sofia A
authors.initials: SA
authors.lastname: Oliveira
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D000368:Aged; D002545:Brain Ischemia / Q000150:complications / Q000453:epidemiology*; D002352:Carrier Proteins / Q000235:genetics*; D016022:Case-Control Studies; D005006:Ethnicity; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011174:Portugal / Q000453:epidemiology; D012313:RNA / Q000235:genetics; D012307:Risk Factors; D018401:Sample Size; D013030:Spain / Q000453:epidemiology; D020521:Stroke / Q000453:epidemiology* / Q000209:etiology / Q000235:genetics*
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D012313:RNA