title: PDE4D and ALOX5AP genetic variants and risk for Ischemic Cerebrovascular Disease in Sweden.
abstract: BACKGROUND
  Genetic variants in Phosphodiesterase 4D (PDE4D) and 5-lipoxygenase activating protein (ALOX5AP) have been shown to confer risk of Ischemic Cerebrovascular Disease (ICVD) in Iceland. We investigated whether these variants associate with ICVD in Sweden.
  
  
  METHODS
  Previously published PDE4D and ALOX5AP gene variants were genotyped for cases (685) and controls (751). In PDE4D this consisted of SNP41, SNP45 and microsatellite AC008818-1 and in ALOX5AP four SNPs that define the HapA haplotype.
  
  
  RESULTS
  The PDE4D SNPs, showed a non-significant risk in the ICVD group which increased for the Large Artery Atherosclerosis subtype (SNP45: RR=1.43, P=0.063, SNP41: RR=1.57, P=0.018). The SNP haplotype GA (SNP45, SNP41) showed an increased risk for LAA (RR=1.58, P=0.016) and the combined LAA and Cardioembolism (CE) (RR=1.34, P=0.031) subgroups. As the SNPs are in strong LD, this haplotype corresponds to the complement of the protective haplotype in the Icelandic study. No allele of the microsatellite marker, showed association to stroke or any subtype and nor did the Icelandic PDE4D at-risk haplotype (GA0). We did not confirm the association between ALOX5AP HapA haplotype and ICVD, but a non-significant risk was observed in the LAA subtype.
  
  
  CONCLUSIONS
  Our PDE4D findings although non-significant considering the number of markers and phenotypes tested, are consistent with the association observed in the original study, with a trend observed in the whole ICVD group, which was strengthened in the stroke subtype LAA and the combined group of LAA and CE stroke. This supports the notion that PDE4D contributes to the risk of developing stroke.
authors.affiliation: Department of Neurology, Neuro-angiological Research Center, Karolinska Institutet, Karolinska University Hospital Huddinge, S-141 86 Huddinge, Sweden. konstantinos.kostulas@karolinska.se
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Kostulas
authors.forename: Solveig
authors.initials: S
authors.lastname: Gretarsdottir
authors.forename: Vasilios
authors.initials: V
authors.lastname: Kostulas
authors.forename: Andrei
authors.initials: A
authors.lastname: Manolescu
authors.forename: Anna
authors.initials: A
authors.lastname: Helgadottir
authors.forename: Gudmar
authors.initials: G
authors.lastname: Thorleifsson
authors.forename: Larus J
authors.initials: LJ
authors.lastname: Gudmundsson
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gulcher
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.forename: Jan
authors.initials: J
authors.lastname: Hillert
mesh_terms: D058927:5-Lipoxygenase-Activating Proteins; D000368:Aged; D000369:Aged, 80 and over; D002352:Carrier Proteins / Q000235:genetics*; D002561:Cerebrovascular Disorders / Q000235:genetics*; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012307:Risk Factors; D013548:Sweden
chemical_list: D058927:5-Lipoxygenase-Activating Proteins; C548592:ALOX5AP protein, human; D002352:Carrier Proteins; D008565:Membrane Proteins; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human