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Association of integrin alpha2 gene variants with ischemic stroke.

ABSTRACT: Genetic variants in the gene encoding integrin alpha2 (ITGA2) have been reported to be associated with an increased risk for ischemic stroke. The purpose of this study was to investigate the association between haplotype-tagging single-nucleotide polymorphisms (tSNPs) in ITGA2 and risk of ischemic stroke in a collection of North American stroke cases and controls. The study included 484 cases and 263 controls. Thirteen tSNPs were genotyped. Association tests at and across each tSNP were performed, including haplotype association analysis. Secondary analyses considered stroke subtypes on the basis of Trial of Org 10172 in Acute Stroke Treatment (TOAST) criteria. We observed significant association between tSNP rs3756541 (additive model, odds ratio (OR), 1.49; 95% confidence interval (CI), 1.11 to 2.04; P=0.009) and disease and a trend toward association at rs2303124 (recessive model, OR, 1.56; 95% CI, 1.05 to 2.33; P=0.03). These associations remained significant in the haplotype analyses. The associated tSNPs did not distinguish stroke etiology after application of TOAST criteria. Our results suggest that genetic variability within ITGA2 may confer risk for ischemic stroke independent of conventional risk factors. These results provide additional support for a role for platelet receptor genes in the pathogenesis of ischemic stroke of diverse subtypes.

SUBMITTER: Matarin M

PROVIDER: S-EPMC2629802 | biostudies-literature | 2008 Jan

REPOSITORIES: biostudies-literature

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Association of integrin alpha2 gene variants with ischemic stroke.

Matarin Mar M Brown W Mark WM Hardy John A JA Rich Stephen S SS Singleton Andrew B AB Brown Robert D RD Brott Thomas G TG Worrall Bradford B BB Meschia James F JF

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20070530 1

Genetic variants in the gene encoding integrin alpha2 (ITGA2) have been reported to be associated with an increased risk for ischemic stroke. The purpose of this study was to investigate the association between haplotype-tagging single-nucleotide polymorphisms (tSNPs) in ITGA2 and risk of ischemic stroke in a collection of North American stroke cases and controls. The study included 484 cases and 263 controls. Thirteen tSNPs were genotyped. Association tests at and across each tSNP were performe ...[more]

PMID: 17534386

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Project description:Previous reports demonstrate that the Î±2-integrin (Î±2) mediates pancreatic ductal adenocarcinoma (PDAC) cell interaction with collagens. We found that untransformed pancreatic ductal epithelial cells and well-differentiated PDAC cells use Î±2 exclusively to adhere and migrate on collagenI. In contrast, poorly-differentiated PT45P1 and MIAPaCa2 cells demonstrate reduced reliance on, or complete loss of Î±2, respectively. Further, well-differentiated PDAC lines exhibit reduced in vitro invasion compared to poorly-differentiated lines, and Î±2-blockade suppressed invasion of well-differentiated lines exclusively. Based on these data and the demonstrated role of Î±2 in maintaining tissue architecture in other organs, we hypothesized that Î±2 may actually suppress the malignant phenotype in PDAC. Accordingly, stable ectopic expression of Î±2 in MIAPaCa2 cells (MP2-Î±2) retarded in vitro invasion. MP2-Î±2 cells maintained on collagenI were more invasion-retarded than MP2-Î±2 cells maintained in standard tissue culture, and demonstrated higher Î±2Î²1 expression that was reflected in faster and more complete adhesion/migration on collagenI. Affymetrix gene expression profiling of Î±2-expressing and mock-transfected cells revealed that kallikrein-related peptidases (KLK)-5, 6 and 7 were specifically upregulated by Î±2. Accordingly, well-differentiated PDAC lines express KLK-5, 6 and 7 and KLK blockade increased invasion as well as collagenI-migration in KLK-positive lines. Importantly, an Î±2 cytoplasmic deletion mutant promoted KLK expression and retarded invasion, while an Î±9Î±2 chimera retarded invasion less efficiently, and did not impact KLK expression. These data demonstrate for the first time that the Î±2-ectodomain and KLKâ??s coordinately regulate a less invasive phenotype in PDAC cells. Experiment Overall Design: Affymetrix global gene arrays were used to analyse differences in gene expression patterns in MIAPaCa2 cells stably reexpressing the alpha2 integrin, a cytoplasmic deletion of the alpha2 integrin (dCYTO) or an alpha9 ectodomain and transmembrane domain/alpha2 cytoplasmic domain chimera, versus vector-only mock controls. RNA was harvested from cells passaged identically and maitained under standard tissue culture conditions or on collagenI- or tenascin FNIII-coated plates.. Experiment Overall Design: Genetic manipulation (stable transgene expression)

Dataset Information

Association of integrin alpha2 gene variants with ischemic stroke.

Publications

Association of integrin alpha2 gene variants with ischemic stroke.

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