Genome-Wide Association Studies of MRI-Defined Bra... [Stroke. 2009] - PubMed result

Stroke. 2009 Dec 31. [Epub ahead of print]

Genome-Wide Association Studies of MRI-Defined Brain Infarcts. Meta-Analysis From the CHARGE Consortium.
Debette S, Bis JC, Fornage M, Schmidt H, Ikram MA, Sigurdsson S, Heiss G, Struchalin M, Smith AV, van der Lugt A, Decarli C, Lumley T, Knopman DS, Enzinger C, Eiriksdottir G, Koudstaal PJ, Destefano AL, Psaty BM, Dufouil C, Catellier DJ, Fazekas F, Aspelund T, Aulchenko YS, Beiser A, Rotter JI, Tzourio C, Shibata DK, Tscherner M, Harris TB, Rivadeneira F, Atwood LD, Rice K, Gottesman RF, van Buchem MA, Uitterlinden AG, Kelly-Hayes M, Cushman M, Zhu Y, Boerwinkle E, Gudnason V, Hofman A, Romero JR, Lopez O, van Duijn CM, Au R, Heckbert SR, Wolf PA, Mosley TH, Seshadri S, Breteler MM, Schmidt R, Launer LJ, Longstreth WT Jr.

For authors representing the Aging Gene-Environment Susceptibility-Reykjavik Study: From Icelandic Heart Association, Kopavogur, Iceland; Department of Radiology, Leiden University Medical Center, Leiden, The Netherlands; University of Iceland, Reykjavik, Iceland; Intramural Research Program, Laboratory of Epidemiology, Demography, and Biometry, National Institute of Aging, Bethesda, Md. For authors representing the Atherosclerosis Risk in Communities Study: From Brown Foundation Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Houston, Tex; Department of Epidemiology, University of North Carolina, Chapel Hill, NC; Department of Neurology, Mayo Clinic, Rochester, Minn; Department of Biostatistics, University of North Carolina, Chapel Hill, NC; Department of Radiology, University of Washington Medical Center, Seattle, Wash; Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Md; Department of Medicine, University of Mississippi Medical Center, Jackson, Miss. For authors representing the Austrian Stroke Prevention Study: From Department of Neurology, Department of Neurogeriatrics, Department of Neuroradiology, Institute of Molecular Biology and Biochemistry, Medical University Graz, Austria; Department of Epidemiology and Biostatistics, Department of Forensic Molecular Biology, the Erasmus MC University Medical Center, Rotterdam, The Netherlands. For authors representing the Cardiovascular Health Study: From Departments of Medicine, Biostatistics, Epidemiology, Health Services, and Neurology, University of Washington, Seattle, Wash; Center for Health Studies, Group Health, Seattle, Wash; Brown Foundation Institute of Molecular Medicine and Human Genetics Center, University of Texas Health Science Center at Houston, Tex; Department of Medicine and Pathology, University of Vermont, Burlington, Vt; Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, Calif; Departments of Neurology and Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pa. For authors representing the Framingham Heart Study: From Department of Neurology, Boston University School of Medicine, Boston, Mass; Department of Biostatistics, Boston University School of Public Health, Boston, Mass; Department of Neurology and Center for Neuroscience, University of California at Davis, Davis, Calif. For authors representing the Rotterdam Study: From Departments of Epidemiology, Neurology, Internal Medicine, Radiology, and Clinical Chemistry, Erasmus MC University Medical Center, Rotterdam, The Netherlands; The Netherlands Consortium of Healthy Aging, The Netherlands. For authors representing the 3C-Dijon Study: From Inserm, Unit 708, Paris, France; Universite' Pierre et Marie Curie-Paris, Paris, France; Service de Neurologie, Hopital Lariboisie;re, Paris, France; Department of Neurology, Peking Union Medical College Hospital, China.

BACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >/=1 MRI infarct). RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample. CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.

PMID: 20044523 [PubMed - as supplied by publisher]

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Genome-Wide Association Studies of MRI-Defined Bra... [Stroke. 2009] - PubMed result