title: TTC7B emerges as a novel risk factor for ischemic stroke through the convergence of several genome-wide approaches.
abstract: We hereby propose a novel approach to the identification of ischemic stroke (IS) susceptibility genes that involves converging data from several unbiased genetic and genomic tools. We tested the association between IS and genes differentially expressed between cases and controls, then determined which data mapped to previously reported linkage peaks and were nominally associated with stroke in published genome-wide association studies. We first performed gene expression profiling in peripheral blood mononuclear cells of 20 IS cases and 20 controls. Sixteen differentially expressed genes mapped to reported whole-genome linkage peaks, including the TTC7B gene, which has been associated with major cardiovascular disease. At the TTC7B locus, 46 tagging polymorphisms were tested for association in 565 Portuguese IS cases and 520 controls. Markers nominally associated in at least one test and defining associated haplotypes were then examined in 570 IS Spanish cases and 390 controls. Several polymorphisms and haplotypes in the intron 5-intron 6 region of TTC7B were also associated with IS risk in the Spanish and combined data sets. Multiple independent lines of evidence therefore support the role of TTC7B in stroke susceptibility, but further work is warranted to identify the exact risk variant and its pathogenic potential.
authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal.
authors.forename: Tiago
authors.initials: T
authors.lastname: Krug
authors.forename: João Paulo
authors.initials: JP
authors.lastname: Gabriel
authors.forename: Ricardo
authors.initials: R
authors.lastname: Taipa
authors.forename: Benedita V
authors.initials: BV
authors.lastname: Fonseca
authors.forename: Sophie
authors.initials: S
authors.lastname: Domingues-Montanari
authors.forename: Israel
authors.initials: I
authors.lastname: Fernandez-Cadenas
authors.forename: Helena
authors.initials: H
authors.lastname: Manso
authors.forename: Liliana O
authors.initials: LO
authors.lastname: Gouveia
authors.forename: João
authors.initials: J
authors.lastname: Sobral
authors.forename: Isabel
authors.initials: I
authors.lastname: Albergaria
authors.forename: Gisela
authors.initials: G
authors.lastname: Gaspar
authors.forename: Jordi
authors.initials: J
authors.lastname: Jiménez-Conde
authors.forename: Raquel
authors.initials: R
authors.lastname: Rabionet
authors.forename: José M
authors.initials: JM
authors.lastname: Ferro
authors.forename: Joan
authors.initials: J
authors.lastname: Montaner
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Vicente
authors.forename: Mário Rui
authors.initials: MR
authors.lastname: Silva
authors.forename: Ilda
authors.initials: I
authors.lastname: Matos
authors.forename: Gabriela
authors.initials: G
authors.lastname: Lopes
authors.forename: Sofia A
authors.initials: SA
authors.lastname: Oliveira
mesh_terms: D000368:Aged; D002545:Brain Ischemia / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D008040:Genetic Linkage; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011174:Portugal; D012307:Risk Factors; D013030:Spain; D020521:Stroke / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism
chemical_list: D009419:Nerve Tissue Proteins