Genetic Dissection of the Canq1 Locus Governing Variation in Extent of the Collateral Circulation 英文参考文献.docVIP

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Genetic Dissection of the Canq1 Locus Governing Variation in Extent of the Collateral Circulation 英文参考文献.doc

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Genetic Dissection of the Canq1 Locus Governing Variation in Extent of the Collateral Circulation 英文参考文献

GeneticDissectionoftheCanq1LocusGoverning VariationinExtentoftheCollateralCirculation ShiliangWang1,3,HuaZhang1,3,TimWiltshire2,RobertSealock1,3,JamesE.Faber1,3 * 1DepartmentofPhysiology,UniversityofNorthCarolinaatChapelHill,ChapelHill,NorthCarolina,UnitedStatesofAmerica, 2DepartmentofGenetics,Universityof NorthCarolinaatChapelHill,ChapelHill,NorthCarolina,UnitedStatesofAmerica,3McAllisterHeartInstitute,UniversityofNorthCarolinaatChapelHill,ChapelHill, NorthCarolina,UnitedStatesofAmerica Abstract Background.:Native(pre-existing)collateralsarearteriole-to-arterioleanastomosesthatinterconnectadjacentarterialtrees and serve as endogenous bypass vessels that limit tissue injury in ischemic stroke, myocardial infarction, coronary and peripheralarterydisease.Theirextent(numberanddiameter)varieswidelyamongmousestrainsandhealthyhumans.We previously identified a major quantitative trait locus on chromosome 7 (Canq1, LOD=29) responsible for 37% of the heritablevariationincollateralextentbetweenC57BL/6andBALB/cmice.WesoughttoidentifycandidategenesinCanq1 responsiblefor collateralvariationin thecerebral pialcirculation, atissuewhosestrain-dependentvariationis sharedby similarvariationinothertissues. Methods and Findings: Collateral extent was intermediate in a recombinant inbred line that splits Canq1 between the C57BL/6andBALB/cstrains.PhenotypingandSNP-mappingofanexpandedpaneloftwenty-oneinformativeinbredstrains narrowed the Canq1 locus, and genome-wide linkage analysis of a SWRxSJL-F2 cross confirmed its haplotype structure. Collateral extent, infarct volume after cerebral artery occlusion, bleeding time, and re-bleeding time did not differ in knockoutmicefortwovascular-relatedgeneslocatedinCanq1,IL4raandItgal.Transcriptabundanceof6outof116genes withinthe95%confidenceintervalofCanq1weredifferentiallyexpressed.2-fold(p-value,0.054150)inthecorticalpia materfromC57BL/6andBALB/cembryosatE14.5,E16.5andE18.5time-pointsthatspantheperiodofcollateralformation. Conclus