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Exploring the interaction between SNP genotype and postmenopausal hormone therapy effects on stroke risk.doc

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Exploring the interaction between SNP genotype and postmenopausal hormone therapy effects on stroke risk

Huangetal.GenomeMedicine2012,4:57 /content/4/7/57 RESEARCH OpenAccess ExploringtheinteractionbetweenSNPgenotype andpostmenopausalhormonetherapyeffects onstrokerisk YingHuang1,DennisGBallinger2,ReneeStokowski3,EricaBeilharz2,JenniferGRobinson4,SiminLiu5, RandalDRobinson6,VictorWHenderson7,JacquesERossouw8andRossLPrentice1* Abstract Background:Genome-wideassociationstudieshaveidentifiedseveralgenomicregionsthatareassociatedwith strokerisk,buttheseprovideanexplanationforonlyasmallfractionoffamilialstrokeaggregation.Genotypeby environmentinteractionsmaycontributefurthertosuchanexplanation.TheWomen’sHealthInitiative(WHI) clinicaltrialfoundincreasedstrokeriskwithpostmenopausalhormonetherapy(HT)andprovidesanefficient settingforevaluatinggenotype-HTinteractiononstrokerisk. Methods:WeexaminedHTbygenotypeinteractionsfor392SNPsselectedfromcandidategenestudies,and 2,371SNPsassociatedwithchangesinbloodproteinconcentrationsafterhormonetherapy,inanalysesthat included2,045postmenopausalwomenwhodevelopedstrokeduringWHIclinicaltrialandobservationalstudy follow-upandone-to-onematchedcontrols.Atwo-stageprocedurewasimplementedwhereSNPspassingthe firststagescreeningbasedonmarginalassociationwithstrokeriskweretestedinthesecondstageforinteraction withHTusingcase-onlyanalysis. Results:Thetwo-stageprocedureidentifiedtwoSNPs,rs2154299andrinthecoagulationfactorXIII subunitA(F13A1)regionandtwoSNPs,rs630431andrs560892,intheproproteinconvertasesubtilisinkexin9 (PCSK9)region,withanestimatedfalsediscoveryrate0.05basedoninteractiontests.Furtheranalysesshowed significantstrokeriskinteractionbetweentheseF13A1SNPsandestrogenplusprogestin(E+P)treatmentfor ischemicstrokeandforischemicandhemorrhagicstrokecombined,andsuggestedinteractionsbetweenPCSK9 SNPswitheitherE+Porestrogen-alonetreatment. Conclusions:Genotypebyenvironmentinteractioninformationmayhelptodefinegenomicregionsrelevantto strokerisk.Two-stageanalysisamongpostmenopausalwomengeneratesnovelhypothesesconcerningtheF13A1 andPCSK9genomi