HLA-B5801遗传标记ppt课件

HLA-B*5801alleleasageneticmarkerforseverecutaneousadversereactionscausedbyallopurinol研发部张艳,1,别嘌呤醇作用,用途：治疗痛风、高尿酸血症等相关疾病。机理：抑制黄嘌呤氧化酶的活性副作用：皮肤不良反应如HSS、SJS和TEN,2,PatientsandControlSubjectsRecruitment,228controlindividuals：(135allopurinol-tolerantsubjects93healthysubjects）51patientswithallopurinolSCAR,3,SNPGenotyping,Atotalof823SNPs：197SNPsfrom4MboftheMHCregion626SNPsselectedfromgenesencodingimmune-relatedmoleculesanddrugmetabolizingenzymes,4,HLAGenotyping,HLAallelesA,B,C,andDRB1,weredeterminedbysequence-specificoligonucleotidereverselineblotPotentialambiguitieswereresolvedbysequencing-basedtyping,5,StatisticalAnalysis,CategoricaldatawerecomparedbetweengroupswithuseofFishersexacttests,andcontinuousdata(presentedasmedian,withrangegiveninparentheses)werecomparedwithuseofttests.AllPvaluesweretwo-tailed;aPvalueof0.05wasconsideredtoindicatestatisticalsignificance.AllelicassociationscreenwascarriedoutbytheCochranArmitageTrendtestforeachSNP.OddsratioswerecalculatedwithHaldanesmodification,whichadds0.5toallcellstoaccommodatepossiblezerocounts.ThecorrectedP(Pc)valueswereadjustedbyusingBonferroniscorrectionformultiplecomparisonstoaccountfortheobservedalleles(17forHLA-A,40forHLA-B,19forHLA-C,and30forHLA-DRB1).Therefore,thePcvaluesweremultipliedbyafactorof387,600.,6,CharacteristicsofPatientsandControls,7,8,SJS(13cases),SJSTEN(5cases),TEN(3cases),andHSS(30cases),9,10,AssociationScreenforCandidateGeneSNPs,Fig.1.ScreeningofcandidateSNPsforassociationwithallopurinol-inducedSCAR.Onthexaxis,823SNPsareorderedbytheirchromosomepositions;197SNPsintheMHCregionarethosenumberedfrom260to456.Ontheyaxis,thelog10PvalueswerecalculatedbycomparisonofthegenotypefrequenciesbetweentheallopurinolSCARpatientsandtolerantgroup.,11,HLAAlleleFrequency,12,Discussion,Infact,theassociationis100%inthattheHLA-BalleleB*5801waspresentinall51patientswithallopurinol-inducedSCAR,withanoddsratioexceedingthatreportedfortheassociationbetweenHLAB27andankylosingspondylitisgenotypingtheB*5801allelemayprovideabetterguidanceofavoidingallopurinol-inducedSCARinpatientswithrenalinsufficiencythandosageadjusting.Thisstudy,togetherwiththepreviousreports,suggeststhatHLA-BallelesandorothergeneticpolymorphismsintheMHCregionmightplayamajorroleinthepathogenesisofimmune-mediatedSCAR.,13,HLA-B*5801isnecessarybutnotsufficient