中國(guó)肥厚性心肌病的修飾基因

HypertrophicCardiomyopathyin

China-modifiergene

HuiRutaiMDBeijingFuWaiHospitalChineseAcademyofMedicalSciences負(fù)擔(dān)BigburdenAmJMed2004,116：63-651millionpatients,4millionsgeneticllyaffected

Genemutationswereidentifiedin27pedigreesamong51FHCM(53%)and12in49sporadicHCM(25%).GenesFrequencyCaucasian*ChineseMutationprevalenceinChineseandCaucasian

-MHC~30~50%24%cMyBPC~15~20%11%cTnT~15~20%1%cTnI<5%3%-Tm<5%EMLC<5%RMLC<5%Cardiac-actin<5%K-voltage-gatedchannelRareTitin<5%PKA-?-MHCRaremtDNARareGenediagnosis&prognosis1.Preclinicaldiagnosis2.Selectivebirthcontrol3.Predictiveprognosis

攜帶MYH7和MYBPC3基因突變患者的6年隨訪結(jié)果

王曙霞，惠汝太等.ClinCardiol.2021;31(3):114*Themajorinterventionincludedsurgicalseptalmyectomy,AlcoholseptalablationandDDDpacemaker

CharacteristicsDurationoffollow-up(yrs)HCM-causinggenePvalue(MYH7vsMYBPC3)nsMYH7(n=52)5.9±1.8MYBPC3(n=18)5.7±1.7Majorintervention*,n80<0.001DeathrelatedtoHCM,n,(%/1000person-year,95%CI)10(32.1,12.5-51.5)4(35.2,13.9-68.9)nsSuddendeath70<0.001stroke01--Heartfailure33--Ageatdeath(yrs)45.1±14.073.5±7.50.03NYHAclassIII~IV61ns攜帶MYH7和MYBPC3基因突變而無臨床病癥者6年隨訪結(jié)果王曙霞，惠汝太等.ClinCardiol.2021;31(3):114.GeneNo.ofcarriers(n=44)No.ofaffectedcarriers(n=9)Meanaffectedage(yrs)Ageatfinalfollow-up(yrs)MYH7279(33.3%)37.3±5.6--MYBPC3170(0%)--46.8±9.7MYH7頭部、桿部及MYBPC3基因突變患者的Kaplan-Meier生存曲線

王曙霞，惠汝太等，ClinCardiol.2021;31:114ModifierGenes相同突變：臨床表現(xiàn)、治療反響的異質(zhì)性：基因突變類型，修飾基因，環(huán)境因素；干預(yù)靶點(diǎn)：改變修飾基因表達(dá)1)王曙霞……惠汝太等:PPAR-γCoactivator-1alpha:ClinChem&LabMed.2007,45:962.2)王曙霞……惠汝太等:ACE2:ChinMedJ

2021;121(1):273)王萍，惠汝太等：MYBPC3.BBRC.2005,8;329(2):796-9.高血壓是LVH的最主要原因，血壓占左心室重量變異的25％遺傳因素占獨(dú)立于血壓之外的左心室重量變異的60％

線粒體氧化長(zhǎng)鏈脂肪酸產(chǎn)生ATP是成人心肌能量的主要來源。成體心臟大約60－90％的ATP來源于脂肪酸氧化〔FAO)。在不同的發(fā)育時(shí)期和生理/病理生理狀態(tài)下，心臟的能量代謝選擇有所不同。能量調(diào)節(jié)的轉(zhuǎn)變主要是通過參與脂肪酸利用的基因表達(dá)來實(shí)現(xiàn)的。而peroxisomeproliferator-activatedreceptors(PPARs)，及PGC1α(proliferators-activatedreceptor-γcoactivator-1α(PGC-1α)gene)是心臟脂肪酸代謝的關(guān)鍵的調(diào)節(jié)因子。PGC1-Gly482Ser(rs8192678)&HCM、LVHaswellasHT入選數(shù)基因型,n(%)Ser482Ser482SerSer482GlyGly482Gly頻率校正前OR(95%CI)校正OR(95%CI)對(duì)照組,n=892170(19.1)441(49.4)281(31.5)68.511HCM,n=27059(21.9)149(55.2)62(23)77.11.54(1.12-2.12)**1.52(1.11-2.11)**LVH,n=1180264(22.4)597(50.6)319(27)731.24(1.03-1.50)*1.15(0.77-1.71)HT,n=1305304(23.3)630(48.3)371(28.4)71.61.16(0.96-1.39)1.07(0.64-1.79)PGC1-Thr394Thr〔rs2970847〕andHCM、LVHaswellasHT人群基因型,n(%)CC基因型TTCTCC頻率CrudeOR(95%CI)AdjustedOR(95%CI)對(duì)照組,n=89468(7.6)382(42.7)444(49.7)49.711HCM,n=27015(5.6)95(35.2)160(59.3)59.31.46(1.10-1.94)**1.49(1.15-1.98)**LVH,n=118080(6.8)418(35.4)682(57.8)57.81.39(1.17-1.65)**1.21(0.84-1.76)HT,n=130689(6.8)514(39.4)703(53.8)53.81.18(1.00-1.40)1.31(0.81-2.12)PPAR-α基因的rs9615784、rs4253654rs4253778多態(tài)位點(diǎn)；以及PPAR-γ基因的Pro12Ala、rs7649970和rs4135245多態(tài)位點(diǎn)均與HCM、LVH和HT無關(guān)聯(lián)，用logistic回歸模型校正了傳統(tǒng)的危險(xiǎn)因素后，仍無相關(guān)性。結(jié)論P(yáng)GC-1α基因Gly482Ser變異和Thr394Thr多態(tài)與HCM發(fā)病風(fēng)險(xiǎn)增加相關(guān)聯(lián)；PPAR-α和PPAR-γ基因及PGC-1α基因的多態(tài)性均不增加LVH發(fā)生的風(fēng)險(xiǎn)；PGC-1α基因可能為HCM的修飾基因。NotassociatedwithhypertensionACE2inRASAtotalof261consecutiveHCMpatientsand609healthycontrolswereenrolledintothisstudy.Wehavegenotyped7SNPsofACE2,ofwhich2SNPs(rs4646156,rs233575)wereprovedtobenotpolymorphicinChinesepopulation.Theminorallelesofother3SNPs(rs4646140,rs879922andrs4240157)weretoolow(<0.01)inChinesepopulation.Atlast,2SNPs(rs2106809andrs6632677)weresuccessfullygenotyped.ACE2polymorphismTheoddratiosofrs2106809andrs6632677forHCMhaplotypeinmenSNPgenotypeOR*(95%CI)PvalueRs2106809T1.34(1.01?1.77)0.04Rs6632677C1.11(1.03?1.21)0.002HaplotypeTC1.59(1.21?1.87)<0.001*Adjustedforage,bodymassindex,systolicbloodpressure,diastolicbloodpressure.ThepolymorphismsofACE2areassociatedwiththemagnitudeofhypertrophyofHCMinmenpopulationrs2106809menwomenCTpvaluesCCCTTTpvaluesMaximalwallthickness(mm)17.9±5.520.0±6.30.0319.8±6.018.2±5.019.9±6.10.64PW(mm)10.4±2.611.1±3.80.1910.5±4.110.9±2.810.8±2.70.89LVIDD(mm)46.3±7.044.0±6.60.0641.8±6.845.3±8.241.9±5.10.19SBP123.2±17.0123.1±210.97