中国肥厚性心肌病的修饰基因ppt课件

1、Hypertrophic Cardiomyopathy in China-modifier gene Hui Rutai MD FuWai Hospital Chinese Academy of Medical Sciences负担负担Big burdenAm J Med 2004,116Am J Med 2004,116：63-6563-651 million patients,1 million patients,4 millions geneticlly affected4 millions geneticlly affected Gene mutations were identifi

2、ed in 27 pedigrees among 51 FHCM (53%) and 12 in 49 sporadic HCM (25%).Genes FrequencyCaucasian*Chinese Mutation prevalence in Chinese and Caucasian -MHC3050%24%cMyBPC1520%11%cTnT1520%1%cTnI5%3% -Tm5%EMLC5%RMLC5%Cardiac -actin5%K-voltage-gated channelRareTitin5%PKA- ? -MHCRaremtDNARareGene diagnosis

3、 & prognosis1.Preclinical diagnosis1.Preclinical diagnosis2.Selective birth control2.Selective birth control3. Predictive prognosis3. Predictive prognosis携带携带MYH7和和MYBPC3基因突变患者的基因突变患者的6年随访结年随访结果果王曙霞，惠汝太等王曙霞，惠汝太等. Clin Cardiol. 2021; 31(3):114 *The major intervention included surgical septal myec

4、tomy, Alcohol septal ablation and DDD pacemaker CharacteristicsDuration of follow-up (yrs)HCM-causing geneP value(MYH7 vs MYBPC3)nsMYH7(n=52)5.91.8MYBPC3(n=18)5.71.7Major intervention *, n800.001Death related to HCM, n, (%/1000 person-year, 95% CI)10(32.1, 12.5-51.5)4(35.2, 13.9-68.9) nsSudden death

5、700.001stroke01-Heart failure33-Age at death (yrs)45.114.073.57.50.03NYHA class III IV61nsGeneNo. of carriers(n=44)No. of affected carriers (n=9)Mean affected age(yrs)Age at final follow-up(yrs)MYH7279 (33.3%)37.35.6-MYBPC3170 (0%)-46.89.7MYH7头部、杆部及头部、杆部及MYBPC3基因突变患者的基因突变患者的Kaplan-Meier生存曲线生存曲线王曙霞，惠

6、汝太等，王曙霞，惠汝太等，Clin Cardiol. 2021;31:11401020304050607080900102030405060708090100global region of MYH7MYBPC3rod region of MYH7age (years)Percent survival一样突变：临床表现、治疗反响的异质性：一样突变：临床表现、治疗反响的异质性：基因突变类型，修饰基因，环境要素；基因突变类型，修饰基因，环境要素；干涉靶点：改动修饰基因表达干涉靶点：改动修饰基因表达1)王曙霞王曙霞惠汝太等惠汝太等: PPAR- Coactivator-1alpha : Clin C

7、hem & Lab Med. 2007, 45:962. 2)王曙霞王曙霞惠汝太等惠汝太等: ACE2: Chin Med J 2021;121(1):27 3) 王萍，惠汝太等：王萍，惠汝太等：MYBPC3. BBRC. 2005,8;329(2):796-9. 高血压是高血压是LVH的最主要缘由，血压占左心的最主要缘由，血压占左心室分量变异的室分量变异的25 遗传要素占独立于血压之外的左心室分量遗传要素占独立于血压之外的左心室分量变异的变异的60 线粒体氧化长链脂肪酸产生线粒体氧化长链脂肪酸产生ATP是成人心肌能是成人心肌能量的主要来源。成体心脏大约量的主要来源。成体心脏大约609

8、0的的ATP来源于脂肪酸氧化来源于脂肪酸氧化FAO)。 在不同的发育时期和生理在不同的发育时期和生理/病理生理形状下，心病理生理形状下，心脏的能量代谢选择有所不同。脏的能量代谢选择有所不同。 能量调理的转变主要是经过参与脂肪酸利用的能量调理的转变主要是经过参与脂肪酸利用的基因表达来实现的。而基因表达来实现的。而 peroxisome proliferator-activated receptors(PPARs)，及，及PGC1(proliferators-activated receptor- coactivator-1 (PGC-1) gene )是心脏脂肪酸是心脏脂肪酸代谢的关键的调理因子

9、代谢的关键的调理因子 。PGC1- Gly482Ser (rs8192678) &HCM、LVH as well as HT入选数入选数基因型基因型, n (%)Ser482Ser482SerSer482GlyGly482Gly频频率率校正前校正前 OR(95% CI)校正校正 OR(95% CI)对照组对照组, 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)31

10、9(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- Thr394Thrrs2970847and HCM 、LVHas well as HT人群人群基因型基因型, n (%)CC 基因型基因型TTCTCC频率频率Crude OR(95% CI)Adjusted OR(95% CI)对照组对照组, n=89468(7.6)382(42.7)444(49.7)49.711HCM, n=27015(5.6)95(35.2)16

11、0(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-PPAR-基因的基因的rs9615784rs9615784、rs4253654 rs4253654 rs4253778rs4253778多态位点；以及多态位点；以及PPAR-PPAR-基因的基因的Pro12Ala Pro1

12、2Ala 、rs7649970rs7649970和和rs4245rs4245多态位点多态位点均与均与HCMHCM、LVHLVH和和HTHT无关联，用无关联，用logisticlogistic回回归模型校正了传统的危险要素后，仍无相归模型校正了传统的危险要素后，仍无相关性。关性。结结 论论PGC-1PGC-1基因基因Gly482SerGly482Ser变异和变异和Thr394ThrThr394Thr多态与多态与HCMHCM发病风险添加相关联；发病风险添加相关联；PPAR-PPAR-和和PPAR-PPAR-基因及基因及PGC-1PGC-1基因的基因的多态性均不添加多态性均不添加LVHLVH发生的风

13、险；发生的风险；PGC-1PGC-1基因能够为基因能够为HCMHCM的修饰基因。的修饰基因。Not associated with hypertensionNot associated with hypertensionACE2 in RASACE2 in RAS A total of 261 consecutive HCM patients and 609 healthy controls were enrolled into this study. We have genotyped 7 SNPs of ACE2, of which 2 SNPs (rs4646156, rs233575)

14、 were proved to be not polymorphic in Chinese population. The minor alleles of other 3 SNPs (rs4646140, rs879922 and rs4240157) were too low (0.01) in Chinese population. At last, 2 SNPs (rs2106809 and rs6632677) were successfully genotyped. ACE2 polymorphismThe odd ratios of rs2106809 and rs6632677

15、 for HCM haplotype in menSNP genotype OR*(95% CI) P valueRs2106809 T 1.34(1.011.77) 0.04Rs6632677 C 1.11(1.031.21) 0.002Haplotype TC 1.59(1.211.87) 0.001*Adjusted for age, body mass index, systolic blood pressure, diastolic blood pressure.The polymorphisms of ACE2 are associated with the magnitude of hypertrophy of HCM in men populationrs2106809menwomenCTp valuesCCCTTTp valuesMaximal wall thickness(mm)17.95.520.06.30.0319.86.018.25.019.96.10.64PW(mm)10.42.611.13.80.1910.54.110.92.810.82.70.89LVIDD(mm)46.37.044.06.60.0641.86.845.38.241.95.10.19SBP123.217.0123.1210.9711