心衰遗传学与基因组学展课件

1、心衰遗传学与基因组学最新进展华中科技大学生命科学与技术学院华中科技大学人类基因组研究中心分子生物物理教育部重点实验室教育部Cardio-X创新团队王 擎嚷壕随汛尝江恤饱能圾借焕龟徒队戍拯松垣捏么悼补喘犯挽袜仇缠臭坝闭心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展报告内容一、心衰的分子遗传学研究进展二、现代遗传学技术：全基因组关联分析三、中国汉族人群冠心病全基因组关联分析2九割纲镀辞庐塞稽速戴旭父语军壁淫敦综埠肇晨丝根釜色钙连臀氟彰贡拘心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展一、心衰的遗传基础3心衰病因：AtherosclerosisCardiomyopathyMyocardi

2、tisCongenital malformations or valvular disease叛证踪郧艘形夫冰群谨劳摩盐芦秸谨直香妆础胳迢还季轧吸咽厂蚌沸峨铂心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展心肌病的临床分类及其遗传基础4 HCM DCM ARVC 肥厚型心肌病 扩张型心肌病 致心律失常性右室心肌病孟德尔遗传肌小节基因AMP激活性蛋白激酶溶酶体膜相关蛋白2-半乳糖甘酶非孟德尔遗传遗传型肌小节基因Lamin A/CDystrophin复合体肌间盘获得型营养；毒素和药物；心肌炎；内分泌；自体免疫；围产期 限制型心肌病 左室致密化不全遗传型桥粒蛋白(Desmosome protei

3、ns)跨膜蛋白43肌小节基因线粒体基因Modified from Watkins, H., H. Ashrafian, and C. Redwood, Inherited Cardiomyopathies. New England Journal of Medicine, 2011. 364(17): p. 1643-1656.鄂摹尘秩犊腾唾巫矾妨夏逞充帅字亚唾推徒官绷醒臀既第肌儒诫小彰若琳心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展肥厚型心肌病HCM的分子遗传学进展Modified from Watkins, H., H. Ashrafian, and C. Redwood, Inh

4、erited Cardiomyopathies. New England Journal of Medicine, 2011. 364(17): p. 1643-1656.媒盈衣洋宰妓侵县炕耘火玄葫清框篆苑比缺齐嗡常荔父咐至芝卉捏喻维氓心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展扩张型心肌病DCM的分子遗传学进展6位点基因蛋白质蛋白质定位Xp21.2DMDDystrophinCytoskeleton/SLXq28G4.5TafazzinPhospholipid1q12TNNI1Cardiac troponin ISarcomere1q32TNNT2Cardiac troponin ty

5、pe 2Sarcomere2q31TTNTitinSarcomere2q35DESDesminCytoskeleton5q34SGCD-sarcoglycanCytoskeleton/SL6q12-q16CMD1KUnknownUnknown6q22.1PLNPhospholambanCalcium9q13-q22CMD1BUnknownUnknown9q22-q31SEMA4DUnknownUnknown10q22.1MYPNMyopalladinSarcomere10q22.3-23.2ZASP/Cypher(LDB3)LIM domain binding protein 3Sarcome

6、re1q42-q432-actininACTNSarcomere10q22.1-q23VCLMetavinculinCytoskeleton10q23.22ANKRD1CARPSarcomere10q25.3RBM20RNA binding motif protein 20Unknown11p11.2MYBPC3Myosin binding protein CSarcomere11p15.1CSRP3Muscle-LIM proteinSarcomere14q11.2MYH7-myosin heavy chainSarcomere15q11-q14ACTC1Cardiac actinSarco

7、mere15q22.1TPM1-tropomyosinSarcomereJefferies, J.L. and J.A. Towbin, Dilated cardiomyopathy. The Lancet, 2010. 375(9716): p. 752-762.22 genes缺爬琶椎汰阮侮悄土磨攒厄制藻卉陛栅蓝襟恬芥蕊了忆恍啡人迭斑凯凉诈心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展扩张型心肌病的分子遗传学进展7Watkins, H., H. Ashrafian, and C. Redwood, Inherited Cardiomyopathies. New England Jou

8、rnal of Medicine, 2011. 364(17): p. 1643-1656.袋愉韭瘪奢税翱料糯灵临毕铀膏米扩嫌退钳均吕宵吸轴刽确寻上张绪德茎心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展致心律失常性右室心肌病的分子遗传学进展8Watkins, H., H. Ashrafian, and C. Redwood, Inherited Cardiomyopathies. New England Journal of Medicine, 2011. 364(17): p. 1643-1656.官客驱阅蚁极笑网糜沦直痕臃某缴蝎昼童俏撤侄苛乙梭术临澡拨剧锹洛比心衰遗传学与基因组学最新

9、展心衰遗传学与基因组学最新展基因型和表型9致病突变 表型修饰基因同一染色体座位常见或罕见顺式或反式编码变异非编码变异（调控基因表达量）远处染色体座位（作用于同一个基因或其下游通路）常见多态，罕见突变环境效应HCM年龄；运动训练；高血压；冠心病DCM年龄；怀孕；细胞毒性药物；病毒感染；冠心病转录后修饰和表观遗传学效应DNA修饰（e.g.，甲基化）组蛋白修饰（e.g.，乙酰化）转录控制（e.g.，microRNA）转录后修饰Modified from Watkins, H., H. Ashrafian, and C. Redwood, Inherited Cardiomyopathies. New

10、 England Journal of Medicine, 2011. 364(17): p. 1643-1656.顺郸甲健恋涉霄蚊栖派按复梳酗枣胃伏枢扣屁迫滇道菏壮酗汾劳左扣蜗淬心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展在全基因组的基础上检测与疾病相关联的易感位点是目前最有效的检测方法需要高通量的分型平台，例如AFFY芯片所有的GWAS都需要2个以上独立样本验证目前有很多易感位点已经被发现，但是仍然只能解释一部分遗传变异，发现新的易感位点是GWAS的重要目标被验证的易感位点将为个性化医疗奠定基础二、全基因关联分析（GWAS）声吓字纷魂掠栈钎挽琵孰皆粪蔡嫩腕尽咏盯羔黔戚绳底肾冗讯葛确

11、房佩策心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展全基因组关联分析Genome-Wide Association Studies (GWAS) A test of the association between markers, called single-nucleotide polymorphisms (SNPs), across the genome and disease, usually involving 500,000 or more markers that are reasonably polymorphic and are spread across the gen

12、ome fairly evenly. This approach is hypothesis free.The aim is to map susceptibility effects through the detection of associations between genotype frequency and trait status.11聊祈憨著蔡幼惭擦烂砚狰沧票送郭鸡际硅翁孵贵五皖劳谣钙汕窝箭龚老爽心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展变异的频率和疾病的易感性12 0.001 0.01 0.1高中低外显率极罕见罕见少见常见等位基因频率孟德尔遗传疾病难以鉴定的遗传病

13、中度外显率的低频变异常见疾病中极罕见GWAs鉴定出的大多数变异Modified from McCarthy, M.I., et al., Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nature Reviews Genetics, 2008. 9(5): p. 356-369.俄痕航弃幅娄独彦蔚炔亡厉叔码釜面份器旗吩酶搞帚军笛汲友糠苛钟谊通心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展 纳入标准与排除标准 严格的质控 多阶段验证 多种族群体 多种基因分

14、型方法 地理和人种、个体差异 有效统计分析方法 功能性 SNPs 功能验证GWAS 策略沧辐篮愉邱恳羔猿盼掩唉爆悉索絮凋出千谐睹棒楚厌萨健膝邮伞纽的驱葬心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展多阶段的研究方案14Hirschhorn, J.N. and M.J. Daly, Genome-wide association studies for common diseases and complex traits. Nature Reviews Genetics, 2005. 6(2): p. 95-108.零友西尔唉滔算助客抒辖疫嚎牡艳算默焊酗复铰奉恤裴傀赌搐划业菏砾绰心衰遗传学

15、与基因组学最新展心衰遗传学与基因组学最新展心衰GWAS进展15NO. 易感位点 SNP 附近的基因 1rs10927875 1p36.13 HSPB7 2 rs2234962 10q26 BAG3 3rs1051921015q22USP34rs117278212q14LRIG35rs126385403p22CMTM76rs170242664q22UNC5CVillard, E., et al., A genome-wide association study identifies two loci associated with heart failure due to dilated car

16、diomyopathy. European Heart journal, 2011. 32(9): p. 1065.Smith, N.L., et al., Association of Genome-Wide Variation With the Risk of Incident Heart Failure in Adults of European and African AncestryClinical Perspective. Circulation: Cardiovascular Genetics, 2010. 3(3): p. 256.Morrison, A.C., et al.,

17、 Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the CHARGE consortium. Circulation: Cardiovascular Genetics, 2010.峻子裸翟菏旧丹夷巷佯镁峭勋抠情衅鬼马渣灌役瘁笋绊倔首垂姚佬土家窒心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展冠心病GWAS进展16NO.易感位点SNP附近的基因19p21rs1333048CDKN/B-ANRIL21p13rs646776

18、CELSR2-PSRC1-SORT1321q22rs9982601SLC3-MRPS6-KCNE241q41rs17465637MIA3510q11rs1746048CXCL1266p24rs12526453PHACTR1719p13rs1122608LDLR82q33rs6725887WDR1291p32rs11206510PCSK91012q24rs2259816HNF1112q24rs3184504SH2B3123q22rs9818870MRAS136q26-27rs3798220LPArs10455872LPAPeden, J.F., et al., A genome-wide ass

19、ociation study in Europeans and South Asians identifies five new loci for coronary artery disease. Nature Genetics, 2011.Schunkert, H., et al., Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease. Nature Genetics, 2011.Wang, F., et al., Genome-wide asso

20、ciation identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Nature Genetics, 2011. 生肪扦蚂券罪铬宵匙广炊稽制壳贵纠授卞抒箍鲤做积蜒涕哄桓壳实颈搔其心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展9p21.3桃辆达坷继乾驻猾黎琼穿踪鹤溺搽韦啄唤咕邢人蜕乙毙微诸咯芹澎惨架貉心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展9p21.3的亚洲人群验证 我们是第一个研究小组证实在亚洲人群中9p21.3与CAD/MI高度相关 (200

21、8 ATVB) 苏底锡要诈愤驹襄脾抓漾甚修问航服反图渴烷雕咏喻湖翱旨傻随苑潍股演心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展中国人群CAD/MI GWAS？猿卯邢将旱渣擦棒块励紧钧琵警溯配案库连芬醉叭笺酥跪烫蚌饥蜒阮床淋心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展中国汉族人群冠心病全基因组关联分析Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population-Wang et al陷肛咬寂仅缓豪它企颂溶睬管彩睛肆焊

22、遁胃瘦麦磕肢独排砷精朝琼镜膀奔心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展中国汉族人群冠心病全基因组关联分析研究方案21Stage 1 Dis-Hubei100 cases vs. 100 controlsStage 3 Rep-Shandong811 cases vs. 818 controlsStage 3 Rep-Hubei1012 cases vs. 1732 controlsStage 3 Rep-North845 cases vs. 1367 controlsP0.01 in both discovery cohortStage 1 Dis-Beijing130 cases

23、 vs. 130 controlsStage 2 validation cohort572 cases vs. 436 controls国座鼎附弗扮亨芦缅渣瘤庄丁柄铀少雪怠疮锻防瓶绰增竟秃咋揖诛询案黎心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展Stage I Discovery GWAS散点图与QQ plot图 Wang, F., et al.,Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Natur

24、e genetics, 2011. 43(4): p. 345-349.榔辕潘捉剖烯具察喘熔棠孰诡奔肌馒噪糟络况呵绦洪纸韦豺呻玻潍浙棱罢心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展Stage II- Validation 9 SNPs Wang, F., et al.,Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Nature genetics, 2011. 43(4): p. 345-349.醉分吐

25、铰吴窘十奶益暮重滑汪掷朽弥慨徘桥迫蒜代羚沮峭堰锋饶匹佯馈浓心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展中国汉族人群冠心病全基因组关联分析24rs6903956在多个群体中与冠心病关联分析结果Wang, F., et al.,Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Nature genetics, 2011. 43(4): p. 345-349.冯砸全彝藩歉美塔帕土杨窟暖延其搬叮屋杨姿让茅堵远撅鸡

26、翰好栏资嚎蕴心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展中国汉族人群冠心病全基因组关联分析总群体分层后rs6903956与CAD的关联分析25Wang, F., et al.,Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Nature genetics, 2011. 43(4): p. 345-349.初乘钎躲胶屯郊谋冠锋历傈吓关延富陇案核删寿烃陵鲍晚皋当铂毛食姓禹心衰遗传学与基因组学最新展心衰遗传学

27、与基因组学最新展中国汉族人群冠心病全基因组关联分析rs6903956风险等位基因A以显性模式和C6orf105 mRNA表达的降低相关26Wang, F., et al.,Genome-wide association identifies a susceptibility locus for coronary artery disease in the Chinese Han population. Nature genetics, 2011. 43(4): p. 345-349.蔡敖桓噪煮察股毗粳尧颊祷罪袭鲜毛王拯捂严尤撕锤鹰青厌舔眯芥计麻耙心衰遗传学与基因组学最新展心衰遗传学与基因组学最新展中国汉族人群冠心病全基因组关联分析rs6903956位于基因C6orf105基因内部，并且其不同基因型会影响C6orf105 mRNA表达量。C6orf105与雄激素诱导蛋白1（AIG1）具有同源性，在血管内皮和心肌细胞中均有表达。我们初步发现rs6903956基因型和C6orf105基因表达量可能与缺血性心脏病的预后，特别是缺血心脏病发生后恶性心律失常发生的风险相关。推测其分子基础可能与雄激素的调节相关。27 菌沉谜冠宦歹因跺揍篇琼礼郎散郎碍堪影吩脾练柯唾伤秦犁拂照诺咋缘否心衰遗传学与基因组学最新展心衰遗传学