心衰遗传学与基因组学最新进展

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.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2.一、心衰的遗传基础心衰病因：

Atherosclerosis

Cardiomyopathy Myocarditis Congenitalmalformationsorvalvulardisease3.心肌病的临床分类及其遗传基础

HCMDCMARVC

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2α-半乳糖甘酶非孟德尔遗传遗传型肌小节基因LaminA/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(Desmosomeproteins)跨膜蛋白43肌小节基因线粒体基因ModifiedfromWatkins,H.,H.Ashrafian,andC.Redwood,InheritedCardiomyopathies.NewEnglandJournalofMedicine,2011.364(17):p.1643-1656.4.肥厚型心肌病HCM的分子遗传学进展ModifiedfromWatkins,H.,H.Ashrafian,andC.Redwood,InheritedCardiomyopathies.NewEnglandJournalofMedicine,2011.364(17):p.1643-1656..扩张型心肌病DCM的分子遗传学进展位点基因蛋白质蛋白质定位Xp21.2DMDDystrophinCytoskeleton/SLXq28G4.5TafazzinPhospholipid1q12TNNI1CardiactroponinISarcomere1q32TNNT2Cardiactroponintype2Sarcomere2q31TTNTitinSarcomere2q35DESDesminCytoskeleton5q34SGCDδ-sarcoglycanCytoskeleton/SL6q12-q16CMD1KUnknownUnknown6q22.1PLNPhospholambanCalcium9q13-q22CMD1BUnknownUnknown9q22-q31SEMA4DUnknownUnknown10q22.1MYPNMyopalladinSarcomere10q22.3-23.2ZASP/Cypher(LDB3)LIMdomainbindingprotein3Sarcomere1q42-q43α2-actininACTNSarcomere10q22.1-q23VCLMetavinculinCytoskeleton10q23.22ANKRD1CARPSarcomere10q25.3RBM20RNAbindingmotifprotein20Unknown11p11.2MYBPC3MyosinbindingproteinCSarcomere11p15.1CSRP3Muscle-LIMproteinSarcomere14q11.2MYH7β-myosinheavychainSarcomere15q11-q14ACTC1CardiacactinSarcomere15q22.1TPM1α-tropomyosinSarcomereJefferies,J.L.andJ.A.Towbin,Dilatedcardiomyopathy.

TheLancet,2010.375(9716):p.752-762.22genes6.扩张型心肌病的分子遗传学进展Watkins,H.,H.Ashrafian,andC.Redwood,InheritedCardiomyopathies.NewEnglandJournalofMedicine,2011.364(17):p.1643-1656.7.致心律失常性右室心肌病的分子遗传学进展Watkins,H.,H.Ashrafian,andC.Redwood,InheritedCardiomyopathies.NewEnglandJournalofMedicine,2011.364(17):p.1643-1656.8.基因型和表型致病突变

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ModifiedfromWatkins,H.,H.Ashrafian,andC.Redwood,InheritedCardiomyopathies.NewEnglandJournalofMedicine,2011.364(17):p.1643-1656.9.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）.全基因组关联分析

Genome-WideAssociationStudies(GWAS)Atestoftheassociationbetweenmarkers,calledsingle-nucleotidepolymorphisms(SNPs),acrossthegenomeanddisease,usuallyinvolving500,000ormoremarkersthatarereasonablypolymorphicandarespreadacrossthegenomefairlyevenly.Thisapproachishypothesisfree.Theaimistomapsusceptibilityeffectsthroughthedetectionofassociationsbetweengenotypefrequencyandtraitstatus.11.变异的频率和疾病的易感性0.0010.010.1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ModifiedfromMcCarthy,M.I.,etal.,Genome-wideassociationstudiesforcomplextraits:consensus,uncertaintyandchallenges.

NatureReviewsGenetics,2008.9(5):p.356-369.12.

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.多阶段的研究方案Hirschhorn,J.N.andM.J.Daly,Genome-wideassociationstudiesforcommondiseasesandcomplextraits.

NatureReviewsGenetics,2005.6(2):p.95-108.14.心衰GWAS进展NO.

易感位点

SNP

附近的基因

1rs109278751p36.13HSPB72rs223496210q26BAG33rs1051921015q22USP34rs117278212q14LRIG35rs126385403p22CMTM76rs170242664q22UNC5CVillard,E.,etal.,Agenome-wideassociationstudyidentifiestwolociassociatedwithheartfailureduetodilatedcardiomyopathy.EuropeanHeartjournal,2011.32(9):p.1065.Smith,N.L.,etal.,AssociationofGenome-WideVariationWiththeRiskofIncidentHeartFailureinAdultsofEuropeanandAfricanAncestryClinicalPerspective.Circulation:CardiovascularGenetics,2010.3(3):p.256.Morrison,A.C.,etal.,GenomicvariationassociatedwithmortalityamongadultsofEuropeanandAfricanancestrywithheartfailure:theCHARGEconsortium.Circulation:CardiovascularGenetics,2010.15.冠心病GWAS进展NO.易感位点SNP附近的基因19p21rs1333048CDKN/B-ANRIL21p13rs646776CELSR2-PSRC1-SORT1321q22rs9982601SLC3-MRPS6-KCNE241q41rs17465637MIA3510q11rs1746048CXCL1266p24rs12526453PHACTR1719p13rs1122608LDLR82q33rs6725887WDR1291p32rs11206510PCSK91012q24rs2259816HNF1112q24rs3184504SH2B3123q22rs9818870MRAS136q26-27rs3798220LPArs10455872LPAPeden,J.F.,etal.,Agenome-wideassociationstudyinEuropeansandSouthAsiansidentifiesfivenewlociforcoronaryarterydisease.NatureGenetics,2011.Schunkert,H.,etal.,Large-scaleassociationanalysisidentifies13newsusceptibilitylociforcoronaryarterydisease.NatureGenetics,2011.Wang,F.,etal.,Genome-wideassociationidentifiesasusceptibilitylocusforcoronaryarterydiseaseintheChineseHanpopulation.NatureGenetics,2011.………16.9p21.3.9p21.3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(2008ATVB)

.中国人群CAD/MIGWAS？.中国汉族人群冠心病全基因组关联分析Genome-wideassociationidentifiesasusceptibilitylocusforcoronaryarterydiseaseintheChineseHanpopulation--Wangetal.中国汉族人群冠心病全基因组关联分析研究方案Stage1Dis-Hubei100casesvs.100controlsStage3Rep-Shandong811casesvs.818controlsStage3Rep-Hubei1012casesvs.1732controlsStage3Rep-North845casesvs.1367controlsP<0.01inbothdiscoverycohortStage1Dis-Beijing130casesvs.130controlsStage2validationcohort572casesvs.436controls21.StageI–DiscoveryGWAS散点图与QQplot图Wang,F.,etal.,Genome-wideassociationidentifiesasusceptibilitylocusforcoronaryarterydiseaseintheChineseHanpopulation.

Naturegenetics,2011.43(4):p.345-349..StageII-Validation9SNPsWang,F.,etal.,Genome-wideassociationidentifiesasusceptibilitylocusforcoronaryarterydiseaseintheChineseHanpopulation.

Naturegenetics,2011.43(4):p.345-349..中国汉族人群冠心病全基因组关联分析rs6903956在多个群体中与冠心病关联分析结果Wang,F.,etal.,Genome-wideassociationidentifiesasusceptibilitylocusforcoronaryarterydiseaseintheChineseHanpopulation.

Naturegenetics,2011.43(4):p.345-349.24.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Wang,F.,etal.,Genome-wideassociationidentifiesasusceptibilitylocusforcoronaryarterydiseaseintheChineseHanpopulation.

Naturegenetics,2011.43(4):p.345-349.25.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C6orf105mRNA表达的降低相关Wang,F.,etal.,Genome-wideassociationidentifiesasusceptibilitylocusforcoronaryarterydiseaseintheChineseHanpopulation.

Naturegenetics,2011.43(4):p.345-349.26.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