心衰遺傳學(xué)與基因組學(xué)最新進展

心衰遺傳學(xué)與基因組學(xué)最新進展華中科技大學(xué)生命科學(xué)與技術(shù)學(xué)院華中科技大學(xué)人類基因組研究中心分子生物物理教育部重點實驗室教育部Cardio-X創(chuàng)新團隊王擎.報告內(nèi)容一、心衰的分子遺傳學(xué)研究進展二、現(xiàn)代遺傳學(xué)技術(shù)：全基因組關(guān)聯(lián)分析三、中國漢族人群冠心病全基因組關(guān)聯(lián)分析2.一、心衰的遺傳基礎(chǔ)心衰病因：

Atherosclerosis

Cardiomyopathy Myocarditis Congenitalmalformationsorvalvulardisease3.心肌病的臨床分類及其遺傳基礎(chǔ)

HCMDCMARVC

肥厚型心肌病

擴張型心肌病致心律失常性右室心肌病孟德爾遺傳肌小節(jié)基因AMP激活性蛋白激酶溶酶體膜相關(guān)蛋白2α-半乳糖甘酶非孟德爾遺傳遺傳型肌小節(jié)基因LaminA/CDystrophin復(fù)合體肌間盤獲得型營養(yǎng)；毒素和藥物；心肌炎；內(nèi)分泌；自體免疫；圍產(chǎn)期

限制型心肌病

左室致密化不全遺傳型橋粒蛋白(Desmosomeproteins)跨膜蛋白43肌小節(jié)基因線粒體基因ModifiedfromWatkins,H.,H.Ashrafian,andC.Redwood,InheritedCardiomyopathies.NewEnglandJournalofMedicine,2011.364(17):p.1643-1656.4.肥厚型心肌病HCM的分子遺傳學(xué)進展ModifiedfromWatkins,H.,H.Ashrafian,andC.Redwood,InheritedCardiomyopathies.NewEnglandJournalofMedicine,2011.364(17):p.1643-1656..擴張型心肌病DCM的分子遺傳學(xué)進展位點基因蛋白質(zhì)蛋白質(zhì)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.擴張型心肌病的分子遺傳學(xué)進展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遺傳學(xué)進展Watkins,H.,H.Ashrafian,andC.Redwood,InheritedCardiomyopathies.NewEnglandJournalofMedicine,2011.364(17):p.1643-1656.8.基因型和表型致病突變

表型修飾基因同一染色體座位常見或罕見順式或反式編碼變異非編碼變異（調(diào)控基因表達量）遠處染色體座位（作用于同一個基因或其下游通路）常見多態(tài)，罕見突變環(huán)境效應(yīng)HCM年齡；運動訓(xùn)練；高血壓；冠心病DCM年齡；懷孕；細胞毒性藥物；病毒感染；冠心病轉(zhuǎn)錄后修飾和表觀遺傳學(xué)效應(yīng)DNA修飾（e.g.，甲基化）組蛋白修飾（e.g.，乙?；┺D(zhuǎn)錄控制（e.g.，microRNA）轉(zhuǎn)錄后修飾ModifiedfromWatkins,H.,H.Ashrafian,andC.Redwood,InheritedCardiomyopathies.NewEnglandJournalofMedicine,2011.364(17):p.1643-1656.9.在全基因組的基礎(chǔ)上檢測與疾病相關(guān)聯(lián)的易感位點是目前最有效的檢測方法需要高通量的分型平臺，例如AFFY芯片所有的GWAS都需要2個以上獨立樣本驗證目前有很多易感位點已經(jīng)被發(fā)現(xiàn)，但是仍然只能解釋一部分遺傳變異，發(fā)現(xiàn)新的易感位點是GWAS的重要目標被驗證的易感位點將為個性化醫(yī)療奠定基礎(chǔ)二、全基因關(guān)聯(lián)分析（GWAS）.全基因組關(guān)聯(lián)分析

Genome-WideAssociationStudies(GWAS)Atestoftheassociationbetweenmarkers,calledsingle-nucleotidepolymorphisms(SNPs),acrossthegenomeanddisease,usuallyinvolving500,000ormoremarkersthatarereasonablypolymorphicandarespreadacrossthegenomefairlyevenly.Thisapproachishypothesisfree.Theaimistomapsusceptibilityeffectsthroughthedetectionofassociationsbetweengenotypefrequencyandtraitstatus.11.變異的頻率和疾病的易感性0.0010.010.1高中低外顯率極罕見罕見少見常見等位基因頻率孟德爾遺傳疾病難以鑒定的遺傳病中度外顯率的低頻變異常見疾病中極罕見GWAs鑒定出的大多數(shù)變異ModifiedfromMcCarthy,M.I.,etal.,Genome-wideassociationstudiesforcomplextraits:consensus,uncertaintyandchallenges.

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

納入標準與排除標準嚴格的質(zhì)控

多階段驗證

多種族群體多種基因分型方法地理和人種、個體差異有效統(tǒng)計分析方法

功能性SNPs

功能驗證GWAS

策略.多階段的研究方案Hirschhorn,J.N.andM.J.Daly,Genome-wideassociationstudiesforcommondiseasesandcomplextraits.

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

易感位點

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進展NO.易感位點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的亞洲人群驗證我們是第一個研究小組證實在亞洲人群中9p21.3與CAD/MI高度相關(guān)(2008ATVB)

.中國人群CAD/MIGWAS？.中國漢族人群冠心病全基因組關(guān)聯(lián)分析Genome-wideassociationidentifiesasusceptibilitylocusforcoronaryarterydiseaseintheChineseHanpopulation--Wangetal.中國漢族人群冠心病全基因組關(guān)聯(lián)分析研究方案Stage1Dis-Hubei100casesvs.100controlsStage3Rep-Shandong811casesvs.818controlsStage3Rep-Hubei1012casesvs.1732controlsStage3Rep-North845casesvs.1367controlsP<0.01inbothdiscoverycohortStage1Dis-Beijing130casesvs.130controlsStage2validationcohort572casesvs.436controls21.StageI–DiscoveryGWAS散點圖與QQplot圖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..中國漢族人群冠心病全基因組關(guān)聯(lián)分析rs6903956在多個群體中與冠心病關(guān)聯(lián)分析結(jié)果Wang,F.,etal.,Genome-wideassociationidentifiesasusceptibilitylocusforcoronaryarterydiseaseintheChineseHanpopulation.

Naturegenetics,2011.43(4):p.345-349.24.中國漢族人群冠心病全基因組關(guān)聯(lián)分析總?cè)后w分層后rs6903956與CAD的關(guān)聯(lián)分析Wang,F.,etal.,Genome-wideassociationidentifiesasusceptibilitylocusforcoronaryarterydiseaseintheChineseHanpopulation.

Naturegenetics,2011.43(4):p.345-349.25.中國漢族人群冠心病全基因組關(guān)聯(lián)分析rs6903956風(fēng)險等位基因A以顯性模式和C6orf105mRNA表達的降低相關(guān)Wang,F.,etal.,Genome-wideassociationidentifiesasusceptibilitylocusforcoronaryarterydiseaseintheChineseHanpopulation.

Naturegenetics,2011.43(4):p.345-349.26.中國漢族人群冠心病全基因組關(guān)聯(lián)分析rs6903956位于基因C6orf105基因內(nèi)