心衰遗传学与基因组学最新进展.ppt

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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,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,3,心衰病因：AtherosclerosisCardiomyopathyMyocarditisCongenital malformations or valvular disease,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

2、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 proteins)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.,肥厚型心肌

3、病HCM的分子遗传学进展,Modified from Watkins,H.,H.Ashrafian,and C.Redwood,Inherited Cardiomyopathies.New England Journal of Medicine,2011.364(17):p.1643-1656.,扩张型心肌病DCM的分子遗传学进展,6,Jefferies,J.L.and J.A.Towbin,Dilated cardiomyopathy.The Lancet,2010.375(9716):p.752-762.,22 genes,扩张型心肌病的分子遗传学进展,7,Watkins,H.,H.Ash

4、rafian,and C.Redwood,Inherited Cardiomyopathies.New England Journal of Medicine,2011.364(17):p.1643-1656.,致心律失常性右室心肌病的分子遗传学进展,8,Watkins,H.,H.Ashrafian,and C.Redwood,Inherited Cardiomyopathies.New England Journal of Medicine,2011.364(17):p.1643-1656.,基因型和表型,9,Modified from Watkins,H.,H.Ashrafian,and

5、C.Redwood,Inherited Cardiomyopathies.New England Journal of Medicine,2011.364(17):p.1643-1656.,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-Wide Association Studies(GWAS),A

6、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 genome fairly evenly.This approach is hypothesis free.The aim is to map susceptibilit

7、y effects through the detection of associations between genotype frequency and trait status.,11,变异的频率和疾病的易感性,12,0.001 0.01 0.1,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.,纳入标准与

8、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,14,Hirschhorn,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.,心衰GWAS进展,15,Villard,E.,et al.,A genome-wide association study identifie

9、s two loci associated with heart failure due to dilated cardiomyopathy.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 Gen

10、etics,2010.3(3):p.256.Morrison,A.C.,et al.,Genomic variation associated with mortality among adults of European and African ancestry with heart failure:the CHARGE consortium.Circulation:Cardiovascular Genetics,2010.,冠心病GWAS进展,16,Peden,J.F.,et al.,A genome-wide association study in Europeans and Sout

11、h 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 association identifies a susceptibility locus for

12、coronary artery disease in the Chinese Han population.Nature Genetics,2011.,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(2008 ATVB),中国人群CAD/MI GWAS？,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

13、et al,中国汉族人群冠心病全基因组关联分析研究方案,21,Stage 1 Dis-Hubei100 cases vs.100 controls,Stage 3 Rep-Shandong811 cases vs.818 controls,Stage 3 Rep-Hubei1012 cases vs.1732 controls,Stage 3 Rep-North845 cases vs.1367 controls,P0.01 in both discovery cohort,Stage 1 Dis-Beijing130 cases vs.130 controls,Stage 2 validat

14、ion cohort572 cases vs.436 controls,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.Nature genetics,2011.43(4):p.345-349.,Stage II-Validation 9 SNPs,Wang,F.,et al.,Genome-wide associ

15、ation identifies a susceptibility locus for coronary artery disease in the Chinese Han population.Nature genetics,2011.43(4):p.345-349.,中国汉族人群冠心病全基因组关联分析,24,rs6903956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 H

16、an population.Nature genetics,2011.43(4):p.345-349.,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,25,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.,中国汉族人群冠心病全基因组关联分析,rs6903956风险等位基因

17、A以显性模式和C6orf105 mRNA表达的降低相关,26,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.,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

18、，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,中国汉族人群冠心病全基因组关联分析,临床上大量的心衰患者其病程持续进展的原因就是冠心病和心梗导致的心肌的破坏或耗损，冠心病患者急性或慢性的心肌缺血加速了心衰的进展。我们发现rs6903956能增加冠心病的发病风险，这提示rs6903956可能参与冠心病的复杂病生理过程，也可能成为一个预测冠心病发病的生物标记，为未来的药物设计提供新的靶点。rs6903956与心衰之间是否存在关联

19、有待进一步的研究。,28,展望,eQTL分析和基因相互作用网路冠心病基因间的交互作用分析C6orf105增加冠心病风险的分子机制研究6p24区域Deep Sequencing,29,展望,30,全基因组关联分析结果的临床转化,31,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.,Editor-in-Chief,谢谢！,一桥飞架南北，天堑变通途。（毛泽东）,