房颤与猝死致病新基因nup155的发现_王擎

王 擎 , Ph.D., M.B.A.华中科技大学生命与技术学院 院 长分子生物物理教育部重点实验室 主 任Director and Professor of Molecular Medicine Center for Cardiovascular Genetics, Cleveland Clinic and Case Western Reserve University 房颤与猝死致病新基因 NUP155的发现遗传信息的核质转运在心脏电信号传导中的关键作用主要内容NUP155突变导致房颤机制二房颤简介三 细胞核孔复合体 ,胞质转运简介一核孔复合体蛋白 NUP155突变导致房颤与猝死四房颤简介一房颤 (Atrial Fibrillation, AF) 房颤是临床最常见的持续性心律失常 据统计，人群患病率接近 1%，在美国影响300万人 我国患者高达 1300万 危害极大，大大提高患者死亡率和脑中风的发生率。正常 ECGQTRRP房颤 ECG无 规则 RR间 期 ,P波消失 ,f波出 现f waveMonogenic AF（单基因遗传）Autosomal dominant Autosomal recessive Complex AF（复杂性 多基因 ）PolygenicGene-gene interactionGene-environment interactionGenetics of AFGenetic Loci and Genes for AFAF Locus Location Gene1 (AF) 10q22 ?2 (AF) 6q14-16 ?3 (AF+LQTS) 4q25-27 ANK24 (AF+LQTS) (AF+SQTS) 11p15.1 KCNQ15 (AF) 21q22 KCNE26 (AF)7 (AF+SQTS)12p137q35KCNA5KCNH28 (AF)9 (AF)17q23-2410q22-24KCNJ2?10 (AF) 5p1511 (AF+DCM) (AF) 3p21 SCN5A12 (AF) 11q24 Kir3.413 (AF) ANF14 (AF) SCN1B15 (AF) SCN2BadAF常显Genetic Loci and Genes for AFAF Locus Location GenearAF1 5p13 arAF1AF Locus Location GeneSomatic AF 1q21 CX40 (CONNEXIN 40)arAF（常隐）Somatic AF（体细胞遗传） 1. Framingham Heart Study (2,234 offsprings): Risk ratio (RR) = 1.85 for offsprings if at least one parent has AF OR = 3.23 with study participants younger than 75 years or to 3.17 when offsprings with overt heart disease were excluded. 2. Icelandic Study (5,269 AF patients and 10,000 controls ): RR = 1.77 for the first-degree relatives = 1.36 for the second-degree relative = 4.67 for first-degree relatives under the age of 60 years 3. MGH Study (110 patients with lone AF ) RR = 8.1 for sons, 9.5 for daughters, 70 for brothers, 34 for sisters, 4 for mothers, and 2 for fathers17 Genetic Component of Complex AFReviewed in Wang QK (2007) Genetic considerations. In Atrial Fibrillation: From Bench to Bedside, eds. Natale A et al.Jurgen Del-Favero, VIB, Belgium全基因组关联分析Association of SNPs on Chromosome 16q22 with AF Variants in ZFHX3 are associated with atrial fibrillation in individuals of European ancestry. Benjamin EJ et al Nat Genet. 2009 Aug;41(8):879-81. Epub 2009 Jul 13. National Heart, Lung, and Blood Institutes Framingham Heart Study ; replicated this association in an independent cohort from the German AF Network A sequence variant in ZFHX3 on 16q22 associates with atrial fibrillation and ischemic stroke. Gudbjartsson DF.Stefansson K. Nat Genet. 2009 Aug;41(8):876-8. Epub 2009 Jul 13. Iceland, replicated in Norway and the United States populations Not associated with AF in a Chinese population全基因组关联分析 Highly Significant Association of a Chromosome 4q25 SNP with Atrial Fibrillation in a Chinese Population Brief Title: Association of a 4q25 SNP with AF in a Chinese Population Lisong Shi, PhD,* Cong Li, BS,* Chuchu Wang, BS,* Yunlong Xia, MD, Gang Wu, MD,| Fan Wang, BS,* Yanzong Yang, MD, Bo Yang, MD,| Chengqi Xu, BS,* Mugen Liu, PhD,* Jingyu Liu, PhD,* Xiang Ren, PhD,* Qiutang Zeng, MD, Xin Tu, MD, PhD,* Qing Kenneth Wang*, PhD, M.B.A. Human Genetics 2009, In press 2009 Aug 26. Epub ahead of print Allelic association of rs2200733 T allele Chromosome 4q25 with AF in a Chinese PopulationCharacteristic(case/control)rs2200733(case/control) OR (95%CI) p-valueTotal AF(385/851) 0.646 (0.503) 1.81 (1.21-3.20) 3.710-11Sex male(237/561) 0.654 (0.508) 1.83 (1.47-2.29) 8.510-8female(146/290) 0.634 (0.493) 1.77 (1.33-2.37) 8.610-5Age =60 (188/851) 0.621 (0.503) 1.62 (1.17-2.23) 0.003AF type lone AF(125/851) 0.708 (0.503) 2.40 (1.80-3.20) 1.310-9other AF(258/851) 0.616 (0.503) 1.59 (1.30-1.94) 6.210-7AF+CAD (68/96) 0.610 (0.531) 1.38 (0.88-2.16) 0.155AF+HT (148/482) 0.622 (0.505) 1.61 (1.23-2.10) 0.00045Genotypic association of rs2200733 T allele Chromosome 4q25 with AF in a Chinese PopulationModel Observed p Adjusted p Empirical pGenotype 1.710-11 1.010-9 1.010-6Dominant 4.110-12 1.710-11 1.010-6Recessive 0.00042 0.0016 0.00053Additive 9.310-11 1.010-9 1.010-6Conclusions 1. Highly significant association between SNP rs2200733 on chromosome 4q25 and AF in the mainland Chinese Han population 2. More significant associaiton with a higher OR in the lone AF group than in the other AF group 3. Expand the association between rs2200733 and AF from a Hong Kong population to a more representative Chinese Han population 4. These results indicate that there exists an important AF gene on chromosome 4q25, and future studies should focus on identification of the specific AF gene at the locus 新 房颤基因的发现核孔复合体蛋白 NUP155突变导致房颤与猝死 二Genetic Linkage of Autosomal Recessive AF to Chromosome 5p13 in the Expanded arAF1 Family and Fine Mapping 隐性遗传房颤基因定位于染色体 5p13Autosomal Recessive AF (arAF1)Oberti et al. Circulation, 2004Zhang et al, Cell, 2008Genetic Linkage of Autosomal Recessive AF to Chromosome 5p13 in the Expanded arAF1 Family and Fine Mapping隐性遗传房颤基因定位于染色体 5p13 候选基因（共 at arAF1)NUP155 G A(R391H) Causes AF发现 NUP155基因 R391H突变Mutation R391H in NUP155 Co-Segregates with AF in the arAF1 Family NUP155基因 R391H突变导致房颤Mutation R391H in NUP155 Causes AFNUP155基因 R391H突变发生在非常保守氨基酸位点R391H突 变 在 1700对 照 样 本中不存在三 细胞核孔复合体 ,胞质转运简介核膜的功能是阻止大分子物质在细胞核与细胞质间的自由转移Nuclear Pore Complexes (NPC) (核孔复合体 )调节细胞核与细胞质间大分子物质转移通过核孔复合体 ,蛋白质和 RNAs有选择性转移 ,固定细胞核 ,细胞质中各自成份 ,调控基因表达C. L. Stewart et al., Science 318, 1408 -1412 (2007) Overview of nuclear envelope organization核膜构造The Nuclear Pore Complex核孔复合体 3,000-5,000/细胞 直径 120 nm 由 50 to 100 种蛋白质组成 (nucleoporins or NUPs) in vertebrates 50,000-125,000 kDa in vertebrates, 30 times the size of a ribosome经过 核孔复合体的大分子转运mRNArRNAsnRNAtRNATranscription factorsRNA polymeraseSplicing factorsDNA polymeraseReplication protein