生物谷:来自冰岛雷克雅未克市deCODE Genetics,Landspitali大学医院的科学家与香港中文大学威尔亲王医院(Prince of Wales Hospital)等处的研究人员合作进行全基因组扫描分析,发现了心房颤动(Atrial fibrillation,AF)与4号染色体两个序列突变之间的相关性,为进一步加深对AF患病遗传与分子机制的了解提供了重要全面的资料。这一研究成果公布在Nature网络版上。
心房颤动(Atrial fibrillation,AF)简称房颤,是一种十分常见的心律失常。据统计60岁以下的患病率为1%,并随年龄而增加。这种人类中最常见的持续性心律失常(cardiac arrhythmia)的发作呈阵发性或持续性。房颤时,心房内激动传导的方向不一致,频率快而且不规整,这使心房丧失了有效的收缩功能。房颤时心房的激动频率高达300~600次/分,虽然由于房室结的保护作用可使这些激动不能全部到达心室,但是心室率(心率)仍然可达到100~160次/分,不仅比正常窦性心律快得多,而且节律绝对不整齐。
近期的研究证实了AF的遗传来源,并且发现了钾离子通道(potassium-channel)基因与AF家族的联系,但这只是引发AF的一小部分遗传因素。
在这篇文章中,研究人员进行了一次全基因组扫描分析,并进一步在三个欧洲血统种群,和一个中国香港种群中进行遗传复制研究,结果发现4号染色体(4q25)上的两个序列突变(sequence variants)与AF有极大的相关性。其中欧洲血统35%的个体至少有一个突变,每增加一个copy患上AF的几率就会增加1.72和1.39。而在中国人群中这一相关性更加明显:75%的个体携带,AF患病风险增加1.42%,同时患有典型性心房扑动(atrial flutter)的个体中也观察到了更大的相关性。
这两个突变都与PITX2毗邻,后者已知在心脏左右不对称中扮演了一个关键的角色。这一研究对于进一步加深对AF患病遗传与分子机制的了解提供了重要全面的资料,并且为AF类相关疾病的基因治疗提出了新的靶标。
原始出处:
Nature advance online publication 1 July 2007 | doi:10.1038/nature06007; Received 6 April 2007; Accepted 11 June 2007; Published online 1 July 2007
Variants conferring risk of atrial fibrillation on chromosome 4q25
Daniel F. Gudbjartsson1, David O. Arnar2, Anna Helgadottir1, Solveig Gretarsdottir1, Hilma Holm2, Asgeir Sigurdsson1, Adalbjorg Jonasdottir1, Adam Baker1, Gudmar Thorleifsson1, Kristleifur Kristjansson1, Arnar Palsson1, Thorarinn Blondal1, Patrick Sulem1, Valgerdur M. Backman1, Gudmundur A. Hardarson1, Ebba Palsdottir1, Agnar Helgason1, Runa Sigurjonsdottir2, Jon T. Sverrisson3, Konstantinos Kostulas4, Maggie C. Y. Ng5, Larry Baum5, Wing Yee So5, Ka Sing Wong5, Juliana C. N. Chan5, Karen L. Furie6, Steven M. Greenberg6, Michelle Sale6, Peter Kelly6, Calum A. MacRae7, Eric E. Smith6, Jonathan Rosand6, Jan Hillert4, Ronald C. W. Ma5, Patrick T. Ellinor7, Gudmundur Thorgeirsson2, Jeffrey R. Gulcher1, Augustine Kong1, Unnur Thorsteinsdottir1 & Kari Stefansson1
deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland
Division of Cardiology, Department of Medicine, Landspitali University Hospital, 101 Reykjavik, Iceland
Department of Medicine, Akureyri Regional Hospital, 600 Akureyri, Iceland
Department of Neurology, Karolinska Institutet at Karolinska University Hospital, Huddinge S-141 86, Sweden
Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Shatin, Hong Kong
Department of Neurology,
Cardiology Division and Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA
Correspondence to: Daniel F. Gudbjartsson1Kari Stefansson1 Correspondence and requests for materials should be addressed to D.F.G. (Email: daniel.gudbjartsson@decode.is) or K.S. (Email: kstefans@decode.is).
Abstract
Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in humans and is characterized by chaotic electrical activity of the atria1. It affects one in ten individuals over the age of 80 years, causes significant morbidity and is an independent predictor of mortality2. Recent studies have provided evidence of a genetic contribution to AF3, 4, 5. Mutations in potassium-channel genes have been associated with familial AF6, 7, 8, 9, 10 but account for only a small fraction of all cases of AF11, 12. We have performed a genome-wide association scan, followed by replication studies in three populations of European descent and a Chinese population from Hong Kong and find a strong association between two sequence variants on chromosome 4q25 and AF. Here we show that about 35% of individuals of European descent have at least one of the variants and that the risk of AF increases by 1.72 and 1.39 per copy. The association with the stronger variant is replicated in the Chinese population, where it is carried by 75% of individuals and the risk of AF is increased by 1.42 per copy. A stronger association was observed in individuals with typical atrial flutter. Both variants are adjacent to PITX2, which is known to have a critical function in left–right asymmetry of the heart13, 14, 15.
附:
威尔斯亲王医院是一所分区急症医院,亦是香港中文大学教学医院,于1984年启用,座落沙田小沥源,是一间大型的急症全科医院,亦是香港中文大学的教学医院,肩负培训医疗人材及领导医学研究的重要使命。全院约有病床1,200张,员工约3,500人,是新界东部的区域医院,服务范围广泛,为沙田、大埔及北区的居民提供服务。
该院除了提供廿四小时急症服务外,并附设李嘉诚专科诊所,提供全面的专科门诊服务。另外,包玉刚爵士癌症中心及包黄秀英女士儿童癌症中心,于1994年11月正式启用,致力为病人提供最先进的癌症治疗服务,以及集中资源发展癌症的研究及教育工作。
而赛马会创伤及急症中心于2002年3月正式启用,为受创伤及情况危急的病人提供综合的紧急医疗服务。
威尔斯亲王医院是香港中文大学的教学医院,肩负培训医疗人才及领导医学研究的使命。本院自创立至今已联同香港中文大学培训了超过 2,306位医生,在学术交流及医学研究方面更有卓越成就。双方透过互相合作及协调,达至本院的宗旨:在病人全面护理,医护人员训练及医学研究方面,提供最高质素的服务。
此外,透过双方的合作,可以互相分享经验、提高专业水平,更可引进新科技、进行大型科研和进一步提升服务水平。