Association of human connexin40 gene polymorphisms with atrial vulnerability as a risk factor for idiopathic atrial fibrillation
Association of human connexin40 gene polymorphisms with atrial vulnerability as a risk factor for idiopathic atrial fibrillation
复制标题
DOI：
10.1161/01.res.0000141134.64811.0a
复制
发表时间：
2004-08-20
影响因子：
20.1
通讯作者：
Hauer, RNW
中科院分区：
文献类型：
--
作者：
Firouzi, M;Ramanna, H;Hauer, RNW
心脏间隙连接的分布、密度和性质的改变被认为是潜在的致心律失常因素，间隙连接介导心肌细胞的电耦合。我们最近报道了心房缝隙连接蛋白连接蛋白40（Cx40）基因调控区的2个连锁多态性，位于核苷酸-44（G->A）和+71（A->G），与家族性心房静止相关。本研究探讨这些Cx40多态性是否与体内心房易损性增加和心律失常易感性相关。在30例无结构性心脏病的受试者中，其中14例记录了散发性阵发性房颤（AF），16例无AF病史，使用越来越积极的心房刺激方案评估AF的诱导。计算了耐火度的空间离散系数（CD）。CD定义为右心房部位记录的12个局部平均间歇间期的SD，表示为总体平均间歇间期的百分比。Cx40基因型通过直接DNA测序确定。受试者根据正常或增加的CD进行分层，临界值为3.0，因为CD>3.0与增强的心房易损性密切相关。与CD小于或等于3.0的受试者相比，在离散度增加的受试者中（n=13），次要Cx40等位基因（-44 A）和-44 AA基因型的患病率显著较高（n=17; P=0.00046和P=0.025;比值比为6.7和7.4）和对照人群（n=253; P=0.00002和P=3.90x10（-7））。与-44GG基因型相比，-44AA基因型携带者具有显著更高的CD值（6.37+/-1.21vs2.38 +/-0.39，P =0.018），而杂合子具有中间值（3.95+/-1.38，NS）。所有CD增加的受试者均有特发性AF病史，而CD正常的受试者仅为1例。有房颤史的受试者中-44 A等位基因和-44 AA基因型的频率显著高于无房颤史的受试者（P=0.0019和P=0.031;比值比5.3和6.2）。这项研究提供了强有力的证据，证明Cx40多态性与心房脆弱性增强和房颤风险增加有关。本文全文可在http：//circres在线获取。ahajournals.org.
Alterations in distribution, density, and properties of cardiac gap junctions, which mediate electrical coupling of cardiomyocytes, are considered potentially arrhythmogenic. We recently reported 2 linked polymorphisms within regulatory regions of the gene for the atrial gap junction protein connexin40 (Cx40) at nucleotides -44 (G-->A) and +71 (A-->G), which were associated with familial atrial standstill. The present study examined whether these Cx40 polymorphisms were associated with increased atrial vulnerability in vivo and arrhythmia susceptibility. In 30 subjects without structural heart disease, of whom 14 had documented sporadic paroxysmal atrial fibrillation (AF) and 16 had no AF history, inducibility of AF was assessed using an increasingly aggressive atrial stimulation protocol. Coefficient of spatial dispersion of refractoriness (CD) was calculated. CD was defined as the SD of 12 local mean fibrillatory intervals recorded at right atrial sites, expressed as a percentage of the overall mean fibrillatory interval. Cx40 genotypes were determined by direct DNA sequencing. Subjects were stratified according to normal or increased CD with a cutoff value of 3.0, because CD>3.0 was previously shown to be strongly associated with enhanced atrial vulnerability. The prevalence of the minor Cx40 allele (-44A) and -44AA genotype was significantly higher in subjects with increased dispersion (n=13) compared with those with CDless than or equal to3.0 (n=17; P=0.00046 and P=0.025; odds ratios of 6.7 and 7.4) and a control population (n=253; P=0.00002 and P=3.90x10(-7)). Carriers of -44AA genotype had a significantly higher CD compared with those with -44GG genotype (6.37+/-1.21 versus 2.38+/-0.39, P=0.018), whereas heterozygotes had intermediate values (3.95+/-1.38, NS). All subjects with increased CD had a history of idiopathic AF compared with only 1 subject with normal CD. The -44A allele and -44AA genotype were significantly more frequent in subjects with prior AF than in those without (P=0.0019 and P=0.031; odds ratios 5.3 and 6.2). This study provides strong evidence linking Cx40 polymorphisms to enhanced atrial vulnerability and increased risk of AF. The full text of this article is available online at http://circres. ahajournals.org.