Sen-Chowdhry Srijita, Syrris Petros, Pantazis Antonios, Quarta Giovanni, McKenna William J, Chambers John C
Department of Epidemiology, Imperial College, St Mary's Campus, London, United Kingdom.
Circ Cardiovasc Genet. 2010 Aug;3(4):323-30. doi: 10.1161/CIRCGENETICS.109.935262. Epub 2010 Jun 22.
Arrhythmogenic cardiomyopathy is one of the leading causes of sudden cardiac death in the < or =35-year age group. The broad phenotypic spectrum encompasses left-dominant and biventricular subtypes, characterized by early left ventricular involvement, as well as the classic right-dominant form, better known as arrhythmogenic right ventricular cardiomyopathy. Mendelian inheritance patterns are accompanied by incomplete penetrance and variable expressivity, the latter manifesting as diversity in morphology, arrhythmic burden, and clinical outcomes.
To investigate the role of mutational heterogeneity, genetic modifiers and environmental influences in arrhythmogenic cardiomyopathy, we studied phenotype variability in 9 quantitative traits among an affected-only sample of 231 cases from 48 families. Heritability was estimated by variance component analysis as a guide to the combined influence of mutational and genetic background heterogeneity. Nested ANOVA was used to distinguish mutational and genetic modifier effects. Heritability estimates ranged from 20% to 77%, being highest for left ventricular ejection fraction and right-to-left ventricular volume ratio and lowest for the ventricular arrhythmia grade, suggesting differing genetic and environmental contributions to these traits. ANOVA models indicated a predominant mutation effect for the left ventricular lesion score, an indicator of the extent of fat and late enhancement on cardiovascular magnetic resonance. In contrast, the modifier genetic effect appeared significant for right ventricular end-diastolic volume, ejection fraction, and lesion score; left ventricular ejection fraction; ventricular volume ratio; and arrhythmic events.
Systematic investigation of modifier genes and environmental influences will be pivotal to understanding clinical diversity in arrhythmogenic cardiomyopathy, refining prognostication, and developing targeted therapies.
致心律失常性心肌病是35岁及以下年龄组心脏性猝死的主要原因之一。广泛的表型谱包括左心室为主型和双心室亚型，其特征为早期左心室受累，以及经典的右心室为主型，即更熟知的致心律失常性右心室心肌病。孟德尔遗传模式伴有不完全外显率和可变表达性，后者表现为形态、心律失常负荷和临床结局的多样性。
为了研究突变异质性、遗传修饰因子和环境影响在致心律失常性心肌病中的作用，我们在来自48个家族的231例仅受累样本中，研究了9个数量性状的表型变异性。通过方差成分分析估计遗传力，以此作为突变和遗传背景异质性联合影响的指导。采用嵌套方差分析来区分突变和遗传修饰因子的作用。遗传力估计值范围为20%至77%，左心室射血分数和右心室与左心室容积比最高，室性心律失常分级最低，提示这些性状的遗传和环境贡献不同。方差分析模型表明，左心室病变评分（心血管磁共振成像上脂肪和延迟强化程度的指标）存在主要的突变效应。相比之下，修饰基因效应在右心室舒张末期容积、射血分数和病变评分；左心室射血分数；心室容积比；以及心律失常事件方面似乎具有显著性。
对修饰基因和环境影响进行系统研究对于理解致心律失常性心肌病的临床多样性、完善预后评估以及开发靶向治疗至关重要。
