Supplementary Material for: Association between hypertrophic cardiomyopathy and variations in sarcomere gene and calcium channel gene in adults

Introduction: Calcium channel gene variations have been reported to be associated with hypertrophic cardiomyopathy (HCM) in family, but the relationship between calcium channel gene variations and HCM remains undefined in population.
Methods: A total of 719 HCM unrelated patients were initially enrolled. Finally, 371 patients were identified based on inclusion and exclusion criteria, including 145 patients with gene negative, 28 patients with a single rare calcium channel gene variation (calcium gene variation), 162 patients with a single pathogenic/likely pathogenic sarcomere gene variation (sarcomere gene variation) and 36 patients with a single pathogenic/likely pathogenic sarcomere gene variation and a single rare calcium channel gene variation (double gene variations). Then the demographic, electrocardiographic, echocardiographic and follow-up data were collected.
Results: Patients with double gene variations were at an earlier age and had more percent of family history of HCM, and had thicker walls, higher left ventricular outflow tract pressure gradient, more pathological Q waves, and more bundle branch block as compared with those with single sarcomere gene variation. During the follow-up period, patients with double gene variations had more primary endpoints than other three groups (p=0.0013). Multivariate analysis showed that double gene variations was the independent predictor of for primary endpoint events in patients (HR 4.82, 95% CI 1.77 to 13.2; p=0.002).
Conclusion: We found that patients with double gene variations had more severe HCM phenotype and prognosis. The pathogenesis effects of sarcomere gene variation and calcium channel gene variation may be cumulative in HCM populations.

研究背景：已有研究报道，家族性肥厚型心肌病（hypertrophic cardiomyopathy, HCM）的发生与钙通道基因（calcium channel gene）变异存在相关性，但在人群水平上，钙通道基因变异与HCM的关联仍未明确。
研究方法：本研究最初纳入719例无亲缘关系的肥厚型心肌病患者，最终根据纳入与排除标准筛选出371例受试者，分为四组：基因阴性者145例、仅携带罕见钙通道基因变异者28例（钙基因变异组）、仅携带单个致病性/可能致病性（pathogenic/likely pathogenic）肌节基因（sarcomere gene）变异者162例（肌节基因变异组），以及同时携带单个致病性/可能致病性肌节基因变异与单个罕见钙通道基因变异者36例（双基因变异组）。随后收集所有受试者的人口学资料、心电图数据、超声心动图数据及随访数据。
研究结果：与仅携带肌节基因变异的患者相比，双基因变异组患者发病年龄更早、HCM家族史阳性率更高、心室壁更厚、左心室流出道压力梯度更高、病理性Q波发生率更高，且束支传导阻滞发生率亦更高。随访期间，双基因变异组的主要终点事件发生率显著高于其余三组（p=0.0013）。多因素分析显示，双基因变异是HCM患者主要终点事件的独立预测因素（风险比HR=4.82，95%置信区间CI：1.77~13.2，p=0.002）。
研究结论：本研究发现，携带双基因变异的HCM患者具有更严重的疾病表型与不良预后。在HCM人群中，肌节基因变异与钙通道基因变异的致病效应可能存在累积协同作用。