Observational studies on the general population have suggested that airflow obstruction associates with left ventricular (LV) filling. To limit the influence of environmental risk factors/exposures, we used a Mendelian randomisation (MR) approach based on common genetic variations and tested whether a causative relation between airflow obstruction and LV filling can be detected. We used summary statistics from large genome-wide association studies (GWAS) on the ratio of forced expiratory volume in 1 s to forced vital capacity (FEV1/FVC) measured by spirometry and the LV end-diastolic volume (LVEDV) as assessed by cardiac magnetic resonance imaging. The primary MR was based on an inverse variance weighted regression. Various complementary MR methods and subsets of the instrument variables were used to assess the plausibility of the findings. We obtained consistent evidence in our primary MR analysis and subsequent sensitivity analyses that reducing airflow obstruction leads to increased inflow to the LV (odds ratio [OR] from inverse variance weighted regression 1.05, 95% confidence interval [CI] 1.01–1.09, P = 0.0172). Sensitivity analyses indicated a certain extent of negative horizontal pleiotropy and the estimate from biased-corrected MR-Egger was adjusted upward (OR 1.2, 95% CI 1.09–1.31, P < 0.001). Prioritisation of single genetic variants revealed rs995758, rs2070600 and rs7733410 as major contributors to the MR result. Our findings indicate a causal relationship between airflow obstruction and LV filling in the general population providing genetic context to observational associations. The results suggest that targeting (even subclinical) airflow obstruction can lead to direct cardiac improvements, demonstrated by an increase in LVEDV. Functional annotation of single genetic variants contributing most to the causal effect estimate could help to prioritise biological underpinnings.

中文翻译：

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气流阻塞对左心室充盈的因果影响的遗传证据：孟德尔随机化研究

对一般人群的观察性研究表明，气流阻塞与左心室 (LV) 充盈有关。为了限制环境风险因素/暴露的影响，我们使用基于常见遗传变异的孟德尔随机化 (MR) 方法，并测试是否可以检测到气流阻塞和 LV 充盈之间的因果关系。我们使用了来自大型全基因组关联研究 (GWAS) 的汇总统计数据，即 1 秒内用力呼气量与通过肺活量测定法测量的用力肺活量 (FEV1/FVC) 和由心脏评估的 LV 舒张末期容积 (LVEDV) 之比。磁共振成像。主要 MR 基于逆方差加权回归。各种互补的 MR 方法和仪器变量的子集用于评估结果的合理性。我们在主要 MR 分析和随后的敏感性分析中获得了一致的证据，即减少气流阻塞会导致流入 LV 的流量增加（来自逆方差加权回归的比值比 [OR] 1.05，95% 置信区间 [CI] 1.01–1.09，P = 0.0172）。敏感性分析表明存在一定程度的负水平多效性，并且上调了偏差校正 MR-Egger 的估计值（OR 1.2，95% CI 1.09–1.31，P < 0.001）。单个遗传变异的优先级显示 rs995758、rs2070600 和 rs7733410 是 MR 结果的主要贡献者。我们的研究结果表明，一般人群中气流阻塞和 LV 充盈之间存在因果关系，为观察关联提供了遗传背景。结果表明，靶向（甚至亚临床）气流阻塞可导致直接的心脏改善，这表现为 LVEDV 的增加。对因果效应估计贡献最大的单个遗传变异的功能注释可能有助于优先考虑生物学基础。