Department of Epidemiology and Health Statistics, School of Public Health, Hangzhou Medical College, Hangzhou, China.
JC School of Public Health and Primary Care, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China.
Front Endocrinol (Lausanne). 2021 Nov 25;12:777487. doi: 10.3389/fendo.2021.777487. eCollection 2021.
Observational studies have shown possible bidirectional association between type 2 diabetes (T2D) and pulmonary function, but the causality is not well defined. The purpose of this study is to investigate genetic correlation and causal relationship of T2D and glycemic traits with pulmonary function.
By leveraging summary statistics from large-scale genome-wide association studies, linkage disequilibrium score regression was first implemented to quantify genetic correlations between T2D, glycemic traits, and several spirometry indices. Then both univariable and multivariable Mendelian randomization analyses along with multiple pleiotropy-robust methods were performed in two directions to assess the causal nature of these relationships.
Forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) showed significant genetic correlations with T2D and fasting insulin levels and suggestive genetic correlations with fasting glucose and hemoglobin A1c. In Mendelian randomization analyses, genetically predicted higher FEV1 (OR = 0.77; 95% CI = 0.63, 0.94) and FVC (OR = 0.82; 95% CI = 0.68, 0.99) were significantly associated with lower risk of T2D. Conversely, genetic predisposition to higher risk of T2D exhibited strong association with reduced FEV1 (beta = -0.062; 95% CI = -0.100, -0.024) and FEV1 (beta = -0.088; 95% CI = -0.126, -0.050) and increased FEV1/FVC ratio (beta = 0.045; 95% CI = 0.012, 0.078). We also found a suggestive causal effect of fasting glucose on pulmonary function and of pulmonary function on fasting insulin and proinsulin.
The present study provided supportive evidence for genetic correlation and bidirectional causal association between T2D and pulmonary function. Further studies are warranted to clarify possible mechanisms related to lung dysfunction and T2D, thus offering a new strategy for the management of the two comorbid diseases.
观察性研究表明，2 型糖尿病（T2D）与肺功能之间可能存在双向关联，但因果关系尚不清楚。本研究旨在探讨 T2D 及血糖特征与肺功能之间的遗传相关性和因果关系。
利用大规模全基因组关联研究的汇总统计数据，首先采用连锁不平衡评分回归量化 T2D、血糖特征与几项肺活量指数之间的遗传相关性。然后，在两个方向上进行单变量和多变量孟德尔随机化分析以及多种多效稳健方法，以评估这些关系的因果性质。
1 秒用力呼气容积（FEV1）和用力肺活量（FVC）与 T2D 和空腹胰岛素水平呈显著遗传相关，与空腹血糖和糖化血红蛋白呈提示性遗传相关。在孟德尔随机化分析中，遗传预测的更高的 FEV1（OR=0.77；95%CI=0.63，0.94）和 FVC（OR=0.82；95%CI=0.68，0.99）与 T2D 风险降低显著相关。相反，T2D 发病风险升高的遗传倾向与 FEV1 降低（beta=-0.062；95%CI=-0.100，-0.024）和 FEV1 降低（beta=-0.088；95%CI=-0.126，-0.050）以及 FEV1/FVC 比值升高（beta=0.045；95%CI=0.012，0.078）密切相关。我们还发现空腹血糖对肺功能以及肺功能对空腹胰岛素和胰岛素原具有提示性的因果关系。
本研究为 T2D 与肺功能之间的遗传相关性和双向因果关系提供了支持性证据。需要进一步的研究来阐明与肺功能障碍和 T2D 相关的可能机制，从而为这两种合并症的管理提供新的策略。
