背景:先前的研究强调了抗糖尿病药物在抑制慢性阻塞性肺疾病(COPD)恶化方面的潜在益处,然而,抗糖尿病药物对COPD风险的作用仍不确定.
方法:本研究采用孟德尔随机化(MR)方法来评估与六类抗糖尿病药物靶标相关的遗传变异与COPD的因果关系。COPD的主要结局来自全球生物库Meta分析倡议(GBMI)联盟,包括对12个队列的荟萃分析,包括81,568例病例和1,310,798例对照。HbA1c的汇总数据来自英国生物银行,涉及344182人。对2型糖尿病(T2DM)进行阳性对照分析,以验证工具变量的选择。该研究应用基于摘要数据的MR(SMR)和双样本MR进行效果评估,并进一步采用共定位分析来验证遗传变异的证据。
结果:SMR分析显示,血液中KCNJ11基因表达水平升高与COPD风险降低相关(OR=0.87,95%CI=0.79-0.95;p=0.002),而DPP4表达增加与COPD发病率增加相对应(OR=1.18,95%CI=1.03-1.35;p=0.022).此外,MR分析中的主要方法表明PPARG介导的HbA1c与FEV1(OR=1.07,95%CI=1.02-1.13;P=0.013)和FEV1/FVC(OR=1.08,95%CI=1.01-1.14;P=0.007)之间呈正相关,SLC5A2介导的HbA1c与FEV1/FVC呈负相关(OR=0.86,95%CI=0.74-1.00;P=0.045)。未检测到与结果表型的共定位证据(所有PP。H4<0.7)。
结论:本研究为抗糖尿病药物在改善COPD和肺功能方面的作用提供了提示性证据。将来有必要进行进一步更新的MR分析,在获得更广泛和全面的数据之后,来验证我们的结果。
BACKGROUND: Previous research has emphasized the potential benefits of anti-diabetic medications in inhibiting the exacerbation of Chronic Obstructive Pulmonary Disease (COPD), yet the role of anti-diabetic drugs on COPD risk remains uncertain.
METHODS: This study employed a Mendelian randomization (MR) approach to evaluate the causal association of genetic variations related to six classes of anti-diabetic drug targets with COPD. The primary outcome for COPD was obtained from the Global Biobank Meta-analysis Initiative (GBMI) consortium, encompassing a meta-analysis of 12 cohorts with 81,568 cases and 1,310,798 controls. Summary-level data for HbA1c was derived from the UK Biobank, involving 344,182 individuals. Positive control analysis was conducted for Type 2 Diabetes Mellitus (T2DM) to validate the choice of instrumental variables. The study applied Summary-data-based MR (SMR) and two-sample MR for effect estimation and further adopted colocalization analysis to verify evidence of genetic variations.
RESULTS: SMR analysis revealed that elevated KCNJ11 gene expression levels in blood correlated with reduced COPD risk (OR = 0.87, 95% CI = 0.79-0.95; p = 0.002), whereas an increase in DPP4 expression corresponded with an increased COPD incidence (OR = 1.18, 95% CI = 1.03-1.35; p = 0.022). Additionally, the primary method within MR analysis demonstrated a positive correlation between PPARG-mediated HbA1c and both FEV1 (OR = 1.07, 95% CI = 1.02-1.13; P = 0.013) and FEV1/FVC (OR = 1.08, 95% CI = 1.01-1.14; P = 0.007), and a negative association between SLC5A2-mediated HbA1c and FEV1/FVC (OR = 0.86, 95% CI = 0.74-1.00; P = 0.045). No colocalization evidence with outcome phenotypes was detected (all PP.H4 < 0.7).
CONCLUSIONS: This study provides suggestive evidence for anti-diabetic medications\' role in improving COPD and lung function. Further updated MR analyses are warranted in the future, following the acquisition of more extensive and comprehensive data, to validate our results.