Current topics in medicinal chemistry · 2026
Target Perturbation of Genetically Proxied Antidiabetic Drug Targets and Pneumonia Risk: A Mendelian Randomization Analysis.
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Lin Siyi, Xu Hongxia, Xia Jingyan, Xu Feng
Аннотация
INTRODUCTION: Type 2 Diabetes Mellitus (T2DM) and various antidiabetic medications have been linked to the incidence and mortality of pneumonia, yet the causality remains unclear. This Mendelian Randomization (MR) study aimed to evaluate the potential causal relationships between them.
METHODS: We conducted two-sample MR analyses utilizing genetic instruments associated with T2DM and 6 antidiabetic drug targets (PPARG, GIPR, GLP1R, INSR, ABCC8, and KCNJ11), focusing on 9 pneumonia subtypes. Pneumonia patients for discovery and validation cohorts were sourced from FinnGen, GWAS Catalog, and other large consortia. Meta-analysis was performed to integrate the results of two cohorts. Additionally, Summary-data-based Mendelian Randomization (SMR) was performed as an exploratory analysis to explore potential gene-expression-mediated signals. Statistical power was calculated using mRnd to assess the robustness of MR estimates.
RESULTS: MR analyses identified strong connections between ABCC8/KCNJ11 and cytomegaloviral pneumonitis (OR = 5.000 × 10-4, 95% CI: 6.046 × 10-6-0.043, P = 0.0008) and between GIPR and pneumonia (OR = 1.088, 95% CI: 1.022-1.159, P = 0.008). Nominal associations of PPARG, ABCC8/KCNJ11, GLP1R, and INSR with pneumonia, bacterial pneumonia, and pneumococcal pneumonia were detected, which should be interpreted cautiously given limited power. Exploratory SMR analysis linked ABCC8 (OR = 0.977, 95% CI: 0.955-0.999, P = 0.042) and GIPR (OR = 0.662, 95% CI: 0.469-0.935, P = 0.020) to pneumonia risk. No statistically significant bias due to pleiotropy or genetic confounding was found by sensitivity analyses.
DISCUSSION: The study systematically explored the causality between T2DM, 6 antidiabetic drug targets, and pneumonia risks.
CONCLUSION: Certain genetically proxied antidiabetic drug targets are associated with pneumonia risk, providing hypothesis-generating insights for future mechanistic research and clinical evaluation. However, caution is warranted in interpreting rare pneumonia subtypes with limited case numbers. Future studies with larger sample sizes and diverse populations are needed for validation.
METHODS: We conducted two-sample MR analyses utilizing genetic instruments associated with T2DM and 6 antidiabetic drug targets (PPARG, GIPR, GLP1R, INSR, ABCC8, and KCNJ11), focusing on 9 pneumonia subtypes. Pneumonia patients for discovery and validation cohorts were sourced from FinnGen, GWAS Catalog, and other large consortia. Meta-analysis was performed to integrate the results of two cohorts. Additionally, Summary-data-based Mendelian Randomization (SMR) was performed as an exploratory analysis to explore potential gene-expression-mediated signals. Statistical power was calculated using mRnd to assess the robustness of MR estimates.
RESULTS: MR analyses identified strong connections between ABCC8/KCNJ11 and cytomegaloviral pneumonitis (OR = 5.000 × 10-4, 95% CI: 6.046 × 10-6-0.043, P = 0.0008) and between GIPR and pneumonia (OR = 1.088, 95% CI: 1.022-1.159, P = 0.008). Nominal associations of PPARG, ABCC8/KCNJ11, GLP1R, and INSR with pneumonia, bacterial pneumonia, and pneumococcal pneumonia were detected, which should be interpreted cautiously given limited power. Exploratory SMR analysis linked ABCC8 (OR = 0.977, 95% CI: 0.955-0.999, P = 0.042) and GIPR (OR = 0.662, 95% CI: 0.469-0.935, P = 0.020) to pneumonia risk. No statistically significant bias due to pleiotropy or genetic confounding was found by sensitivity analyses.
DISCUSSION: The study systematically explored the causality between T2DM, 6 antidiabetic drug targets, and pneumonia risks.
CONCLUSION: Certain genetically proxied antidiabetic drug targets are associated with pneumonia risk, providing hypothesis-generating insights for future mechanistic research and clinical evaluation. However, caution is warranted in interpreting rare pneumonia subtypes with limited case numbers. Future studies with larger sample sizes and diverse populations are needed for validation.