Abstract 11578: Genome-Wide Pleiotropy Analysis of Coronary Artery Disease and Pneumonia

Introduction: Pneumonia correlates strongly with coronary artery disease (CAD) risk, and influenza vaccination reduces CAD risk in trials. Elucidating shared pathways may elucidate novel insights regarding residual CAD risk. Hypothesis: Genetic alleles exhibit pleiotropy for pneumonia and CAD, and may be leveraged for causal inference. Methods: We performed genome-wide pleiotropy analyses CAD and pneumonia with the PLACO method using summary statistics from CARDIoGRAMplusC4D (CAD) and FinnGen v4 (pneumonia). For genes near independently replicated SNPs (in UK and Mass General Brigham Biobanks) and expressed in GTEx v8 tissues, we examined the causal effects of index and interacting (by STRING) gene expression with CAD and pneumonia through Mendelian randomization (MR). Lastly, we examined for interactions between prioritized SNPs and smoking status on incident CAD and pneumonia risks. Results: Among 115 SNPs with significant genetic pleiotropy between CAD and pneumonia, 90 of them were replicated, and nearby genes ( ADAMTS7 , IL6R ) showed heritable gene expression. Across tissues, increased ADAMTS7 expression consistently showed decreased risk for CAD and increased risk for pneumonia, and increased IL6R expression showed increased risk for CAD and decreased risk for pneumonia. Among genes that interacted closely with ADAMTS7 and IL6R , NLRP3 similarly demonstrated significant causal effects on CAD and pneumonia in the same directions as that of ADAMTS7 . Sensitivity analysis using multiple MR methods yielded consistent results. The presence of ADAMTS7 p.Ser214Pro conferred a significantly reduced risk of CAD among non-smokers but not those who ever smoked ( P interaction 0.01) and a significantly increased risk of pneumonia only among those who ever smoked ( P interaction 0.0003). Conclusions: Genetic immune-inflammatory axes of CAD linked to respiratory infections implicate ADAMTS7 and IL6R , and related genes.