Genetic Predisposition and Pharmacological Effects Shape the Divergent Effects of Type 2 Diabetes on Atherosclerosis

Abstract

Type 2 diabetes mellitus (T2D) increases the risk of atherosclerotic diseases, including coronary artery disease (CAD), but decreases that for abdominal aortic aneurysm (AAA), forming an intriguing diabetes-atherosclerosis paradox. We investigate how genetic underpinnings and drug effects shape these complex relationships. A robust positive correlation between T2D and CAD is found throughout the genome, whereas the weak genetic correlation between T2D and AAA is counter-balanced by two-thirds positive and one-third negative correlations. Through single nucleotide variant colocalization, gene annotation, pathway enrichment, and cell type associations, we discover that these positive correlations entail immune responses, whereas the negative correlation is characterized by beta-cell dysfunction and lipid metabolism. Furthermore, the effects of 98 canonical cardiovascular and metabolic drugs are elucidated by pathway pairing and drug-target Mendelian Randomization, revealing that the widely prescribed metformin and glitazones are also protective against atherosclerosis, whereas statins raise the T2D risk. Through screening the plasma proteome against 660 anti-inflammatory drugs, we identify 14 targets and 8 drugs for anti-inflammatory treatments of T2D and atherosclerosis. Our study discovers that both disease-disease and drug-disease interplay contribute to the complex relationships between diabetes and atherosclerosis. Importantly, immune responses synergize with diabetes and atherosclerotic diseases, suggesting anti-inflammatory therapies as a unified treatment strategy.