Abstract 715: Genetically Proxied Inhibition Of L-2-Hydroxyglutarate Dehydrogenase Reduces The Risk Of Coronary Artery Disease: A Mendelian Randomization And Network Medicine Study

Abstract

Introduction: L-2-hydroxyglutarate dehydrogenase (L2HGDH) deletion-induced L-2-hydroxyglutarate accumulation plays a cardioprotective role in hypoxic conditions by eliminating reactive oxygen species. However, there has been no causal evidence in real-world clinical data. Hypothesis: We examined the potential therapeutic effects of L2HGDH inhibition on coronary artery disease (CAD) using Mendelian randomization (MR) and network medicine analyses. Methods: We used nine L2HGDH -proxied genetic variants associated with blood 2-hydroxyglutarate levels (6,287 European individuals) as genetic instruments, and performed a two-sample MR analysis using the CARDIoGRAMplusC4D meta-analysis datasets of CAD (60,801 cases and 123,504 controls). A protein-protein interaction network analysis was also performed to determine the potential therapeutic effects of L2HGDH inhibition on a CAD disease module. Results: Genetically proxied inhibition of L2HGDH associated with 2-hydroxyglutarate levels decreased the risk of CAD (odds ratio [OR] 0.486, 95% confidence interval [CI] 0.242-0.977, P=0.043). This potential causal association between L2HGDH inhibition and CAD was unlikely to be biased by horizontal pleiotropy. Network proximity analysis showed that L2HGDH is significantly closer to the CAD disease module in the human heart protein-protein interactome (P=0.016). Conclusions: In conclusion, our MR and network analyses suggest potential causal and pathobiological associations between genetically proxied inhibition of L2HGDH and CAD. Our findings may have therapeutic implications for L2HGDH inhibitors in CAD.