Genetically proxied inhibition of L-2-hydroxyglutarate dehydrogenase reduces the risk of coronary artery disease: A Mendelian randomization study

BackgroundL-2-hydroxyglutarate dehydrogenase (L2HGDH) deletion-induced L-2-hydroxyglutarate accumulation plays a cardioprotective role in hypoxic conditions. However, there has been no causal evidence in real-world clinical data. We aimed to examine the causal effects of L2HGDH inhibition on coronary artery disease (CAD) and myocardial infarction (MI) using Mendelian randomization (MR) analysis. MethodsWe used nine L2HGDH-proxied genetic variants associated with blood 2-hydroxyglutarate levels as genetic instruments, and performed two-sample MR analysis using the CARDIoGRAMplusC4D meta-analysis datasets of CAD (60,801 CAD cases and 123,504 controls) and MI (34,541 MI cases and 261,984 controls). ResultsGenetically proxied inhibition of L2HGDH associated with 2-hydroxyglutarate levels potentially decreased the risk of CAD (odds ratio [OR] 0.486, 95% confidence interval [CI] 0.242-0.977, P=0.043) but was not associated with the risk of MI (OR 0.676, 95% CI 0.312-1.463, P=0.320). This potentially causal association between L2HGDH inhibition and CAD was unlikely to be biased by horizontal pleiotropy, whereas there might be a weak instrument bias. ConclusionOur MR analysis suggests the potential association between genetically proxied inhibition of L2HGDH and CAD. Our findings may have therapeutic implications for L2HGDH inhibitors in CAD, and further large-scale clinical studies are needed.