Effect of L-arginine, asymmetric dimethylarginine, and symmetric dimethylarginine on ischemic heart disease risk: A Mendelian randomization study

Background L-arginine is a commonly consumed dietary conditional essential amino acid found in food items and supplements, which is closely related to asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). L-arginine is thought to increase nitric oxide and be cardioprotective, whereas ADMA and SDMA may inhibit nitric oxide synthesis and increase cardiovascular disease risk. Unexpectedly, L-arginine increased mortality in a small trial. To clarify the effects of these potential targets of intervention, we assessed the risk of ischemic heart disease (IHD) by genetically determined L-arginine, ADMA, and SDMA. Methods Single nucleotide polymorphisms (SNPs) contributing to L-arginine, ADMA, and SDMA, at genome-wide significance, were applied to the CARDIoGRAMplusC4D 1000 Genomes–based genome-wide association study IHD case (n = 60,801, ~70% myocardial infarction)-control (n = 123,504) study. We obtained unconfounded estimates using instrumental variable analysis by combining the Wald estimators for each SNP, taking into account any correlation between SNPs using weighted generalized linear regression. Results Higher L-arginine was associated with higher risk of IHD (odds ratio [OR] 1.18 per SD increase, 95% CI 1.03-1.36) and of myocardial infarction (OR 1.29, 95% CI 1.10-1.51), based on 2 SNPs from MED23. Symmetric dimethylarginine had an OR of 1.07 per SD (95% CI 0.99-1.17) for IHD based on 5 SNPs from AGXT2. Asymmetric dimethylarginine had and OR of 1.08 per SD (95% CI 0.99-1.19) for IHD based on 4 SNPs from DDAH1. Conclusion L-arginine could possibly cause IHD. Given that L-arginine occurs in many common dietary items, investigation of its health effect is required.