title: Effect of l-arginine, asymmetric dimethylarginine, and symmetric dimethylarginine on ischemic heart disease risk: A Mendelian randomization study.
abstract: 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.
  
  
  CONCLUSIONS
  l-arginine could possibly cause IHD. Given that l-arginine occurs in many common dietary items, investigation of its health effect is required.
authors.affiliation: School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. Electronic address: ayslryan@hku.hk.
authors.forename: Shiu Lun
authors.initials: SL
authors.lastname: Au Yeung
authors.affiliation: School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China. Electronic address: cindylin@connect.hku.hk.
authors.forename: Shi Lin
authors.initials: SL
authors.lastname: Lin
authors.affiliation: Department of Pediatrics, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China. Electronic address: hshslam@cuhk.edu.hk.
authors.forename: Hung San Hugh Simon
authors.initials: HS
authors.lastname: Lam
authors.affiliation: School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China; City University of New York Graduate School of Public Health and Health Policy, New York, NY. Electronic address: cms1@hku.hk.
authors.forename: Catherine Mary
authors.initials: CM
authors.lastname: Schooling
mesh_terms: D001120:Arginine / Q000031:analogs & derivatives / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D056892:Mediator Complex / Q000235:genetics*; D057182:Mendelian Randomization Analysis; D009203:Myocardial Infarction / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D000637:Transaminases / Q000235:genetics*
chemical_list: C492159:MED23 protein, human; D056892:Mediator Complex; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine; D000637:Transaminases; C019635:Alanine-glyoxylate transaminase