title: Genetic and environmental determinants of dimethylarginines and association with cardiovascular disease in patients with type 2 diabetes.
abstract: OBJECTIVE
  To investigate determinants of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), including single nucleotide polymorphisms (SNPs), in the DDAH1, DDAH2, and AGXT2 genes and their associations with prevalent and incident cardiovascular disease (CVD) in older adults with type 2 diabetes mellitus.
  
  
  METHODS
  Prevalent CVD was assessed in men and women aged 60-75 years with type 2 diabetes as part of the Edinburgh Type 2 Diabetes Study (ET2DS), and the participants were prospectively followed up for 4 years for incident CVD. Dimethylarginines were measured in 783 of these subjects, and genotyping for tag SNPs in the DDAH1, DDAH2, and AGXT2 genes was performed in 935 subjects.
  
  
  RESULTS
  Plasma ADMA levels were significantly associated with SNPs in DDAH1 (top SNP rs1554597; P = 9.0E-09), while SDMA levels were associated with SNPs in AGXT2 (top SNP rs28305; P = 1.3E-04). Significant, independent determinants of plasma ADMA were sex, L-arginine, creatinine, fasting glucose, and rs1554597 (all P < 0.05; combined R(2) = 0.213). Determinants of SDMA were age, sex, creatinine, L-arginine, diabetes duration, prevalent CVD, and rs28305 (all P < 0.05; combined R(2) = 0.425). Neither dimethylarginine was associated with incident CVD. None of the investigated SNPs were associated with overall CVD, although subgroup analysis revealed a significant association of AGXT2 rs28305 with intermittent claudication.
  
  
  CONCLUSIONS
  Our study in a well-characterized population with type 2 diabetes does not support reported associations or causal relationship between ADMA and features of diabetes or CVD.
authors.affiliation: Corresponding author: Maike Anderssohn, m.anderssohn@uke.de.
authors.forename: Maike
authors.initials: M
authors.lastname: Anderssohn
authors.forename: Stela
authors.initials: S
authors.lastname: McLachlan
authors.forename: Nicole
authors.initials: N
authors.lastname: Lüneburg
authors.forename: Christine
authors.initials: C
authors.lastname: Robertson
authors.forename: Edzard
authors.initials: E
authors.lastname: Schwedhelm
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Williamson
authors.forename: Mark W J
authors.initials: MW
authors.lastname: Strachan
authors.forename: Ramzi
authors.initials: R
authors.lastname: Ajjan
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Grant
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Böger
authors.forename: Jackie F
authors.initials: JF
authors.lastname: Price
mesh_terms: D000368:Aged; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood / Q000235:genetics; D002318:Cardiovascular Diseases / Q000097:blood / Q000453:epidemiology*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000453:epidemiology* / Q000235:genetics; D003925:Diabetic Angiopathies / Q000453:epidemiology / Q000209:etiology; D004777:Environment; D005260:Female; D005838:Genotype; D006801:Humans; D007383:Intermittent Claudication / Q000453:epidemiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: C487735:dimethylarginine; C024917:symmetric dimethylarginine; C018524:N,N-dimethylarginine; D001120:Arginine