title: Circulating methylarginine levels and the decline in renal function in patients with chronic kidney disease are modulated by DDAH1 polymorphisms.
abstract: In patients with chronic kidney disease, high plasma levels of the endogenous nitric oxide synthase inhibitor, asymmetric dimethylarginine, are thought to contribute to decline in renal function. Here we took a candidate gene approach to determine any causal role of asymmetric dimethylarginine in the progression of chronic kidney disease. The impact of single-nucleotide polymorphisms in the genes encoding the two isoforms of the asymmetric dimethylarginine-degrading enzyme, dimethylarginine dimethylaminohydrolase (DDAH1 and DDAH2), on enzyme expression, plasma asymmetric dimethylarginine levels, and longitudinal changes in estimated glomerular filtration rate were determined in various patient groups. There was evidence suggesting that the rs17384213 DDAH1 GG genotype was associated with increased expression of its mRNA in kidney allografts. Healthy subjects carrying the rs17384213 G allele had lower plasma asymmetric dimethylarginine, and a similar borderline association was found in patients with chronic kidney disease. This allele, however, was independently associated with a steeper decline in renal function in two separate cohorts of patients with chronic kidney disease. We conclude that polymorphisms in DDAH1 alter the rate of decline of glomerular filtration rate in subjects with chronic kidney disease. Our findings show that DDAH1 modulates plasma asymmetric dimethylarginine and contributes to the decline in renal function. However, it appears that increases in circulating methylarginine did not mediate progressive kidney injury.
authors.affiliation: Centre for Nephrology, Division of Medicine, University College London Medical School, London, UK. b.caplin@medsch.ucl.ac.uk
authors.forename: Ben
authors.initials: B
authors.lastname: Caplin
authors.forename: Dorothea
authors.initials: D
authors.lastname: Nitsch
authors.forename: Herpreet
authors.initials: H
authors.lastname: Gill
authors.forename: Richard
authors.initials: R
authors.lastname: Hoefield
authors.forename: Scott
authors.initials: S
authors.lastname: Blackwell
authors.forename: Douglas
authors.initials: D
authors.lastname: MacKenzie
authors.forename: Jackie A
authors.initials: JA
authors.lastname: Cooper
authors.forename: Rachel J
authors.initials: RJ
authors.lastname: Middleton
authors.forename: Philippa J
authors.initials: PJ
authors.lastname: Talmud
authors.forename: Peter
authors.initials: P
authors.lastname: Veitch
authors.forename: Jill
authors.initials: J
authors.lastname: Norman
authors.forename: David C
authors.initials: DC
authors.lastname: Wheeler
authors.forename: James M
authors.initials: JM
authors.lastname: Leiper
mesh_terms: D000483:Alleles; D000581:Amidohydrolases / Q000235:genetics*; D001120:Arginine / Q000031:analogs & derivatives* / Q000097:blood; D016022:Case-Control Studies; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D004791:Enzyme Inhibitors / Q000097:blood*; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D005838:Genotype; D005919:Glomerular Filtration Rate / Q000235:genetics; D006801:Humans; D007676:Kidney Failure, Chronic / Q000097:blood*; D008137:Longitudinal Studies; D008297:Male; D011110:Polymorphism, Genetic; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D012333:RNA, Messenger; C018524:N,N-dimethylarginine; D001120:Arginine; D000581:Amidohydrolases; C059999:dimethylargininase