title: Common genetic variation in a basal promoter element alters DDAH2 expression in endothelial cells.
abstract: Synthesis of the vasodilator nitric oxide (NO) can be inhibited by the endogenous methylarginines L-NMMA and ADMA. ADMA is elevated in a number of cardiovascular disorders in which NO availability is reduced. Elimination of ADMA from the body occurs primarily by enzymatic breakdown through the action of DDAH, of which two isoforms exist, DDAH1 and DDAH2. In this study we have identified a core promoter region of the DDAH2 gene, and transcription factor sites that play an important role in the regulation of DDAH2 expression. Using PCR-SSCP analysis we also identified six common polymorphisms. One of these polymorphisms (an insertion/deletion at position -871) within the core promoter element influenced basal transcription. The discovery of a functional polymorphism within the DDAH2 promoter suggests that there may be common, individual differences in the ability to metabolise ADMA in vivo, that in turn, might underlie susceptibility to cardiovascular disease.
authors.affiliation: Centre for Clinical Pharmacology and Therapeutics, Department of Medicine, University College London, UK.
authors.forename: L C
authors.initials: LC
authors.lastname: Jones
authors.forename: C T L
authors.initials: CT
authors.lastname: Tran
authors.forename: J M
authors.initials: JM
authors.lastname: Leiper
authors.forename: A D
authors.initials: AD
authors.lastname: Hingorani
authors.forename: P
authors.initials: P
authors.lastname: Vallance
mesh_terms: D000581:Amidohydrolases / Q000096:biosynthesis* / Q000235:genetics*; D001483:Base Sequence; D002318:Cardiovascular Diseases / Q000235:genetics; D003001:Cloning, Molecular; D018899:CpG Islands; D004727:Endothelium / Q000378:metabolism*; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009569:Nitric Oxide / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D011401:Promoter Regions, Genetic; D020033:Protein Isoforms; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection
chemical_list: D020033:Protein Isoforms; D009569:Nitric Oxide; D000581:Amidohydrolases; C059999:dimethylargininase