Sequence Variation in DDAH1 and DDAH2 Genes Is Strongly and Additively Associated with Serum ADMA Concentrations in Individuals with Type 2 Diabetes 英文参考文献.docVIP

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Sequence Variation in DDAH1 and DDAH2 Genes Is Strongly and Additively Associated with Serum ADMA Concentrations in Individuals with Type 2 Diabetes 英文参考文献.doc

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SequenceVariationinDDAH1andDDAH2GenesIs StronglyandAdditivelyAssociatedwithSerumADMA ConcentrationsinIndividualswithType2Diabetes SotoodehAbhary1*,KathrynP.Burdon1,AbrahamKuot1,ShahrbanouJavadiyan1,MalcolmJ.Whiting3, NicholasKasmeridis2,NikolaiPetrovsky2,JamieE.Craig1 1DepartmentofOphthalmology,FlindersMedicalCentreandFlindersUniversity,Adelaide,SouthAustralia,Australia,2DepartmentofEndocrinology,FlindersMedical CentreandFlindersUniversity,Adelaide,SouthAustralia,Australia,3ChemicalPathologyLaboratory,SAPathology,Adelaide,SouthAustralia,Australia Abstract Background: Asymmetric dimethylarginine (ADMA), present in human serum, is an endogenous inhibitor of nitric oxide synthase and contributes to vascular disease. Dimethylarginine dimethylaminohydrolase (DDAH) is an ADMA degrading enzymethathastwoisoforms:DDAHIandDDAHII.WesoughttodeterminewhetherserumADMAlevelsintype2diabetes areinfluencedbycommonpolymorphismsintheDDAH1andDDAH2genes. Methodology/Principal Findings: Relevant clinical parameters were measured and peripheral whole blood obtained for serum and genetic analysis on 343 participants with type 2 diabetes. Serum ADMA concentrations were determined by massspectroscopy.TwentysixtagSNPsintheDDAH1and10intheDDAH2geneweregenotypedinallsubjectsandtested forassociation withserum ADMAlevels. Several SNPsandhaplotypes inthe DDAH geneswerestronglyassociated with ADMA levels. Most significantly in the DDAH1 gene, rs669173 (p=2.9661027), rs7521189 (p=6.4061027), rs2474123 (p=0.00082) and r(p=0.00027), and in the DDAH2 gene, rs3131383 (p=0.0029) and the TGCCCAGGAG haplotype (p=0.0012) were significantly associated with ADMA levels. Sub-analysis by diabetic retinopathy (DR) status revealedthesevariantswereassociatedwithADMAlevelspredominantlyinparticipantswithoutDR.Combinedanalysisof themoststronglyassociatedSNPsinDDAH1(rs669173)andDDAH2(rs3131383)revealedanadditiveeffect(p=1.3761028 ) onADMAlevels. Conclusions/Significance:GeneticvariationintheDDAH1and2genes