Genetic and Environmental Determinants of Dimethylarginines and Association With Cardiovascular Disease in Patients With Type 2 Diabetes
Genetic and Environmental Determinants of Dimethylarginines and Association With Cardiovascular Disease in Patients With Type 2 Diabetes
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DOI：
10.2337/dc13-0546
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发表时间：
2014-03-01
期刊：
影响因子：
16.2
通讯作者：
Price, Jackie F.
中科院分区：
文献类型：
--
作者：
Anderssohn, Maike;McLachlan, Stela;Price, Jackie F.
目的研究不对称二甲基精氨酸(ADMA)和对称二甲基精氨酸(SDMA)的决定因素，包括DDAH1、DDAH2和AGXT2基因的单核苷酸多态(SNPs)，及其与老年2型糖尿病患者心血管疾病(CVD)的关系。研究设计和方法作为爱丁堡2型糖尿病研究(ET2DS)的一部分，对60-75岁的老年2型糖尿病患者进行了心血管疾病的流行评估，并对参与者进行了4年的前瞻性随访。结果血浆ADMA水平与DDAH1基因SNPs显著相关(TOP SNP rs1554597；P=9.0E-09)，SDMA水平与AGXT2基因SNPs相关(TOP SNP rs28305；P=1.3E-04)。显著的、独立的血浆ADMA决定因素是性别、L精氨酸、肌酐、空腹血糖和rs1554597(均P<；0.05；合并R2=0.213)。决定SDMA的因素有年龄、性别、肌酐、L-精氨酸、糖尿病病程、心血管疾病患病率和rs28305(P均<0.05；合并R2=0.425)。二甲基精氨酸与心血管事件均无关联。尽管亚组分析显示AGXT2 rs28305与间歇性跛行显著相关，但研究中的SNPs与整体心血管疾病没有关联。结论在一组特征良好的2型糖尿病人群中的研究不支持已报道的ADMA与糖尿病或心血管疾病特征之间的关联或因果关系。
OBJECTIVETo 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.RESEARCH DESIGN AND METHODSPrevalent 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.RESULTSPlasma 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.CONCLUSIONSOur 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.