Asymmetric Dimethylarginine (ADMA), Genetic Variation, and Cardiovascular Disease

越来越多的证据表明，除了胰岛素和血脂异常外， 动脉粥样硬化的异常过程 然而，许多研究已经检查了氧化应激与内分泌失调之间的相互关系！（：l;ian，：and; 冠心病不对称二甲基精氨酸（ADMA）是一氧化氮合酶（NOS）的内源性抑制剂，抗 最近出现了一种潜在的新风险， 代谢酶，二甲基精氨酸二乙氨基水解酶（DDAIHI），并增加 应激抑制组织中的DDAH活性，这导致ADMA的持续水平。ADMA的蓄积， NO合成减少导致共内皮细胞功能障碍，并启动和促进与 动脉粥样硬化血浆ADMA水平与GHD的几个风险因素有关;然而， ADMA的预测价值，DDAH基因的遗传变异，以及男性冠心病的潜在风险， 女性的这一点目前还很有限;这项提案的目的是研究血浆ADMA水平， 在tyvo大型前瞻性队列研究中CilD的生化预测因子：NufsCL健康研究（NHS）和 卫生专业人员随访研究（HPFS）。这两项研究都有超过22年的重复饮食和 生活方式问卷调查数据，从NHf中的32，826名男性和HPFS中的8，225名男性收集的血液样本，以及 巢式病例对照研究，使用先前在非致死性事件病例中存档的生物学标本 心肌梗死或致死性CHD，和/或年龄和吸烟。本方案的具体目标是 to;！;）探讨血浆ADM与肿瘤坏死因子的关系 男子和妇女的控制环境i; 2.）：利用现有的前瞻性数据来检查intelligence 在生活方式和其他健康因素之间;和血浆ADMA以激发潜力;机制;和3.） 检查DDAH基因的遗传变异与血浆ADMA水平和男性和女性GHD的风险， 妇女这些发现可能会导致新的治疗干预措施，以消除ADMA的影响，并预防 动脉粥样硬化和心血管疾病的进展。

Growing evidence suggests that pathways in addition to innaraination and dyslipidemia contribute tothe undtsrlyiiig processes of atherosclen3sis;endathelial dysfunction, a Howcvcr,:,fGw studies liave examined tlielhterreiatioiis between oxidative istressj.endiottielial dysfui!(:l;ian,:and; CHD. Asymmetric dimethylarginlne (ADMA) Is an endogenous inliibitor of nitricoxidesynthase (NOS), anti has recently emerged p a potential novel risk mpt^ker iiietabolizedljy the enzyme, dimethylarginine diraethylaminohydrolase (DDAiHI), and increa stress inhibit DDAH activity in the tissues, which leads to sustained levels of ADMA. Accumulatipri ofADMA and reduced NO synthesis leads coendothellalciysfunction and also initiates and promoteiu processes involved with atherogenesis. Plasrha ADMA levels have been associated with several risk factors oif GHD; however, data on the predictive valite of ADMA, genetic variation iii the DDAH giene, arid the prospective risk of CHD in men and women have th its far been limited; The goal of this proposal is to irtvestigate plasma ADMA: levels as a novel biochemical predictor of CilD among tyvo large prospective cohort studies: the NufsCLs' Health Study (NHS) and the Health Professionals Foliow-up Study (HPFS). Both studies have over 22 years of repeated dietary and lifestyle questionnaire data, blood samples collected from 32,826'wonVen in NHf and,l,:8,225:men in HPFS, and nested case-control studies with biologiical specimens previously archived among Incident cases of nonfaial mypcardialinfari:tion or fatal CHD, and/age and smoking thatched conti"ols. The specific aims of this prpposal are to;!;) exaniihe^the'prospective relationship between plasma ADM control settings among men and womeri; 2.):UtiIlze the existing prospective data toexamine inteiTelations betvveen lifestylts^tlietai-y, arid other hiealth faCtoi-s,;and plasma ADMA to elueidale potential; mechanistris; and 3.) examine the.genetic variation in the DDAH gene with plasma ADMA levels and risk bf.GHD in both men and women. These findings may lead to new therapeutic interventions vvhich inhibltthe effects of ADMA arid prevent che progression df atherosclerosis and cardiovascular disease.