A Novel Loss-of-Function DDAH1 Promoter Polymorphism Is Associated With Increased Susceptibility to Thrombosis Stroke and Coronary Heart Disease
A Novel Loss-of-Function DDAH1 Promoter Polymorphism Is Associated With Increased Susceptibility to Thrombosis Stroke and Coronary Heart Disease
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一种新的 DDAH1 启动子功能丧失多态性与血栓性中风和冠心病的易感性增加相关
DOI：
10.1161/circresaha.109.215616
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发表时间：
2010-04-02
影响因子：
20.1
通讯作者：
Wang, Dao Wen
中科院分区：
文献类型：
--
作者：
Ding, Hu;Wu, Bin;Wang, Dao Wen
原理：不对称二甲基精氨酸 (ADMA) 是一种内源性精氨酸类似物，可抑制一氧化氮合酶，在内皮功能障碍中发挥重要作用。目的：在本研究中，我们测试了重要的 ADMA 水解基因二甲基精氨酸二甲氨基水解酶 1 (DDAH1) 的新遗传变异是否与中国汉族人群中风和冠心病 (CHD) 易感性相关。方法和结果：通过重测序，我们在 DDAH1 启动子中鉴定出一种新的 4 核苷酸缺失/插入变体。插入等位基因破坏了金属调节转录因子1的结合，导致体外DDAH1转录活性和体内DDAH1 mRNA水平显着降低，进而增加血浆ADMA水平以及ADMA与L-精氨酸的比率。我们最初对 1388 名中风患者和 1027 名对照者以及 576 名冠心病患者和 557 名对照者进行了多态性基因分型，然后在另外的独立病例对照队列中重复了我们的研究，其中包括 961 名中风患者和 822 名对照者以及 482 名冠心病患者和 1072 名对照者。在对两种疾病的两个样本中的环境因素进行调整后，我们发现-396 4N ins等位基因与血栓性中风和CHD风险增加显着相关（血栓性中风发现集：比值比[OR]=1.35，P=0.032；复制集：OR=1.51，P=0.006；CHD发现集：OR=1.45，P=0.035；复制集： OR=1.47，P=0.003）。结论：我们的结果表明，DDAH1 功能丧失多态性与血栓性中风和冠心病风险增加相关。
Rationale: Asymmetrical dimethylarginine (ADMA), an endogenous arginine analogue, inhibits nitric oxide synthases and plays an important role in endothelial dysfunction. Objective: In the present study, we tested whether a novel genetic variant in dimethylarginine dimethylaminohydrolase 1 (DDAH1), an important ADMA hydrolyzing gene, was associated with stroke and coronary heart disease (CHD) susceptibility in the Chinese Han population. Methods and Results: By resequencing, we identified a novel 4-nucleotide deletion/insertion variant in the DDAH1 promoter. The insertion allele disrupted binding of metal-regulatory transcription factor 1, which resulted in significant reduction of in vitro DDAH1 transcriptional activity and in vivo DDAH1 mRNA level, and in turn, increased plasma ADMA level and the ratio of ADMA to l-arginine. We initially genotyped the polymorphism in 1388 stroke patients and 1027 controls as well as 576 CHD patients and 557 controls and then replicated our study in additional independent case-control cohorts comprising 961 stroke patients and 822 controls and 482 CHD patients and 1072 controls. We identified that the −396 4N ins allele was significantly associated with increased risk of thrombosis stroke and CHD after adjusting for environmental factors in both samples for both diseases (thrombosis stroke discovery set: odds ratio [OR]=1.35, P=0.032; replication set: OR=1.51, P= 0.006; CHD discovery set: OR=1.45, P=0.035; replication set: OR=1.47, P=0.003). Conclusions: Our results suggest that the DDAH1 loss-of-function polymorphism is associated with both increased risk of thrombosis stroke and CHD.