Department of Internal Medicine-Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, 1095# Jiefang Ave., Wuhan, People's Republic of China.
Circ Res. 2010 Apr 2;106(6):1145-52. doi: 10.1161/CIRCRESAHA.109.215616. Epub 2010 Feb 18.
Asymmetrical dimethylarginine (ADMA), an endogenous arginine analogue, inhibits nitric oxide synthases and plays an important role in endothelial dysfunction.
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.
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).
Our results suggest that the DDAH1 loss-of-function polymorphism is associated with both increased risk of thrombosis stroke and CHD.
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并在血管内皮功能障碍中发挥重要作用。
本研究旨在检测二甲基精氨酸二甲氨基水解酶 1（DDAH1）中一个新的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，DDAH1 是 ADMA 水解的关键基因。
通过重测序，我们在 DDAH1 启动子中发现了一个新的 4 核苷酸缺失/插入变异。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 DDAH1mRNA 水平显著降低，进而增加了血浆 ADMA 水平和 ADMA 与 L-精氨酸的比值。我们最初对 1388 例中风患者和 1027 例对照、576 例 CHD 患者和 557 例对照进行了该多态性的基因分型，然后在包含 961 例中风患者和 822 例对照、482 例 CHD 患者和 1072 例对照的两个独立病例对照队列中进行了重复研究。我们发现，-396 4N ins 等位基因与两种疾病的环境因素调整后的血栓性中风和 CHD 风险增加显著相关（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）。
我们的结果表明，DDAH1 失功能多态性与血栓性中风和 CHD 的风险增加有关。
