中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (8): 1592-1597.doi: 10.4103/1673-5374.303037

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

二甲精氨酸二甲胺水解酶2 (-449 G/C) G等位基因与中国东北地区脑白质疏松发病呈正相关：一项组间配对病例对照双盲研究

  

  • 出版日期:2021-08-15 发布日期:2021-01-13
  • 基金资助:

    哈尔滨市科技局基金项目（2014RFQGJ042）；哈尔滨医科大学科研创新基金（2016LCZX06）；黑龙江自然科学基金项目（H2016027）

DDAH2 (-449 G/C) G allele is positively associated with leukoaraiosis in northeastern China: a double-blind, intergroup comparison, case-control study

Ying Fan1, *, #, Qiang Gao1, #, Jia-Xin Guan1, #, Lei Liu1, Ming Hong2, Li Jun3, Li Wang1, Hai-Feng Ding1, Li-Hong Jiang1, Bo-Yu Hou1, Mei Li1, Zhi-Qiang Song1, De-Qin Sun1, Chao-Qi Yan4, *, Lan Ma1, *   

  1. 1Department of Geriatrics, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China; 2Department of Geriatrics, Tongling Municipal Hospital, Tongling, Anhui Province, China; 3Department of Cardiovascular Medicine, Shanxi Cardiovascular Hospital, Taiyuan, Shanxi Province, China; 4Physical Examination Center, The 2nd Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang Province, China
  • Online:2021-08-15 Published:2021-01-13
  • Contact: Ying Fan, PhD, fanyingyan@163.com; Chao-Qi Yan, PhD, yanchaoqi2002@163.com; Lan Ma, PhD, lilyma70@163.com.
  • Supported by:
    This study was supported by the Foundation of Harbin Science Technology Bureau of China, No. 2014RFQGJ042 (to YF), Harbin Medical University Scientific Research Innovation Fund of China, No. 2016LCZX06 (to QG), and the Natural Science Foundation of Heilongjiang of China, No. H2016027 (to QG).

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摘要：

脑血管内皮功能障碍参与了白质病变的进展。不对称二甲基精氨酸是一氧化氮的竞争性抑制剂，可在脑白质疏松患者中高表达。二甲精氨酸二甲胺水解酶是一种水解酶，可负责消除不对称二甲精氨酸，能在心脑血管疾病的发病机制中发挥作用。尚不清楚二甲精氨酸二甲胺水解酶基因多态性是否影响脑白质疏松血浆不对称二甲基精氨酸水平。此次组间配对病例对照双盲试验纳入了来自中国东北的46例脑白质疏松和46例健康对照。结果发现①95.65%脑白质疏松患者基因型为隐性遗传模型（GG和CG基因型），而89.13%健康对照为显性遗传模型（CC和CG基因型）。2组基因型组成存在明显差异(P = 0.0002)。与健康对照相比，脑白质疏松患者G等位基因频率较高，而C等位基因频率较低(χ2 = 13.9580, P = 0.0002)。②GG基因型者不对称二甲基精氨酸浓度高于CG和CC基因型受试者(Kruskal-Wallis H = 24.5955, P < 0.0001)。③DDAH 2（-449 G / C）的GG基因型在脑白质疏松患者中更为常见。④表明DDAH 2（-449 G / C）的G等位基因是脑白质疏松发病的危险因素，且与较高的不对称二甲基精氨酸水平相关。试验于2016年7月28日获得哈尔滨医科大学附属第二医院伦理委员会批准，批准号KY2016-177。

https://orcid.org/0000-0001-7443-1637 (Ying Fan)

关键词: 脑白质疏松, 二甲基精氨酸, 二甲精氨酸二甲胺水解酶2, 基因多态性, 等位基因, 不对称二甲基精氨酸, 一氧化氮, 内皮功能障碍, 脑血管疾病, 临床研究

Abstract: Cerebrovascular endothelial dysfunction is involved in the progression of leukoaraiosis. Asymmetric dimethylarginine is a competitive inhibitor of nitric oxide, which is highly expressed in patients with leukoaraiosis. Dimethylarginine dimethylaminohydrolase (DDAH) is a hydrolytic enzyme that is primarily responsible for eliminating asymmetric dimethylarginine, and it plays a role in the pathogenesis of cardiovascular and cerebrovascular diseases. The DDAH2 subtype is expressed in organs rich in induced nitric oxide synthase, including the heart, the placenta, and the cerebral endothelium during cerebral ischemia, in the stress state, or under neurotoxicity. Overexpression of the DDAH2 gene can inhibit asymmetric dimethylarginine-induced peripheral circulating endothelial cell dysfunction. However, it is unknown whether this polymorphism regulates plasma asymmetric dimethylarginine levels in patients with leukoaraiosis. In this double-blind study, we recruited 46 patients with leukoaraiosis and 46 healthy, matched controls. Plasma asymmetric dimethylarginine levels were determined using enzyme-linked immunoassays. Genomic DNA was isolated from whole blood samples, and polymerase chain reaction, SmaI restriction enzyme digestion, restriction fragment length polymorphisms, and agarose electrophoresis were used to detect DDAH2 (-449 G/C) gene polymorphisms. The results revealed that 95.65% of leukoaraiosis patients had recessive genetic models (GG and CG), while 89.13% of healthy control subjects had dominant genetic models (CC and CG). There was a significant difference in the genotype composition ratio between leukoaraiosis patients and healthy controls (P = 0.0002). The frequency of G alleles in the leukoaraiosis patients (71.74%) was significantly higher than in healthy controls, whereas the frequency of C alleles was lower (χ2 = 13.9580, P = 0.0002). Furthermore, asymmetric dimethylarginine concentrations in subjects with the GG genotype were significantly higher than in subjects with the CG and CC genotypes (Kruskal–Wallis H = 24.5955, P < 0.0001). In addition, the GG genotype of DDAH2 (-449 G/C) was more common in patients with leukoaraiosis. These findings suggest that the G allele of DDAH2 (-449 G/C) is a risk factor for leukoaraiosis morbidity and is correlated with high levels of asymmetric dimethylarginine. This study was approved by the Institutional Ethics Committee of the 2nd Affiliated Hospital of Harbin Medical University of China (approval No. KY2016-177) on July 28, 2016.

Key words: leukoaraiosis, dimethylarginine dimethylaminohydrolase 2, gene polymorphism, allele, asymmetric dimethylarginine, nitric oxide, endothelial dysfunction, cerebrovascular diseases, clinical trial