Department of Medical and Surgical Sciences, University "Magna Graecia" of Catanzaro, Viale Europa, 88100, Catanzaro, Italy.
Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
Cardiovasc Diabetol. 2019 Aug 13;18(1):102. doi: 10.1186/s12933-019-0906-1.
Myocardial infarction is the main mortality cause in patients with type 2 diabetes (T2DM). Endothelial dysfunction due to reduced bioavailability of nitric oxide (NO) is an early step of atherogenesis. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of NO synthesis, and it is metabolized by the enzymes dimethylarginine dimethylaminohydrolase (DDAH) 1 and 2. The functional variant rs9267551 C, in the promoter region of DDAH2, has been linked to increased DDAH2 expression, and lower ADMA plasma levels, and was associated with lower risk of coronary artery disease in large-scale genome-wide association studies (GWAS) performed in the general population. However, it is unknown whether this association holds true in T2DM patients. To address this issue, we investigated whether rs9267551 is associated with risk of myocardial infarction in two cohorts of T2DM patients.
SNP rs9267551 was genotyped in 1839 White T2DM patients from the Catanzaro Study (CZ, n = 1060) and the Gargano Heart Study-cross sectional design (GHS, n = 779). Cases were patients with a previous myocardial infarction, controls were asymptomatic patients with neither previous myocardial ischemia nor signs of it at resting and during a maximal symptom limited stress electrocardiogram.
Carriers of allele rs9267551 C showed a dose dependent reduction in the risk of myocardial infarction [(CZ = OR 0.380, 95% CI 0.175-0.823, p = 0.014), (GHS = 0.497, 0.267-0.923, p = 0.027), (Pooled = 0.458, 0.283-0.739, p = 0.001)] which remained significant after adjusting for sex, age, BMI, smoking, HbA1c, total cholesterol HDL, and triglyceride levels [(CZ = 0.307, 0.106-0.885, p = 0.029), (GHS = 0.512, 0.270-0.970, p = 0.040), (Pooled = 0.458, 0.266-0.787, p = 0.005)].
We found that rs9267551 polymorphism is significantly associated with myocardial infarction in T2DM patients of European ancestry from two independent cohorts. It is possible that in subjects carrying the protective C allele less ADMA accumulates in endothelial cells causing vascular protection as a consequence of higher nitric oxide availability.
心肌梗死是 2 型糖尿病（T2DM）患者的主要死亡原因。由于一氧化氮（NO）生物利用度降低导致的内皮功能障碍是动脉粥样硬化形成的早期步骤。不对称二甲基精氨酸（ADMA）是一种内源性的 NO 合成抑制剂，它由酶二甲基精氨酸二甲氨基水解酶（DDAH）1 和 2 代谢。位于 DDAH2 启动子区域的功能性变体 rs9267551C 与 DDAH2 表达增加和 ADMA 血浆水平降低有关，并与大规模全基因组关联研究（GWAS）中一般人群的冠状动脉疾病风险降低相关。然而，在 T2DM 患者中，这种关联是否成立尚不清楚。为了解决这个问题，我们研究了 rs9267551 是否与 T2DM 患者的心肌梗死风险相关。
在来自卡坦扎罗研究（CZ，n=1060）和加加诺心脏研究-横断面设计（GHS，n=779）的 1839 名白种 T2DM 患者中对 SNP rs9267551 进行了基因分型。病例为既往心肌梗死患者，对照为无症状患者，静息时和最大症状限制心电图检查时均无心肌缺血或心肌缺血迹象。
携带等位基因 rs9267551C 的个体患心肌梗死的风险呈剂量依赖性降低[（CZ=OR 0.380，95%CI 0.175-0.823，p=0.014），（GHS=0.497，0.267-0.923，p=0.027），（汇总=0.458，0.283-0.739，p=0.001）]，经性别、年龄、BMI、吸烟、HbA1c、总胆固醇、高密度脂蛋白和甘油三酯水平校正后仍具有显著性[（CZ=0.307，0.106-0.885，p=0.029），（GHS=0.512，0.270-0.970，p=0.040），（汇总=0.458，0.266-0.787，p=0.005）]。
我们发现 rs9267551 多态性与来自两个独立队列的欧洲裔 T2DM 患者的心肌梗死显著相关。携带保护性 C 等位基因的个体中，内皮细胞中 ADMA 的积累可能较少，导致一氧化氮可用性增加，从而导致血管保护。
