DDAH1 promoter -396 4N insertion variant is associated with increased risk of type 2 diabetes in a gender-dependent manner
DDAH1 promoter -396 4N insertion variant is associated with increased risk of type 2 diabetes in a gender-dependent manner
复制标题
DDAH1启动子-396 4N插入变异与2型糖尿病风险增加相关，且存在性别依赖性
DOI：
10.1002/mgg3.1011
复制
发表时间：
2019
影响因子：
2
通讯作者：
Wang Dao Wen
中科院分区：
文献类型：
--
作者：
Zhu Fasheng;Zhou Chi;Wen Zheng;Wang Dao Wen
背景不对称二甲基精氨酸（ADMA）是一种内源性一氧化氮合酶抑制剂，是糖尿病的促发因素。内源性ADMA被二甲基精氨酸二甲氨基水解酶1（DDAH 1）水解，DDAH 1启动子-396 4 N缺失/插入多态性（DDAH 1：-396_-395 insGCGT）调节其转录活性。本研究旨在探讨这种多态性和2型糖尿病（T2 DM）之间的关联。MethodsIn病例对照研究，所有参与者在两组人群中进行基因分型（发现：1，227 T2 DM患者和1，339对照;复制：1，190例患者和1，651对照）。通过非条件logistic回归模型评估疾病相关性。结果DDAH 1：-396_-395 insGCGT插入等位基因与2型糖尿病的发病风险显著相关（发现：调整优势比[OR] = 1.380，95%CI = 1.128- 1.687，p = 0.002;重复：OR = 1.231，95%CI = 1.007- 1.504，p = 0.043）。携带Ins/Ins等位基因的参与者的胰岛素抵抗的稳态模型评估增加（p= 0.0452）。有趣的是，插入等位基因增加了男性2型糖尿病的风险，但在女性中没有（男性发现：OR = 1.528，95% CI = 1.141- 2.047，p = 0.004;重复：OR = 1.439，95% CI = 1.083- 1.911，p = 0.012;女性发现：OR = 1.218，95%CI = 0.913- 1.626，p = 0.18;重复性：OR = 1.161，95%CI = 0.871- 1.548，p = 0.308）。结论DDAH 1：-396_-395 insGCGT插入等位基因与T2 DM发病风险增加相关，且呈性别依赖性，男性受影响，女性不受影响。
BackgroundAsymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthases, making it a contributing factor for diabetes. Endogenous ADMA is hydrolyzed by dimethylarginine dimethylaminohydrolase 1 (DDAH1), and aDDAH1promoter ‐396 4N deletion/insertion polymorphism (DDAH1:‐396_‐395insGCGT) regulates its transcriptional activity. This study aimed to explore the association between this polymorphism and type 2 diabetes (T2DM).MethodsIn a case–control study, all participants were genotyped for this polymorphism within two sets of populations (discovery: 1,227 T2DM patients and 1,339 controls; replication: 1,190 patients and 1,651 controls). The disease association was assessed by a unconditional logistic regression model. Homeostasis model assessment calculations were conducted among different genotypes.ResultsWe identified thatDDAH1:‐396_‐395insGCGT insertion allele was significantly associated with increased risk of T2DM (discovery: adjusted odds ratio [OR] = 1.380, 95% CI = 1.128–1.687,p= .002; replication: OR = 1.231, 95% CI = 1.007–1.504,p= .043). The homeostasis model assessment of insulin resistance was increased in participants carrying Ins/Ins alleles (p= .0452). Interestingly, the insertion allele increased the risk of T2DM in males but not in females (male discovery: OR = 1.528, 95% CI = 1.141–2.047,p= .004; replication: OR = 1.439, 95% CI = 1.083–1.911,p= .012; female discovery: OR = 1.218, 95% CI = 0.913–1.626,p= .18; replication: OR = 1.161, 95% CI = 0.871–1.548,p= .308).ConclusionTheDDAH1:‐396_‐395insGCGT insertion allele is associated with increased risk of T2DM in a gender‐dependent manner, affects males but not females.