与A1298C多态性相关的启动子高甲基化模式影响糖尿病患者的脂质参数和血糖控制。
The promoter hypermethylation pattern associated with the A1298C polymorphism influences lipid parameters and glycemic control in diabetic patients.
作者信息
Santana Bezerra Herlanny, Severo de Assis Caroline, Dos Santos Nunes Mayara Karla, Wanderley de Queiroga Evangelista Isabella, Modesto Filho João, Alves Pegado Gomes Cecília Neta, Ferreira do Nascimento Rayner Anderson, Pordeus Luna Rafaella Cristhine, de Carvalho Costa Maria José, de Oliveira Naila Francis Paulo, Camati Persuhn Darlene
机构信息
1Scientific Initiation Program, Federal University of Paraiba, Joao Pessoa, Brazil.
2Nutrition Sciences, Federal University of Paraiba, Joao Pessoa, Brazil.
出版信息
Diabetol Metab Syndr. 2019 Jan 15;11:4. doi: 10.1186/s13098-019-0399-9. eCollection 2019.
BACKGROUND
Polymorphisms in the gene encoding methylenetetrahydrofolate reductase (MTHFR) have been investigated as risk factors for microvascular complications of diabetes; however, simultaneous analysis of these polymorphisms and the methylation pattern of the gene has never been conducted. The objective of the present study was to evaluate the simultaneous relationship between methylation and C6TT7 and A1298C polymorphisms with metabolic, inflammatory and oxidative stress parameters related to microvascular complications, diabetic retinopathy (DR) and diabetic nephropathy (DN) in diabetic patients.
METHODS
A total of 107 patients who were diagnosed in the previous 5 to 10 years were recruited and divided into groups with complications (DR and/or DN) or without complications. Methylation analysis of the gene promoter was conducted using the MSP technique, and analysis of the A1298C and C677T polymorphisms was conducted using the restriction fragment length polymorphism (RFLP) assay. Microalbuminuria was determined using urine samples, and other analytes of interest were determined in blood samples using commercial kits. The Mann-Whitney and Chi square statistical tests were used with significance considered at p < 0.05.
RESULTS
Subjects with a hypermethylated profile and the 1298AA genotype showed the highest levels of blood glucose (p = 0.03), total cholesterol (p = 0.0001) and LDL cholesterol (p = 0.0006). The same profile was associated with higher levels of HbA1c (p = 0.025), glycemia (p = 0.04) and total cholesterol (0.004) in the control group and total cholesterol (p = 0.005) and LDL cholesterol (p = 0.002) in the complications group. Serum creatinine was higher in subjects in the hypermethylated group with the genotype 677CC only in the control group (p = 0.0020). The methylated profile in presence of 677CC + 1298AA and the 677CT/TT +1298AA haplotypes showed higher levels of total cholesterol (p = 0.0024; 0.0031) and LDL cholesterol (p = 0.0060; 0.0125) than 1298AC/CC carriers. The fasting glycemia was higher in hypermethylated profile in the presence of 677CC/1298AA haplotype (p = 0.0077).
CONCLUSION
The hypermethylated methylation profile associated with the 1298AA genotype appeared to be connected to higher values of glycemia, total cholesterol and LDL cholesterol.
背景
编码亚甲基四氢叶酸还原酶（MTHFR）的基因多态性已被作为糖尿病微血管并发症的危险因素进行研究；然而，从未对这些多态性与该基因的甲基化模式进行过同步分析。本研究的目的是评估糖尿病患者中甲基化与C677T和A1298C多态性与微血管并发症、糖尿病视网膜病变（DR）和糖尿病肾病（DN）相关的代谢、炎症和氧化应激参数之间的同步关系。
方法
共招募了107例在过去5至10年被诊断的患者，并将其分为有并发症（DR和/或DN）或无并发症的组。使用甲基化特异性PCR（MSP）技术对基因启动子进行甲基化分析，并使用限制性片段长度多态性（RFLP）分析对A1298C和C677T多态性进行分析。使用尿液样本测定微量白蛋白尿，并使用商业试剂盒在血液样本中测定其他感兴趣的分析物。采用Mann-Whitney和卡方统计检验，以p<0.05为有统计学意义。
结果
甲基化水平高且基因型为1298AA的受试者血糖（p=0.03）、总胆固醇（p=0.0001）和低密度脂蛋白胆固醇（p=0.0006）水平最高。在对照组中，相同的甲基化模式与较高的糖化血红蛋白（HbA1c）水平（p=0.025）、血糖水平（p=0.04）和总胆固醇水平（0.004）相关，在并发症组中与总胆固醇水平（p=0.005）和低密度脂蛋白胆固醇水平（p=0.002）相关。仅在对照组中，甲基化水平高且基因型为677CC的受试者血清肌酐较高（p=0.0020）。存在677CC+1298AA和677CT/TT+1298AA单倍型的甲基化模式显示，总胆固醇（p=0.0024；0.0031）和低密度脂蛋白胆固醇（p=0.0060；0.0125）水平高于1298AC/CC携带者。存在677CC/1298AA单倍型时，甲基化水平高的空腹血糖水平较高（p=0.0077）。
结论
与1298AA基因型相关的高甲基化甲基化模式似乎与较高的血糖、总胆固醇和低密度脂蛋白胆固醇值有关。
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