Maeda Makiko, Yamamoto Isamu, Fukuda Masakatsu, Motomura Takashi, Nishida Mari, Nonen Shinpei, Fujio Yasushi, Kasayama Soji, Azuma Junichi
Department of Clinical Evaluation of Medicines and Therapeutics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan.
J Diabetes Complications. 2008 Mar-Apr;22(2):119-25. doi: 10.1016/j.jdiacomp.2006.12.002.
Previously, we have proposed that methylenetetrahydrofolate reductase (MTHFR) gene polymorphism (C677T) could be a risk factor for diabetic retinopathy. To support our suggestion, we examined in detail the association of MTHFR polymorphism with diabetic retinopathy and nephropathy in Japanese type 2 diabetic patients.
Subjects (n=190) were free of cardiovascular diseases and were not on hemodialysis. Retinopathy was assessed according to fundamental differentiation; nephropathy was determined according to urinary albumin level; and MTHFR genotype was determined by polymerase chain reaction-restriction fragment length polymorphism. We also analyzed how hyperglycemia affected these three conditions in 131 patients with glycosylated hemoglobin > or =6.5% and fasting blood sugar > or =110 mg/dl.
The frequency of 677T/677T homozygous subjects with retinopathy was higher than the frequencies of the other two genotypes, and a significant difference was observed in the distribution of the genotypes (677C/677C, 41.9%; 677C/677T, 31.1%; 677T/677T, 61.5%; P<.05). The susceptibility of 677T/677T homozygote to retinopathy approached significance [odds ratio (OR)=2.17; 95% confidence interval (95% CI)=0.87-5.42]. However, in the population with hyperglycemia, the 677T/677T homozygote modified the risk for retinopathy (OR=4.30; 95% CI=1.42-13.1), especially the risk for nonproliferative retinopathy. In contrast, the 677T/677T homozygote did not affect the risk for nephropathy (OR=1.17; 95% CI=0.45-3.05), even in subjects with hyperglycemia (OR=1.50; 95% CI=0.50-4.48).
Our results are highly suggestive of an important role for MTHFR genotype in susceptibility to retinopathy under hyperglycemia, but not to nephropathy. Preventive therapies based on MTHFR polymorphism could delay the onset of retinopathy in type 2 diabetic patients.
此前，我们曾提出亚甲基四氢叶酸还原酶（MTHFR）基因多态性（C677T）可能是糖尿病视网膜病变的一个风险因素。为支持我们的观点，我们详细研究了日本2型糖尿病患者中MTHFR多态性与糖尿病视网膜病变及肾病之间的关联。
研究对象（n = 190）无心血管疾病且未接受血液透析。根据基本分级评估视网膜病变；根据尿白蛋白水平确定肾病；通过聚合酶链反应 - 限制性片段长度多态性确定MTHFR基因型。我们还分析了131例糖化血红蛋白≥6.5%且空腹血糖≥110mg/dl的患者中高血糖如何影响这三种情况。
患有视网膜病变的677T/677T纯合子受试者的频率高于其他两种基因型的频率，并且在基因型分布上观察到显著差异（677C/677C，41.9%；677C/677T，31.1%；677T/677T，61.5%；P <.05）。677T/677T纯合子对视网膜病变的易感性接近显著水平[比值比（OR）= 2.17；95%置信区间（95%CI）= 0.87 - 5.42]。然而，在高血糖人群中，677T/677T纯合子改变了视网膜病变的风险（OR = 4.30；95%CI = 1.42 - 13.1），尤其是非增殖性视网膜病变的风险。相比之下，即使在高血糖受试者中，677T/677T纯合子也不影响肾病风险（OR = 1.17；95%CI = 0.45 - 3.05）（OR = 1.50；95%CI = 0.50 - 4.48）。
我们的结果强烈提示MTHFR基因型在高血糖状态下对视网膜病变的易感性中起重要作用，但对肾病不起作用。基于MTHFR多态性的预防性治疗可能会延缓2型糖尿病患者视网膜病变的发生。
