Analysis of possible association between α-tocopherol transfer protein gene and diabetes mellitus or its clinical complications.

我们发现，与非糖尿病患者相比，糖尿病患者血清α和γ-生育酚水平明显降低。人类α-生育酚转移蛋白（α-TTP）基因内含子4的C-to-T多态性与血清生育酚水平有关（t等位基因与较低水平相关）。我们进一步筛选了人α-TTP基因的基因突变或基因变异，并在推测的转录起始位点上游335个核苷酸处发现了可变数量（9 ~ 12个）的腺嘌呤重复序列。-335A(n)多态性的等位基因频率为：(10) >(11) > >(9)、(10)。内含子4c /T多态性和-335A(n)多态性几乎处于紧密连锁不平衡状态，T等位基因与A(11)-等位基因连锁。293细胞荧光素酶启动子实验表明，含有A(11)-等位基因的报告基因结构的启动子活性明显低于含有A(10)-等位基因的报告基因结构。在糖尿病患者中，t等位基因以及A（11）等位基因已被证明与糖尿病视网膜病变的发生有关[OR=1.76 (95%CI: 1.03-2.89)]。这些结果鼓励进一步研究α-TTP与糖尿病并发症之间的可能关联。

We found that serum levels of α-and γ-tocopherol were significantly decreased in patients with diabetes mellitus as compared with non-diabetic subjects. A C-to-T polymorphism in intron 4 of the human α-tocopherol transfer protein (α-TTP) gene has been shown to be associated with serum tocopherol levels (T-allele associated with lower levels). We further screened the human α-TTP gene for gene mutation or gene variant, and identified a variable number (9〜12) of adenine nucleotide repeat located 335 nucleotides upstream of the putative transcription initiation site. The allelic frequency of the -335A(n) polymorphism was as follows ; A(10)>A(11)>>A(9), A(10). Both the intron 4 C/T polymorphism and the -335A(n) polymorphism were almost in tight linkage disequilibrium, with the T-allele linked to the A(11)-allele. Luciferase promoter assay in 293 cells revealed that the reporter construct containing the A(11)-allele had significantly lower promoter activity than that containing the A(10)-allele. Among diabetic patients, the T-allele, and therefore the A(11)-allele as well, have been shown to be associated with occurrence of diabetic retinopathy [OR=1.76 (95%CI : 1.03-2.89). These results encourage further investigation about possible association between α-TTP and diabetic complications.