Aldose reductase gene polymorphisms and susceptibility to diabetic nephropathy in Type 1 diabetes mellitus
Aldose reductase gene polymorphisms and susceptibility to diabetic nephropathy in Type 1 diabetes mellitus
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DOI：
10.1046/j.1464-5491.2000.00225.x
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发表时间：
2000-02-01
影响因子：
3.5
通讯作者：
Krolewski, AS
中科院分区：
文献类型：
--
作者：
Moczulski, DK;Scott, L;Krolewski, AS
目的探讨1型糖尿病肾病（DN）与醛糖还原酶（AR）基因7 q35区DNA序列变异的关系。在不相关的晚期肾病病例（n = 221）和不相关的正常白蛋白尿对照（n = 193）中，对这种多态性和已知的5 'ALR 2二核苷酸重复多态性进行基因分型。结果在病例-对照研究中，ALR 2基因5 ′端Z-2等位基因携带者发生DN的危险性显著高于非携带者（OR值分别为：杂合子1.6和纯合子2.1，P均< 0.05）。C-106 T多态性T等位基因携带者也是如此（比值比：杂合子为1.6，纯合子为1.9，P < 0.05）。同时携带两种危险等位基因的单倍型在DN患者中过多。在家庭研究中，从杂合子父母的风险等位基因的传输是一致的病例对照研究，过度传输的情况下，trios和控制trios.Conclusions之间的关联DN和AR基因的启动子区域的两个DNA序列变异暗示多元醇通路在1型糖尿病肾脏并发症的发展。进一步研究这些发现的分子机制可能有助于深入了解DN的发病机制。
Aims To investigate association and linkage between DNA sequence variants in the aldose reductase (AR) gene on chromosome 7q35 and diabetic nephropathy (DN) in Type 1 diabetes mellitus.Methods By sequencing the promoter region and 10 exons in eight DN cases and eight controls, a frequent bi-allelic polymorphism (C-106T) was discovered. This polymorphism and the known 5'ALR2 dinucleotide repeat polymorphism were genotyped in unrelated cases with advanced nephropathy (n = 221) and unrelated controls with normoalbuminuria (n = 193). For a family based study, 166 case-trios (case and both parents) and 83 control-trios (control and both parents) were also genotyped.Results In the case-control study, carriers of the Z-2 allele of the 5'ALR2 polymorphism had a significantly higher risk of DN than non-carriers (odds ratios: 1.6 for heterozygotes and 2.1 for homozygotes, P < 0.05 for each). The same was true for carriers of the T allele of the C-106T polymorphism (odds ratios: 1.6 for heterozygotes and 1.9 for homozygotes, P < 0.05 for each). Moreover, the haplotype carrying both risk alleles was in excess in DN cases. In the family study, transmission of risk alleles from heterozygous parents was consistent with the case-control study, excess transmission in case-trios and deficient in control-trios.Conclusions Association between DN and two DNA sequence variants in the promoter region of the AR gene implicates the polyol pathway in the development of kidney complications in Type 1 diabetes mellitus. Further examination of the molecular mechanisms underlying these findings may provide insight into the pathogenesis of DN.