Vionnet Nathalie, Tregouët David, Kazeem Gbenga, Gut Ivo, Groop Per-Henrik, Tarnow Lise, Parving Hans-Henrik, Hadjadj Samy, Forsblom Carol, Farrall Martin, Gauguier Dominique, Cox Roger, Matsuda Fumihiko, Heath Simon, Thévard Alexandre, Rousseau Rachel, Cambien François, Marre Michel, Lathrop Mark
INSERM U525, Centre National de Génotypage, 2, Rue Gaston Crémieux, 91006 Evry Cedex, France.
Diabetes. 2006 Nov;55(11):3166-74. doi: 10.2337/db06-0271.
Linkage studies have mapped loci for diabetic nephropathy and associated phenotypes on chromosome 3q. We studied 14 plausible candidate genes in the linkage region because of their potential role in vascular complications. In a large-scale study of patients from Denmark, Finland, and France who have type 1 diabetes, 1,057 case and 1,127 control subjects, as well as 532 trios, were investigated for association with diabetic nephropathy. We analyzed 69 haplotype-tagging single nucleotide polymorphisms and nonsynonymous variants that were identified by sequencing. Polymorphisms in three genes, glucose transporter 2 (SLC2A2), kininogen (KNG1), and adiponectin (ADIPOQ), showed nominal association with diabetic nephropathy in single-point analysis. The T-allele of SLC2A2_16459CT was associated with a decreased risk of diabetic nephropathy (odds ratio 0.79 [95% CI 0.66-0.96], P = 0.016), whereas the T-allele of KNG_7965CT and the A-allele of ADIPOQ_prom2GA were associated with increased risk of nephropathy (1.17 [1.03-1.32], P = 0.016; 1.46 [1.11-1.93], P = 0.006, respectively). Analyses of the transmission disequilibrium test showed similar trends only for ADIPOQ_prom2GA with the overtransmission of the A-allele to patients with diabetic nephropathy (1.52 [0.86-2.66], P = NS) and of the G-allele to patients without diabetic nephropathy (0.50 [0.27-0.92], P = 0.026). The overall significance for this variant (nominal P = 0.011) suggests that ADIPOQ might be involved in the development of diabetic nephropathy.
连锁研究已将糖尿病肾病及相关表型的基因座定位到3号染色体长臂上。由于其在血管并发症中的潜在作用，我们研究了该连锁区域内14个可能的候选基因。在一项针对来自丹麦、芬兰和法国的1型糖尿病患者的大规模研究中，对1057例病例和1127例对照受试者以及532个三联体进行了糖尿病肾病相关性调查。我们分析了通过测序鉴定出的69个单倍型标签单核苷酸多态性和非同义变异。在单点分析中，葡萄糖转运蛋白2（SLC2A2）、激肽原（KNG1）和脂联素（ADIPOQ）这三个基因中的多态性与糖尿病肾病呈名义上的关联。SLC2A2_16459CT的T等位基因与糖尿病肾病风险降低相关（优势比0.79 [95%可信区间0.66 - 0.96]，P = 0.016），而KNG_7965CT的T等位基因和ADIPOQ_prom2GA的A等位基因与肾病风险增加相关（分别为1.17 [1.03 - 1.32]，P = 0.016；1.46 [1.11 - 1.93]，P = 0.006）。传递不平衡检验分析仅显示ADIPOQ_prom2GA有类似趋势，即A等位基因向糖尿病肾病患者的过度传递（1.52 [0.86 - 2.66]，P = 无显著性差异）以及G等位基因向无糖尿病肾病患者的传递（0.50 [0.27 - 0.92]，P = 0.026）。该变异的总体显著性（名义P = 0.011）表明脂联素可能参与糖尿病肾病的发生发展。
