Al-Kateb Hussam, Mirea Lucia, Xie Xinlei, Sun Lei, Liu Michelle, Chen Hongtao, Bull Shelley B, Boright Andrew P, Paterson Andrew D
Program in Genetics and Genome Biology, Hospital of Sick Children Research Institute, Toronto, ON, Canada.
Diabetes. 2007 Aug;56(8):2161-8. doi: 10.2337/db07-0376. Epub 2007 May 18.
We sought to determine if any common variants in the gene for vascular endothelial growth factor (VEGFA) are associated with long-term renal and retinal complications in type 1 diabetes.
A total of 1,369 Caucasian subjects with type 1 diabetes from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) Study had an average of 17 retinal photographs and 10 renal measures over 15 years. In the DCCT/EDIC, we studied 18 single nucleotide polymorphisms (SNPs) in VEGFA that represent all linkage disequilibrium bins (pairwise r(2) > or = 0.64) and tested them for association with time to development of severe retinopathy, three or more step progression of retinopathy, clinically significant macular edema, persistent microalbuminuria, and severe nephropathy.
In a global multi-SNP test, there was a highly significant association of VEGFA SNPs with severe retinopathy (P = 6.8 x 10(-5))-the four other outcomes were all nonsignificant. In survival analyses controlling for covariate risk factors, eight SNPs showed significant association with severe retinopathy (P < 0.05). The most significant single SNP association was rs3025021 (hazard ratio 1.37 [95% CI 1.13-1.66], P = 0.0017). Family-based analyses of severe retinopathy provide evidence of excess transmission of C at rs699947 (P = 0.029), T at rs3025021 (P = 0.013), and the C-T haplotype from both SNPs (P = 0.035). Multi-SNP regression analysis including 15 SNPs, and allowing for pairwise interactions, independently selected 6 significant SNPs (P < 0.05).
These data demonstrate that multiple VEGFA variants are associated with the development of severe retinopathy in type 1 diabetes.
我们试图确定血管内皮生长因子（VEGFA）基因中的任何常见变异是否与1型糖尿病的长期肾脏和视网膜并发症相关。
来自糖尿病控制与并发症试验（DCCT）/糖尿病干预与并发症流行病学（EDIC）研究的总共1369名患有1型糖尿病的白种人受试者在15年中平均有17张视网膜照片和10次肾脏测量。在DCCT/EDIC中，我们研究了VEGFA中的18个单核苷酸多态性（SNP），这些多态性代表了所有连锁不平衡区域（成对r(2)≥0.64），并测试它们与严重视网膜病变发生时间、视网膜病变三步或更多步进展、临床显著性黄斑水肿、持续性微量白蛋白尿和严重肾病的相关性。
在一项全面的多SNP测试中，VEGFA SNP与严重视网膜病变存在高度显著相关性（P = 6.8×10(-5)），其他四个结果均无显著性。在控制协变量风险因素的生存分析中，8个SNP与严重视网膜病变显示出显著相关性（P < 0.05）。最显著的单个SNP关联是rs3025021（风险比1.37 [95% CI 1.13 - 1.66]，P = 0.0017）。基于家系的严重视网膜病变分析提供了证据，表明rs699947处的C（P = 0.029）、rs3025021处的T（P = 0.013）以及两个SNP的C - T单倍型过度传递（P = 0.035）。包括15个SNP并考虑成对相互作用的多SNP回归分析独立选择了6个显著的SNP（P < 0.05）。
这些数据表明多个VEGFA变异与1型糖尿病严重视网膜病变的发生相关。
