What Is the Contribution of Two Genetic Variants Regulating VEGF Levels to Type 2 Diabetes Risk and to Microvascular Complications?
What Is the Contribution of Two Genetic Variants Regulating VEGF Levels to Type 2 Diabetes Risk and to Microvascular Complications?
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DOI：
10.1371/journal.pone.0055921
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发表时间：
2013-02-06
期刊：
影响因子：
3.7
通讯作者：
Visvikis-Siest, Sophie
中科院分区：
文献类型：
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作者：
Bonnefond, Amelie;Saulnier, Pierre-Jean;Visvikis-Siest, Sophie
血管内皮生长因子（VEGF）是一种参与组织生长和器官修复过程，特别是血管生成的关键趋化因子。循环VEGF水平升高被认为在2型糖尿病（T2 D）微血管并发症，特别是糖尿病视网膜病变中起作用。最近，一项全基因组关联研究确定了两种常见的单核苷酸多态性（SNP; rs6921438和rs 10738760），解释了循环VEGF水平的近一半差异。考虑到VEGF对T2 D及其并发症的假定贡献，我们的目的是评估这些VEGF相关SNP对T2 D、肾病和视网膜病风险以及相关性状变异的影响。在几项病例对照研究中对SNP进行了基因分型：法国和丹麦的T2 D研究（N-病例= 6，920-N-对照= 3，875和N-病例= 3，561-N-对照= 2，623;法国的两项研究，一项是糖尿病肾病（N-病例= 1，242-N-对照= 860），另一组用于糖尿病视网膜病变（N-病例= 1，336-N-对照= 1，231）。在一项基于法国普通人群的队列（N = 4，760）和两项法国T2 D研究（N = 3，480）中分析了每种SNP对数量性状的影响。使用逻辑回归或线性回归评估SNP关联。在法国人群中，我们发现rs6921438的G等位基因（显示增加循环VEGF水平）与T2 D风险增加之间存在关联（OR = 1.15; P = 3.7 x 10（-5））。此外，相同的等位基因与较高的糖化血红蛋白水平相关（β = 0.02%; P = 9.2 × 10 - 3）。然而，这些发现在丹麦人中没有得到证实。相反，SNP rs 10738760与法国或丹麦人群中的T2 D无关。尽管有足够的统计功效，但我们没有发现rs6921438或rs 10738760对糖尿病微血管并发症或T2 D患者相关性状的变化有任何显著影响。尽管SNP rs6921438和rs 10738760对循环VEGF的变化有影响，但我们没有发现SNP rs6921438和rs 10738760与T2 D、糖尿病肾病或视网膜病变的风险之间存在任何关联。VEGF和T2 D及其并发症之间的联系可能是间接的，比预期的更复杂。
Vascular endothelial growth factor (VEGF) is a key chemokine involved in tissue growth and organ repair processes, particularly angiogenesis. Elevated circulating VEGF levels are believed to play a role in type 2 diabetes (T2D) microvascular complications, especially diabetic retinopathy. Recently, a genome-wide association study identified two common single nucleotide polymorphisms (SNPs; rs6921438 and rs10738760) explaining nearly half of the variance in circulating VEGF levels. Considering the putative contribution of VEGF to T2D and its complications, we aimed to assess the effect of these VEGF- related SNPs on the risk of T2D, nephropathy and retinopathy, as well as on variation in related traits. SNPs were genotyped in several case-control studies: French and Danish T2D studies (N-cases = 6,920-N-controls = 3,875 and N-cases = 3,561-N-controls = 2,623; respectively), two French studies one for diabetic nephropathy (N-cases = 1,242-N-controls = 860) and the other for diabetic retinopathy (N-cases = 1,336-N-controls = 1,231). The effects of each SNP on quantitative traits were analyzed in a French general population- based cohort (N = 4,760) and two French T2D studies (N = 3,480). SNP associations were assessed using logistic or linear regressions. In the French population, we found an association between the G-allele of rs6921438, shown to increase circulating VEGF levels, and increased T2D risk (OR = 1.15; P = 3.7 x 10(-5)). Furthermore, the same allele was associated with higher glycated hemoglobin levels (beta = 0.02%; P = 9.2 x 10(-3)). However, these findings were not confirmed in the Danes. Conversely, the SNP rs10738760 was not associated with T2D in the French or Danish populations. Despite having adequate statistical power, we did not find any significant effects of rs6921438 or rs10738760 on diabetic microvascular complications or the variation in related traits in T2D patients. In spite of their impact on the variance in circulating VEGF, we did not find any association between SNPs rs6921438 and rs10738760, and the risk of T2D, diabetic nephropathy or retinopathy. The link between VEGF and T2D and its complications might be indirect and more complex than expected.