Diabetic retinopathy (DR) is a microvascular complication of diabetes and proliferative diabetic retinopathy (PDR) is the most vision threatening form of DR and the leading cause of blindness in individuals aged 20-74 years. Genetic endowment is thought to play a role in development of DR. The adenosine A2 receptor (ADORA2A) is associated with decreased tissue impairment caused by inflammation, hypoxia, and oxidative stress, while vascular endothelial growth factor (VEGF) is associated with hypertension, vascular permeability, and neoangiogenesis, and is elevated in those with DR. The aim of this study was to determine if the ADORA2A or the VEGF genes are associated with prevalent baseline PDR (PBPDR) or prospective incident PDR (PIPDR) in participants of the Epidemiology of Diabetes Complications (EDC) prospective study of childhood onset type 1 diabetes. Two tagging single nucleotide polymorphisms (tSNPs) of the ADORA2A gene (rs2236624 and rs4822489) and 4 SNPs of the VEGF gene (rs2146323, rs833069, rs699947, rs10434) were genotyped and assessed for association with prevalence and incidence of PDR, while controlling for traditional covariates.
Univariate analysis of ADORA2A rs2236624 was associated with PBPDR [OR=1.68; (95%CI=1.11-2.54); p=0.03] and PIPDR [HR=0.17; (95%CI=0.04-0.69); p=0.01]. These associations were sustained in the multivariate analysis with rs2236624-CT being significantly associated with PBPDR [OR=2.17; (95%CI=1.24-3.81); p=0.03]. In the Cox analysis rs2236624-CT [HR= 1.54; (95%CI=1.08-2.18); p=0.02] and rs2236624-TT [HR=0.10; (95%CI=0.01-0.72); p= 0.02] were significantly associated with PIPDR. Analysis of the rs4822489 tSNP found an association between the GT genotype and PIPDR in the univariate analysis [HR=1.53; (95%CI: =1.12-2.09); p=0.008], and in the multivariate analyses [HR=1.57; (95%CI: =1.13-2.17); p=0.0067] after controlling for covariates. To determine if there was increased risk associated with the 4822489 genotypes and PBPDR participants were stratified into late onset (PDR ≥25 years T1d duration), early onset (PDR<25 years T1D duration), and protected (No PDR during follow-up) groups. Those with the GT genotype had a significantly increased association [OR=1.93; (95%CI: =1.11-3.35); p=0.03] with early onset PDR compared to the protected group. The association between the GT genotype of the rs4822489 tSNP was only marginally significant [OR=1.73; (95%CI: =0.89-3.36); p=0.12] in the multivariate analyses after controlling for covariates. Furthermore univariately, the GG genotype of VEGF rs10434 was marginally [OR=1.3; (95%CI=0.75-2.28); p=0.14) associated with PBPDR but, multivariately significantly [OR=2.47; (95%CI=1.15-5.3); p=0054] associated with baseline PBPDR. Hypertension status [OR=3.93 (95%CI=1.98-7.8); p =<0.0001] low density lipoprotein [OR=1.01; (95%CI=1.004-1.02); p=0.0050] and duration [OR=1.21 (95%CI=1.12-1.3); p=<0.0001] were also significantly associated with PBPDR. None of the VEGF SNPs were associated with PIPDR. Additional analysis showed a significant (p=0.045) direct univariate association between the AG genotype of rs10434 and hypertension.
In the EDC population heterozygosity for the rs2236624 tSNP of the ADORA 2A gene is associated with susceptibility to PDR while homozygosity for the (T) allele of rs2236624 tSNP is associated with protection form development of incident PDR. While homozygosity of the VEGF rs10434 tSNP is associated with baseline prevalent PDR and heterozygosity for the rs10434 tSNP is associated with baseline prevalent hypertension.
|Advisor:||Orchard, Yvette J.|
|School:||University of Pittsburgh|
|School Location:||United States -- Pennsylvania|
|Source:||DAI-B 70/03, Dissertation Abstracts International|
|Keywords:||Adenosine A2 receptor, Diabetic retinopathy, Single nucleotide polymorphisms, Type 1 diabetes, VEGF|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be