| BackgroundDiabetes mellitus, a chronic endocrine metabolic disease, is due to relative lack of insulin in the human body. With the rapid global prevalence of diabetes, the number is projected to rise to438million by2030, and40%of them are expected to have some form of retinopathy in the late stage. Diabetic retinopathy (DR), one of the most common microvascualr complications of diabetes mellitus, is the leading cause of blindness in working-aged adults. Several factors have been strongly implicated in the development of DR through different pathways. It is well known that there is strong evidence for a genetic component in the development of DR. Studies have shown that Erythropoietin (EPO) and Transcription factor7like2(TCF7L2) gene single nucleotide polymorphisms (SNPs) were significantly associated with DR in Caucasian population. EPO, a glycoprotein hormone that stimulates the production of red blood cells, acts as a double-edged sword in the pathogenesis of DR. In the early stage of DR, the higher expression of EPO is needed as a neuroprotective factor. In advanced stages, EPO could enhance the effects of vascular endothelial growth factor (VEGF), contributing to neovascularization and, in consequence, worsening PDR. TCF7L2, a highly variable transcription factor, plays an important role in insulin resistance, blood-glucose homeostasis, beta cell function and Wnt signal pathway. Previous report demonstrate that patient with the high level of insulin resistance are more likely to have advanced retinopathy compared with insulin-sensitive ones. The Wnt signaling mediates pathological vascular growth in proliferative retinopathy. The associations between EPO, TCF7L2gene SNPs and DR in T2DM population was investigated in this study.ObjectiveThe aim of the present study was to investigate whether the polymorphisms of EPO gene (rs1617640, rs507392and rs551238) and TCF7L2gene (rs11196205) were correlated with DR, and to explore the pathogenesis of DR in T2DM population.MethodsA total of792patients with Type2diabetes mellitus (T2DM) were involved in this case-control study. The subjects were classified into two groups:patients with DR (DR group, n=448) and patients without DR (DNR group, n=344). The DR group was further subdivided into those with proliferative DR (PDR group, n=220) and those with non-proliferative DR (NPDR group, n=228). Total genomic DNA was extracted from the peripheral venous blood of each individual. The genotyping of EPO and TCF7L2gene polymorphisms was conducted using polymerase chain reaction-ligase detection reaction (PCR-LDR) sequence method. The differences in the categorical clinical data (age, gender, blood glucose, HbAlc level and duration of disease) were compared by student s test and chi-square test. SNPs genotyping results were screen for Hardy-Weinberg equilibrium (HWE) using chi-square test. Distributions of alleles, genotypes in dominant, recessive and additive models were estimated using chi-square test. Linkage disequilibrium (LD) and hapoltype analyses were performed using SHEsis and Haploview respectively. p<0.05was considered statistically significant.Results(1) EPO SNP rs1617640Allele distributionNo significant difference was detected in the allele frequency of SNP rs1617640between DR and DNR, PDR and DNR, NPDR and DNR groups (p>0.05).Genotype distribution In dominant, recessive and additive models, no significant difference was observed in the genotype distributions between DR and DNR, PDR and DNR, NPDR and DNR groups (p>0.05).(2) EPO SNP rs507392Allele distributionNo significant difference was detected in the allele frequency of SNP rs1617640between DR and DNR, PDR and DNR, NPDR and DNR groups (p>0.05).Genotype distributionIn recessive model, the frequency of genotype CC in DR (OR=0.44,95%CI:0.22-0.86,p=0.012) and PDR (OR=0.19,95%CI:0.06-0.66,p=0.003) groups was significantly lower than DNR group, and no significant difference was found between NPDR and DNR groups. In additive model, the frequency of genotype CC in DR (CC vs. TT:OR=0.45,95%CI:0.23-0.89, p=0.021) and PDR (CC vs. TT:OR=0.18,95%CI:0.05-0.63,p=0.002) groups was significantly lower than DNR group. In dominant model, no significant difference was detected between DR and DNR, PDR and DNR, NPDR and DNR groups (p>0.05).(3) EPO SNP rs551238Allele distributionThe frequency of allele C in PDR group was significantly lower than DNR group (OR=0.72,95%CI:0.52-0.99,p=0.049). No significant difference was detected in the allele frequency of SNP rs551238between DR and DNR, PDR and DNR, NPDR and DNR groups (p>0.05).Genotype distributionIn recessive model, the frequency of genotype CC in DR (OR=0.40,95%CI:0.20-0.79,p=0.010) and PDR (OR=0.18,95%CI:0.05-0.61,p=0.002) groups was significantly lower than DNR group, and no significant difference was found between NPDR and DNR groups (p>0.05). In additive model, the frequency of genotype CC in DR (CC vs. AA:OR=0.42,95%CI:0.21-0.83,p=0.016) and PDR (CC vs. AA: OR=0.18,95%CI:0.05-0.62, p=0.002) groups was significantly lower than DNR group. In dominant model, no significant difference was detected between DR and DNR, PDR and DNR, NPDR and DNR groups (p>0.05).(4) LD and haplotype analysesHigh LD was revealed among SNPs rs1617640, rs507392and rs551238of EPO gene (D’>0.90). Haplotype analyses did not provide any evidence for an association between any haplotype and DR, PDR or NPDR (p>0.05).(5) TCF7L2SNP rs11196205Allele distributionNo significant difference was detected in the allele frequency of SNP rs1617640between DR and DNR, PDR and DNR, NPDR and DNR groups (p>0.05).Genotype distributionIn dominant model, no significant difference was detected between DR and DNR, PDR and DNR, NPDR and DNR groups (p>0.05).ConclusionsThis study indicated that EPO SNPs rs507392and rs551238were significantly associated with DR and PDR, and the carriers of genotype CC might have a decreased risk of DR and PDR. No significant associations were found between EPO SNP rs1617640or TCF7L2SNP rs11196205and DR and PDR. |
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