Combinations of polymorphisms in the regulatory regions of cytokine genes are associated with diabetic retinopathy in type 2 diabetic patients

Abstract

Diabetic retinopathy (DR) is one of the leading causes of avoidable blindness worldwide. Chronic low-grade inflammation and abnormal angiogenesis, which is considered to be principal components of DR pathogenesis, is accompanied by imbalance in cytokine production. It was shown that single-nucleotide polymorphisms (SNPs) in the promoters of cytokine genes affect the cytokine production in normal and pathological conditions. Accordingly, we aimed to assess the frequencies of combinations of SNPs from promoters of cytokine genes in type 2 diabetic subjects with and without DR.Materials and methods: We enrolled 201 caucasian subjects with type 2 diabetes, including 90 ones with non-proliferative or preproliferative retinopathy and 111 subjects without DR. Eight SNPs, located in the gene promoters of TNFA (rs1800630, rs1800629, rs361525), IL1B (rs1143627), IL4 (rs2243250), IL6 (rs1800795) and IL10 (r1800896, rs1800872), were investigated. In groups of patients with and without DR, the frequencies of alleles, genotypes and their combinations, odds ratios and specificity were calculated. The networks between genes and quartiles of glycated hemoglobin A1c (HbA1c) were visualized with Cytoscape.Results. We revealed 36 combinations of SNPs with different frequencies in the groups of patients with and without DR. In the combinations associated with DR with a specificity >99% homozygous GG genotype in position -174 of IL6 (rs1800795), CT genotype in position -31 of IL1B (rs1143627), СС genotype in position -592 of IL10 (rs1800872), CT genotype in position -590 of IL4 (rs2243250) were the most frequently detected variants. High levels of HbA1c (>9.8%) were associated with combinations of CA genotype in position -863 TNFA (rs1800630) with homozygous variants GG in positions -238 and -308 TNFA (rs1800629, rs361525).Conclusion. Genetic combinations, associated with DR in type 2 diabetic subjects, include homozygous variants in polymorphic positions of the gene promoters of IL6 (rs1800795), IL1B (rs1143627) and TNFA (rs1800630, rs1800629, rs361525). The combinations of the variants of cytokine genes with a high level of HbA1c can be an important mechanism for realizing of individual genetic predisposition to the development of DR.

Keywords

• сахарный диабет
• диабетическая ретинопатия
• полиморфизм генов
• цитокины
• гликированный гемоглобин