Association Of ICAM-1 And HMGA1 Gene Variants With Diabetic Retinopathy

PURPOSEDiabetes is a chronic metabolic diseases of the endocrine system, the absolute or relative lack of insulin results in this disease. The number of patients with diabetes increased year by year. Long duration and hyperglycemia state is confirmed the main reason that leads to the formation of DR, and some other factors involved in the occurrence and development of DR. A large number of studies show that genetic factors may play an important role in the pathogenesis of DR. Previous studies found that intercellular adhesion molecule 1 (ICAM-1) and high mobility group Al (HMGA1) can lead to insulin resistance, which resulted in diabetes. Insulin resistance can predispose patients to DR, possibly by enhancing vascular susceptibility to the long-term effects of chronic hyperglycaemia. Moreover, inflammation is postulated to act as an important factor in the development of diabetic microvascular disease. As an inflammatory cytokine, ICAM-1 is expressed on many cell types and is involved in both monocyte and lymphocyte adhesion to the endothelium. ICAM-1 is involved in the formation of DR by inflammation. HMGAl is the architectural transcription factor, which binds to AT-rich regions of DNA, functions in the pathogenesis of T2DM via a regulation of insulin receptor (INSR) gene expression. HMGAl is a novel downstream nuclear target of the insulin receptor signaling pathway. The present study was purposed to examine the correlation of single nucleotide polymorphism (SNP) rs5498 in ICAM-1 gene, IVS5-13insC variant in HMGA1 gene and DR in T2DM patients and to evaluate the influences of these gene variations on the susceptibility of DR.METHODS1. Meta-analysis of DR and ICAM-1 gene polymorphism:Searching the PubMed database, ISI Web of Knowledge, the Cochrane Central Register of Controlled Trials, CNKI and Wanfang database to collect ICAM-1 genotype distribution of DR patients. Review Manager 5.0 software was used on statistical analyses. For continuous outcomes data, the means and standard deviations were used to calculate the estimated mean difference (MD). Heterogeneity was assessed using the chi-square test by calculating I2. A funnel plot was conducted to evaluate publication bias.2. Case-control study:792 patients with T2DM were included. The participants were categorized into two groups:the DR group consisted of the proliferative DR (PDR) group with 220 patients, and the nonproliferative DR (NPDR) group with 228 patients; the diabetes without retinopathy (DNR) group, comprised 344 patients who had no signs of DR. Genomic DNA was extracted from peripheral venous blood using PCR-LDR, Polymorphism rs5498 in ICAM-1 gene and IVS5-13insC variant in HMGA1 gene were genotyped.SPSS software 17.0 was used for statistical analysis. The differences in the categorical clinical data were compared by student’s test and chi-square test, including age, gender, duration of disease, blood glucose and HbAlc level. Genotype distributions and allele frequency of studied gene variants, using chi-square test for Hardy-Weinberg equilibrium (HWE). Genetic analyses for additive, dominant and recessive models were performed on ICAM-1 genotype data using chi-square test. ORs and 95% CIs were calculated to measure the strength of the association between the variants of ICAM-1 gene, HMGA1 gene and risk of DR. All statistical tests were two-sided, p<0.05 was considered statistically significant.RESULTS1. Meta-analysisThe meta-analysis showed that a significant association about ICAM-1 gene SNP rs5498 and DR (codominant model, OR:1.45,95%CI:1.06-1.99,p=0.02; recessive model, OR:1.78,95%CI:1.13-2.83,p=0.01).2. Case control study(1) ICAM-1 gene rs5498Allele distributionNo statistic difference was detected in the allele frequencies between DR. and DNR, PDR or NPDR and DNR, PDR and NPDR groups respectively (p>0.05).Genotype distributionIn additive, dominant and recessive models, no significant difference was found in each genotype group of SNP rs5498 in ICAM-1 respectively (p>0.05). (2) HMGA1 gene IVS5-13insC variantNo significant association were found between DR and DNR, PDR or NPDR and DNR, PDR and NPDR groups respectively (p>0.05) in distribution of IVS5-13insC variant and wild-type in HMGA1 gene。CONCLUSIONSMeta-analysis showed that the ICAM-1 gene rs5498 was significantly associated with DR in T2DM patients. However, the case-control study revealed that SNP rs5498 in ICAM-1 gene and IVS5-13insC variant in HMGA1 gene were not associated with the susceptibility of DR in the Chinese T2DM cohort.