ICAM-1 K469E polymorphism is a genetic determinant for the clinical risk factors of T2D subjects with retinopathy in Indians: A population-based case-control study

Abstract

Objective: Elevated levels of intercellular adhesion molecule-1 (ICAM-1) are demonstrated in diabetes complications. The current study aims to understand association of K469E (rs5498) in ICAM-1 gene, in type 2 diabetic (T2D) subjects with retinopathy. Design: Case-control study. Setting: Sankara Nethralaya Diabetic Retinopathy Epidemiology and Molecular Genetic Study, an epidemiology study (on prevalence of diabetic retinopathy in T2D subjects (T2DR) from south India) and outpatient department of Sankara Nethralaya, a tertiary care hospital, in Chennai, India. Participants: A total of 356 T2D subjects of >15 years of diabetes duration, with (n=199) and without (n=157) retinopathy. Methods: The rs5498 polymorphism was genotyped by direct sequencing. Multivariate analysis for various clinical covariates was done using SPSS V.14. Comparative assessment of structure stability, folding rate of the variants were assessed using bioinformatics tools like STRIDE, MuPro, ModellerV97, fold rate server, etc. Results: The AA genotype of rs5498 was seen at a higher frequency in the retinopathy group (p=0.012). The risk for diabetic retinopathy (DR) increased in the presence of AA genotype (OR=1.89-4.82) after the sequential addition of various clinical covariates. Multivariate logistic regression analysis showed 8.26 times high risk for developing DR in the AG genotype (p=0.003). Structural superimposition of ICAM-1 wild type (K469) and variant (E469) showed 0.943 Å of backbone root mean square deviation as calculated by PYMOL software. A difference in the fold rate time was also observed between the wild type (5.4/s) and variant (3.3/s). Conclusions: This study shows that allele A of rs5498 in ICAM-1 is a putative risk predisposing allele for T2D retinopathy and its clinical covariates in Indian population. The folding rate of the protein decreases for the A allele implicating a potential effect on the structure and function of ICAM-1.