Genetic and Biological Effects of ICAM-1 E469K Polymorphism in Diabetic Kidney Disease

Abstract

Diabetic kidney disease (DKD) is a complex disease, in which local inflammatory stress results from both metabolic and hemodynamic derangements. Intercellular adhesion molecule 1 (ICAM-1) is an acute-phase protein marker of inflammation. In the recent years, clinical observations have reported that increased serum/plasma ICAM-1 levels are positively correlated with albuminuria in the patients with type 1 (T1D) and type 2 diabetes (T2D). Genetic association studies have demonstrated that genetic polymorphisms, including SNP rs5498 (E469K, G/A), in the ICAM1 gene is associated with DKD. rs5498 is a nonsynonymous SNP and caused by substitution between E (Glu) and K (Lys) for ICAM-1 protein. In this review, we first summarized the genetic effects of ICAM1 E469K polymorphism in DKD and then demonstrated the possible changes of ICAM-1 protein crystal structures according to the genotypes of this polymorphism. Finally, we discussed the genetic effects of the ICAM1 E469K polymorphism and the biological role of increased circulating ICAM-1 protein and its formation changes in DKD.

Figure 1

Genotype distribution of the ICAM1 E469K polymorphism and circulating ICAM-1 levels in type 1 and type 2 diabetes with or without diabetic kidney disease. Genotype distribution patterns (top) showed a high frequency of heterozygous genotypes in type 1 diabetes (T1D) subjects with or without diabetic kidney disease (DKD) (Figure 1(a)) and type 2 diabetes (T2D) patients with or without DKD (Figure 1(b)). According to the genotypes, serum/plasma ICAM-1 levels were analyzed (bottom). In T1D subjects with DKD, the heterozygous ICAM1 E469K carriers had higher circulating ICAM-1 levels than what in homozygous E469E and K469K carriers (P < 0.05, adjusted for age and sex) (Figure 1(c)). The similar finding was found in T2D patients with DKD (P < 0.05, adjusted for age and sex) (Figure 1(d)). Data were replicated and modified from Ma et al. 2006 and Abu Seman et al. 2013.

Figure 2

Structural context of the ICAM1 E469K polymorphism. The structures are shown as ribbon cartoon diagrams. (a) Model of the dimeric ICAM-1 ectodomain bound to the αI domain of integrin LFA-1 reconstructed by combining two crystal structures. Glu-469 in domain 5 is shown with its sidechain atoms as spheres. The Mg²⁺ ion at the center of the LFA-1/ICAM-1 binding site is shown as a silver sphere. (b) Detailed view of the region boxed in (a). Sidechains of Glu-469 and nearby residues are shown in stick representation, and Glu-469 is emphasized with thicker stick. The boundary between the G β-strand in D4 that continues into the A β-strand in D5 is shown with a dotted line in the cyan ICAM-1 monomer.

Figure 3

Possible cellular mechanism of ICAM1 in the development of diabetic kidney disease. This schematic diagram implicates that ICAM1 DNA transcription in the nuclei and mRNA translation in plasma of endothelium cells is increased under a diabetic condition with hyperglycemia. Subsequently, the ICAM-1 protein expression on the surface of endothelium cells is upregulated. ICAM-1 protein binding activity with leukocyte adhesion protein-1 (LEA-1), which is from blood, is increased, while heterozygous of ICAM-1 E469K protein likely more actively binds with LFA-1. Thereby, more and more lymphocytes from blood due to combining ICAM-1 and IFA-1 are transferred through endothelium cells in glomeruli and peritubular capillaries of the nephron in the kidney. Consequently, injure of kidney glomeruli and tubular has occurred.