Polymorphisms in the receptor for advanced glycation end-products (RAGE) gene and circulating RAGE levels as a susceptibility factor for non-alcoholic steatohepatitis (NASH)

Abstract

Non-alcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome and major cause of chronic liver disease in developed countries. Its prevalence is increasing in parallel with the prevalence of obesity and other components of the metabolic syndrome. As the liver is central to the clearance and catabolism of circulating advanced glycosylation end-products (AGEs), AGEs and their cognate receptors-RAGE (receptor for AGEs) system might be involved in NAFLD in obese patients. To examine this, we investigated four common polymorphisms of RAGE gene: 1704G/T (rs184003), G82S (rs2070600), -374T/A (rs1800624) and -429T/C (rs1800625) in 340 obese patients with metabolic syndrome. and protein levels of AGE and RAGE. This is the first study to describe association of 4 common polymorphisms with non-alcoholic steatohepatitis (NASH) as well as to examine protein levels of RAGE and AGE. Univariate analysis showed patients carrying the rs1800624 heterozygote genotype (AT) exhibited 2.36-fold increased risk of NASH (odds ratio (OR) = 2.36; 95% confidence interval (95% CI): 1.35-4.19) after adjusting for confounders. The minor allele -374 A has been shown to suppress the expression of RAGE protein. The protein levels of esRAGE, total sRAGE and AGE protein levels did not correlate with each other in obese patients with no liver disease, indicative of RAGE signaling playing an independent role in liver injury. In obese patients with non-NASH NAFLD and NASH respectively, esRAGE protein showed strong positive correlation with total sRAGE protein. Further, haplotype analysis of the 4 SNPs, indicated that haplotype G-A-T-G was significantly associated with 2-fold increased risk for NASH (OR = 2.08; 95% CI: 1.21-3.5; P = 0.006) after adjusting for confounders. In conclusion, the presented data indicate that the G-A-T-G haplotype containing minor allele at position -374 A and major allele at position -429T, 1704G, and G82S G could be regarded as a marker for NASH.

Fig 1. The intensity of the grey color in each pairwise SNP comparison is a measure of the strength of LD as measured by r².Dark grey boxes indicate a r² of 1 (100% linkage), and the gradation of color to white indicates progressively smaller r², values indicative of weaker LD.

Notes: Columns 1 to 3 are: rs2070600, rs1800625 and rs1800624; Rows 1 to 3 are: rs184003, rs1800624 and rs1800625.