Genetic polymorphisms of RAGE and risk of ulcerative colitis in a Chinese population

Abstract

The receptor for advanced glycation end products (RAGE) and its proinflammatory ligands are critically implicated in the pathological progression of ulcerative colitis (UC). Functional polymorphisms in the regulatory elements and/or ligand-binding regions of the RAGE gene affect the expression and function of RAGE and thus may increase susceptibility to UC. In this study, a total of 266 unrelated UC patients and 247 control subjects were analyzed for 3 RAGE single nucleotide polymorphisms (SNPs) (-429 T/C, -374 T/A, and G82S) using an improved small-amplicon high resolution melting curve (HRM) analysis assay. Serum levels of soluble RAGE (sRAGE) were determined by a double sandwich ELISA system. The genotypes, alleles and haplotypes were analyzed and compared between UC patients and control subjects. Three pairs of genotyping primers for three RAGE polymorphism loci (-429 T/C, -374 T/A, and G82S) were developed based on HRM. Significant differences in the allele distribution of the G82S polymorphism was found among UC cases and controls from a Chinese population. Carriers of the RAGE G82S variant genotype were at higher risk of UC (OR=2.594, 95% CI: 1.778-3.784, P<0.001) than homozygous wild-type individuals. Further analyses revealed that the 82 (GS+SS) variant genotype was associated with patients who have extended UC (OR=1.924, 95% CI: 1.163-3.181, P=0.010), and a family history of inflammatory bowel disease (IBD) (OR=1.923, 95% CI: 1.049-3.521, P=0.032). The polymorphisms -374 T/A and -429 T/C did not demonstrate any association with UC, but an association was found between the -374(TA+AA) variant genotypes and the serum sRAGE level (P=0.002). Moreover, haplotypes T/A/A and T/A/G showed significantly different frequencies between UC patients and controls (OR=3.337, 95% CI: 1.892-6.091, P=0.026; OR=0.530, 95% CI: 0.351-0.801, P=0.002). The present study developed novel primers based on HRM to provide preliminary evidence in a Chinese population that the RAGE polymorphism is involved in genetic susceptibility to UC and that the 82(GS+SS) genotype of G82S is a risk factor for UC. Furthermore, RAGE polymorphisms may be related to the location of UC as well as a family history of IBD in a Chinese population.

Keywords: Receptor for advanced glycation end products; Single nucleotide polymorphism; Ulcerative colitis.