Molecular study of receptor for advanced glycation endproduct gene promoter and identification of specific HLA haplotypes possibly involved in chronic fatigue syndrome

Int J Immunopathol Pharmacol. Jul-Sep 2009;22(3):745-54. doi: 10.1177/039463200902200320.


The receptor for advanced glycation end product (RAGE) is thought to play an important role in inflammation. Chronic fatigue syndrome (CFS) is a long-lasting fatigue that compromises at least 50% of a subject's daily activities without other known cause. Immune dysfunction has been implicated and an association with a peculiar genetic cytokine profile, predisposing to an immunomodulatory response of inflammatory nature, was found. The aim of this study is to analyse RAGE polymorphisms and HLA-DRB1 alleles in seventy-five Italian CFS patients and 141 controls matched for age, sex and ethnicity. These two groups underwent genomic study for RAGE 374T/A and 429C/T promoter polymorphisms; moreover, 46 patients and 186 controls were typed for HLA-DRB1 at low resolution molecular level. Of these, 31 patients and 99 controls also underwent high resolution analysis to define the HLA-DRB1*11 and DRB1*13 alleles. The haplotypes RAGE-374T, DRB1*04; RAGE-374T, DRB1*09; RAGE-374T, DRB1*11; RAGE-374A, DRB1*13; RAGE-429T, DRB1*04 and RAGE-429C, DRB1*11 were significantly more frequent in CFS patients, whereas RAGE-429C, DRB1*07 would seem protective. A significantly lower frequency of DRB1*1104 (5.4% vs 12.9% p=0.04, OR=0.39) and a significantly higher frequency of HLA-DRB1*1301 (13.0% vs 5.1% p=0.006, OR= 2.79) were found in CFS patients. A synergic effect was observed with RAGE polymorphism. The OR values strengthened in the following cis combinations: RAGE-374A, HLA-DRB1*1104 (OR=0.27) and RAGE-374A, HLADRB1*1301 (OR=6.23). HLA haplotypes rather than single alleles of RAGE or of DRB1 genes seem to be involved in CFS, probably including a subregion of major interest.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Case-Control Studies
  • Fatigue Syndrome, Chronic / epidemiology
  • Fatigue Syndrome, Chronic / genetics*
  • Fatigue Syndrome, Chronic / immunology
  • Gene Frequency
  • Genetic Predisposition to Disease
  • HLA-DR Antigens / genetics*
  • HLA-DRB1 Chains
  • Haplotypes
  • Humans
  • Italy
  • Linkage Disequilibrium
  • Odds Ratio
  • Polymorphism, Genetic*
  • Promoter Regions, Genetic*
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic / genetics*
  • Risk Assessment
  • Risk Factors


  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • Receptor for Advanced Glycation End Products
  • Receptors, Immunologic