Susceptibility role of soluble HLA-G and HLA-G 14-bp insertion/deletion polymorphism in inflammatory bowel disease

Abstract

Background Inflammatory bowel disease (IBD) is a group of chronic inflammatory disorders of the gastrointestinal tract. It is fundamentally related to a dysregulated immune response in the intestinal mucosa against microbiota in genetically predisposed individuals. Among the genetic and immunological factors that are suggested to have role in etiology and pathogenesis of IBD are human leukocyte antigen (HLA)-G molecules. Therefore, soluble HLA-G (sHLA-G) serum level and genetic association with HLA-G 14-bp insertion (Ins)/deletion (Del) polymorphism was analyzed in 100 IBD patients; 50 ulcerative colitis (UC) and 50 Crohn’s disease (CD), and 100 controls. Results sHLA-G level was significantly elevated in IBD patients compared to controls (174.7 ± 27.1 vs. 126.8 ± 15.1; corrected probability [pc] < 0.001). The level was also elevated in UC patients compared to CD patients but the difference was not significant (180.5 ± 27.1 vs. 168.9 ± 26.3; p = 0.059). Receiver operating characteristic analysis confirmed the significance of sHLA-G in total IBD, UC, and CD patients (area under curve = 0.944, 0.961, and 0.927, respectively). The genetic association was analyzed under five genetic models (allele, recessive, dominant, overdominant, and codominant). At the allele level, Del allele frequency was significantly increased in total IBD patients (Odds ratio [OR] = 1.93; 95% confidence interval [CI] = 1.27–2.94; pc = 0.018) and CD patients (OR = 2.08; 95% CI = 1.23–3.54; pc = 0.042) compared to controls. Among UC patients, a similar increased frequency was observed, but the pc value was not significance (OR = 1.79; 95% CI = 1.07–3.00; p = 0.031). At the genotypic level, Del/Del genotype was associated with a significantly increased IBD-risk in total patients under codominant model (OR = 4.06; 95% CI = 1.56–10.56; pc = 0.024). sHLA-G level was not influenced by the Ins/Del polymorphism. Conclusions This study demonstrated a significant increase in serum level of sHLA-G in UC and CD patients. Further, HLA-G 14-bp Ins/Del polymorphism may be associated with susceptibility to IBD, particularly CD.

Genetic polymorphism of HLA-G gene (G*01:03, G*01:04, and G*01:05N) in Iraqi patients with inflammatory bowel disease (ulcerative colitis and Crohn’s disease)

“…A more recent immunohistochemical study demonstrated increased HLA-G expression in plasma cells/lymphocytes infiltrating the lamina propria in biopsies of UC and CD patients compared to controls, but greater cell staining was found in UC cells compared to CD cells [20]. In a study by our group, serum level of sHLA-G was significantly elevated in UC and CD patients compared to controls [21].…”

“…Two previous studies suggested the importance of HLA-G 14-bp Ins/Del polymorphism in susceptibility to IBD [22,23]. A third study by our group also favored a similar suggestion [21]. To the best knowledge of investigators, other HLA-G variants have not been investigated in IBD.…”

“…The present study demonstrated that serum level of sHLA was significantly increased in UC patients carrier for G*01:04 allele compared to patients without the allele. The Del allele has also been associated with susceptibility to IBD, particularly CD, in Iraqi patients [21]. Thus, both alleles (G*01: 04 and Del) could act synergistically in the context of susceptibility to inflammatory diseases due to their association with immunosuppressive functions of natural killer (NK) cells.…”

“…Two SNPs of HLA-G (rs66554220 and rs1063320) were also associated with low frequency of regulatory CD8+ CD28-T cells [45]. Further studies indicated that HLA-G locus have been associated with higher susceptibility to UC and CD or higher severity of the two diseases [21,23,46]. HLA-G has also been indicated as predictive marker of response to therapy in inflammatory and infectious diseases, as well as cancer [47].…”

“…The data on sHLA-G serum level were obtained from an article previously published by our group in this journal [21]. The level did not show significant differences between participants (patients or controls) who had the G*01:04 or G*01:05N allele and those who did not have the allele.…”