Some genetic determinants of celiac disease, the role of HLA haplotyping in clinical settings and HLA-DQ haplotypes in a group of 306 pediatric patients

Czech version

Authors: M. Kubina; I. Čierna; D. Székyová; L. Kovács
Authors‘ workplace: II. detská klinika LF UK a DFNsP Bratislava, Slovenská republika
Published in: Gastroent Hepatol 2016; 70(6): 475-479
Category:
doi: https://doi.org/10.14735/amgh2016475

Overview

Celiac disease is a chronic immune-mediated small bowel enteropathy with autoimmune traits triggered by gluten ingestion that develops in genetically predisposed individuals. The prevalence of celiac disease is around 1%, although almost 40% of the general population has the major genetic predisposing factor and conditio sine qua non of celiac disease: the HLA-DQ2/DQ8 haplotype. Taking into account the exclusion criteria for HLA-DQ2/8 typing, 306 patients that were followed for celiac disease in the Gastroenterology Ambulance of the 2^nd Pediatric Clinic of Comenius University, Faculty of Medicine and Children’s Hospital Bratislava, were subjected to the scrutiny of this test. Fifty-four out of 306 children (17%) not carrying the pathognomonic allele were subjected to the gluten challenge test, which excluded the possibility of celiac disease in 50 of these patients. The diagnosis was changed to non-celiac gluten sensitivity in three patients based on their response to dietary gluten.

Key words:
celiac disease – immunogenetics – haplotypes – HLA-DQ2 antigen – HLA-DQ8 antigens

The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.

The Editorial Board declares that the manuscript met the ICMJE „uniform requirements“ for biomedical papers.

Submitted:
21.10.2016

Accepted:
20.11.2016

Sources

1. Chen L. The gastrointestinal tract. In: Robbins S et al. Robbins and Cotran pathologic basis of disease. 7th ed. Philadelphia: Saunders 2005: 843.

2. Koehler P, Wieser H, Konitzer K (eds). Celiac disease and gluten: multidisciplinary challenges and opportunities. Amsterdam: Academic Press 2014: 46.

3. Tripathi A, Lammers KM, Goldblum Set al. Identification of human zonulin, a physiological modulator of tight junctions, as prehaptoglobin-2. Proc Natl Acad Sci 2009; 106(39): 16799–16804. doi: 10.1073/ pnas.0906773106.

4. Fasano A. Zonulin and Its regulation of intestinal barrier function: the biological door to inflammation, autoimmunity, and cancer. Physiol Rev 2011; 91(1): 151–175. doi: 10.1152/ physrev.00003.2008.

5. Lammers KM, Lu R, Brownley J et al. Gliadin induces an increase in intestinal permeability and zonulin release by binding to the chemokine receptor CXCR3. Gastroenterology 2008; 135 (1): 194–204. doi: 10.1053/ j.gastro.2008.03.023.

6. Heyman M, Abed J, Lebreton C et al. Intestinal permeability in coeliac disease: insight into mechanisms and relevance to pathogenesis. Gut 2012; 61(9): 1355–1364. doi: 10.1136/ gutjnl-2011-300327.

7. Bernardo D, Garrote JA, Fernández-Salazar L et al. Is gliadin really safe for non-coeliac individuals? Production of interleukin 15in biopsy culture from non-coeliac individuals challenged with gliadin peptides. Gut 2007; 56(6): 889–890.

8. Nilsen EM, Lundin KE, Krajci P et al. Gluten specific, HLA-DQ restricted T cells from coeliac mucosa produce cytokines with Th1 or Th0 profile dominated by interferon gamma. Gut 1995; 37(6): 766–776.

9. Sollid LM. Molecular basis of celiac disease. Annu Rev Immunol 2000; 18(1): 53–81.

10. Lahdenperä A, Ludvigsson J, Fälth-Magnusson K et al. The effect of gluten-free diet on Th1-Th2-Th3-associated intestinal immune responses in celiac disease. Scand J Gastroenterol 2015; 46(5): 538–549.doi: 10.3109/ 00365521.2011.551888.

11. Monteleone G, Monteleone I, Fina D et al. Interleukin-21 enhances T-helper cell type I signaling and interferon- g production in Crohn’s disease. Gastroenterology 2005; 128(3): 687–694.

12. Siegel M, Strnad P, Watts RE et al. Extracellular transglutaminase 2 is catalytically inactive, but is transiently activated upon tissue injury. PloS One 2008; 3(3): 1861. doi: 10.1371/ journal.pone.0001861.

13. Vader LW, de Ru A, van der Wal Y. Specificity of tissue transglutaminase explains cereal toxicity in celiac disease. J Exp Med 2002; 195(5): 643–649.

14. Petersen J, Montserrat V, Mujico JR et al.T-cell receptor recognition of HLA-DQ2-gliadin complexes associated with celiac disease. Nat Struct Mol Biol 2014; 21(5): 480–488. doi: 10.1038/ nsmb.2817.

15. Ricaño-Ponce I, Wijmenga C, Gutierrez-Achury J et al. Genetics of celiac dis-ease. Best Pract Res Clin Gastroenterol 2015; 29(3): 399–412. doi: 10.1016/ j.bpg.2015.04.004.

16. Gutierrez-Achury J, Zhernakova A, Pulit SL et al. Fine mapping in the MHC region accounts for 18% additional genetic risk for celiac disease. Nature Genetics 2015; 47(6): 577–578. doi: 10.1038/ ng.3268.

17. Koning F. Pathophysiology of celiac dis-ease. J Pediatr Gastroenterol Nutr 2014; 59 (Suppl 1): S1–S4. doi: 10.1097/ 01.mpg.0000450391.46027.48.

18. Stokes PL, Asquith P, Holmes GK et al.Histocompatibility antigens associated with adult coeliac disease. Lancet 1972; 2(7769): 162–164.

19. Karell K, Louka AS, Moodie SJ et al. HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the european genetics cluster on celiac disease. Hum Immunology 2003; 64(4): 469–477.

20. Vader W, Stepniak D, Kooy Y et al. The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T cell responses. Proc Natl Acad Sci U S A 2003; 100(21): 12390–12395.

21. Megiorni F, Mora B, Bonamico M et al. HLA-DQ and risk gradient for celiac disease. Human Immunology 2009; 70(1): 55–59.doi: 10.1016/j.humimm.2008.10.018.

22. Gonzalez-Galarza FF, Christmas S, Middleton D et al. Allele frequency net: a database and online repository for immune gene frequencies in worldwide populations. Nucleic Acids Res 2011; 39 (Database issue): D913–919. doi: 10.1093/nar/gkq1128.

23. Sollid LM. Molecular basis of celiac disease. Annu Rev Immunol 2000; 18: 53–81.

24. Aronsson CA, Lee HS, Liu E et al. Age at gluten introduction and risk of celiac disease. Pediatrics 2015; 135(2): 239–245. doi: 10.1542/peds.2014-1787.

25. Szajewska H, Shamir R, Chmielewska A et al. Systematic review with meta-analysis: early infant feeding and coeliac disease – update 2015. Aliment Pharmacol Ther 2015; 41(11): 1038–1054. doi: 10.1111/apt.13163.

26. Sarno M, Discepolo V, Troncone R et al.Risk factors for celiac disease. Ital J Pediatr 2015; 41: 57. doi: 10.1186/s13052-015-0166-y.

27. Chirdo FG, Rumbo M, Añón MC et al. Presence of high levels of non-degraded gliadin in breast milk from healthy mothers. Scand J Gastroenterol 1998; 33(11): 1186–1192.

28. Ivarsson A, Hernell O, Nyström L et al.Children born in the summer have increased risk for coeliac disease. J Epidemiol Community Health 2003; 57(1): 36–39.

29. Lionetti E, Catassi C. Co-localization of gluten consumption and HLA-DQ2and -DQ8 genotypes, a clue to the history of celiac disease. Dig Liver Dis 2014; 46(12): 1057–1063. doi: 10.1016/j.dld.2014.08. 002.