Utility of human leukocyte antigen DQ2 and DQ8 genotypes in Celiac disease: Two sides of the coin
Main Article Content
Abstract
HLA genotyping of DQ2 and DQ8 alleles has been eliminated from the diagnostic algorithm for Celiac Disease (CD) diagnosis in the currently published guidelines by the European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) in 2020. Our study, initiated prior to the publication of 2020 guidelines, evaluated the utility of HLA DQ2 and DQ8 genotyping in the cohort of 537 children with CD and their 1420 first degree relatives (FDRs). We attempted to evaluate its applicability in low middle-income countries like India. Prevalence of CD was observed at 18.52% and 15.68% based on serological and histopathological diagnosis in FDRs. HLA DQA1*0501 and DQB1*0201 alleles were the most frequent alleles observed in index cases (84.4% versus 86.4%), biopsy proven FDRs (77.9% vs 72.15) and serology negative FDRs (67.7% vs 58.3%) (p<0.001). A strong association of DQA1*0501 and DQA1*0301 alleles was observed with high serology positivity (p<0.05). The majority of the subjects in our cohort had histopathologic scores of 3c (54.80%), 3b (22.13%), 3a (22%) and grade 2 (1.05%) (p<0.001). HLA DQB1*0201 was observed as 100% in cases with Marsh grade 2, 72.5% in grade 3a, 82.7% in grade 3b and 85.6% in grade 3c (p=0.017) mucosal lesions. HLA DQA1*0501 and DQB1*0201 alleles of the DQ2 genotype also predicted the severity of intestinal mucosal damage assessed by Marsh grading when used in conjunction with anti tTG-IgA serology. When performed In-house using Polymerase Chain Reaction-Sequence Specific Primers (PCR-SSP) approach, the assay was economical and is still relevant in screening at-risk FDRs for an early diagnosis where In-house diagnostics are already in place.
Article Details
How to Cite
LOMASH, Avinash et al.
Utility of human leukocyte antigen DQ2 and DQ8 genotypes in Celiac disease: Two sides of the coin.
Medical Research Archives, [S.l.], v. 11, n. 1, jan. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/2864>. Date accessed: 21 dec. 2024.
doi: https://doi.org/10.18103/mra.v11i1.2864.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Husby S, Koletzko S, Korponay-Szabó IR, et al. European society for pediatric gastroenterology, hepatology, and nutrition guidelines for the diagnosis of coeliac disease. J Pediatr Gastroenterol Nutr. 2012;54(1):136-160. doi:10.1097/MPG.0b013e31821a23d0
2. Esposito C, Caputo I, Troncone R, Esposito C, Caputo I, Troncone R. New Therapeutic Strategies for Coeliac Disease: Tissue Transglutaminase as a Target. Curr Med Chem. 2007;14(24):2572-2580. doi:10.2174/092986707782023343
3. Singh P, Arora A, Strand TA, et al. Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018;16(6):823-836.e2. doi:10.1016/j.cgh. 2017.06.037
4. Ramakrishna BS. Celiac disease: Can we avert the impending epidemic in India? Indian J Med Res. 2011;133(1):5-8.
5. Lomash A, Venkatakrishnan A, Bothra M, Dhingra B, Kumar P, Kapoor S. Coeliac disease presenting atypically: A much wider spectrum. Trop Doct. Published online February 11, 2021. doi:10.1177/0049475521991348
6. Mishra A, Prakash S, Kaur G, et al. Prevalence of celiac disease among first-degree relatives of Indian celiac disease patients. Dig Liver Dis. 2016;48(3):255-259. doi:10.1016/j.dld. 2015.11.007
7. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of Celiac Disease in At-Risk and Not-At-Risk Groups in the United States. Arch Intern Med. 2013;163:286-292.
8. Husby S, Koletzko S, Korponay-Szabó I, et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr. 2020;70(1):141-156. doi:10.1097/MPG.000000000000 2497
9. Van Der Windt DAWM, Jellema P, Mulder CJ, Kneepkens CMF, Van Der Horst HE. Diagnostic testing for celiac disease among patients with abdominal symptoms: A systematic review. JAMA - J Am Med Assoc. 2010;303(17):1738-1746. doi:10.1001/jama. 2010.549
10. Jain R, Kumar P, Kapoor S, Basu S, Lomash A, Rohatgi S. Reliability of coeliac serology in monitoring dietary adherence in children with coeliac disease on a gluten-free diet. Trop Doct. 2019;49(3):192-196. doi:10.1177/0049475519835732
11. Lomash A, Prasad A, Singh R, et al. Evaluation of the Utility of Amino Acid Citrulline as a Surrogate Metabolomic Biomarker for the Diagnosis of Celiac Disease. Nutr Metab Insights. 2021;14:117863882110606. doi:10.1177/11786388211060603
12. Brown NK, Guandalini S, Semrad C, Kupfer SS. A clinician’s guide to celiac disease HLA genetics. Am J Gastroenterol. 2019;114(10):1587-1592. doi:10.14309/ajg.0000000000000 310
13. Liu E, Rewers M, Eisenbarth GS. Genetic testing: Who should do the testing and what is the role of genetic testing in the setting of celiac disease? Gastroenterology. 2005;128(4 SUPPL. 1). doi:10.1053/j.gastro.2005.02.013
14. Dubé C, Rostom A, Sy R, et al. The prevalence of celiac disease in average-risk and at-risk Western European populations: A systematic review. Gastroenterology. 2005;128(4 SUPPL. 1):57-67. doi:10.1053/j.gastro.2005.02.014
15. Greco L, Romino R, Coto I, et al. The first large population based twin study of coeliac disease. Gut. 2002;50(5):624-628. doi:10.1136/gut.50.5.624
16. Bevan S, Popat S, Braegger CP, et al. Contribution of the MHC region to the familial risk of coeliac disease. J Med Genet. 1999;36(9):687-690. doi:10.1136/jmg.36.9.687
17. Lionetti E, Catassi C. Co-localization of gluten consumption and HLA-DQ2 and -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
18. Amarapurkar DN, Somani VS, Shah AS, Kankonkar SR. HLA - DQ genotyping in celiac disease in western India. Trop Gastroenterol. 2015;36(3):174-178. doi:10.7869/tg.279
19. Pallav K, Kabbani T, Tariq S, Vanga R, Kelly CP, Leffler DA. Clinical Utility of Celiac Disease-Associated HLA Testing. Dig Dis Sci. 2014;59(9):2199-2206.
doi:10.1007/ s10620-014-3143-1
20. Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease. Eur J Gastroenterol Hepatol. 1999;11(10):1185. doi:10.1097/00042737-199910000-00019
21. Ghatak S, Muthukumaran RB, Nachimuthu SK. A simple method of genomic DNA extraction from human samples for PCR-RFLP analysis. J Biomol Tech. 2013;24(4):224-231. doi:10.7171/jbt.13-2404-001
22. Olerup O, Aldener A, Fogdell A. HLA-DQB1 and -DQA1 typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours. Hum Immunol. 1993;36(1):57. doi:10.1016/0198-8859(93)90063-7
23. Doolan A, Donaghue K, Fairchild J, Wong M, Williams AJ. Use of HLA typing in diagnosing celiac disease in patients with type 1 diabetes. Diabetes Care. 2005;28(4):806-809. doi:10.2337/diacare.28.4.806
24. Scola L, Lio D, Candore G, et al. Analysis of HLA-DRB1,DQA1,DQB1 haplotypes in Sardinian centenarians. Exp Gerontol. 2008;43(2):114-118. doi:10.1016/j.exger.2007.06. 007
25. Rostami-Nejad M, Romanos J, Rostami K, et al. Allele and haplotype frequencies for HLA-DQ in Iranian celiac disease patients. World J Gastroenterol. 2014;20(20):6302-6308. doi:10.3748/wjg.v20.i20.6302
26. Uenishi RH, Gandolfi L, Almeida LM, et al. Screening for celiac disease in 1st degree relatives: A 10-year follow-up study. BMC Gastroenterol. 2014;14(1):1-5. doi:10.1186/ 1471-230X-14-36
27. Sood A, Midha V, Sood N, Kaushal V, Puri H. Increasing incidence of celiac disease in india. Am J Gastroenterol. 2001;96(9):2804-2805. doi:10.1111/j.1572-0241.2001.04150.x
28. Wessels MMS, de Rooij N, Roovers L, Verhage J, de Vries W, Mearin ML. Towards an individual screening strategy for first-degree relatives of celiac patients. Eur J Pediatr. 2018;177(11):1585-1592. doi:10.1007/S00431-018-3199-6
29. Subramanian R, Kumar Agrawal D, Agrawal R, Tanwar GS, Sethiya R. HLA Study Regarding the Prevalence of Celiac Disease in Type 1 Diabetes. Orig Res Artic. 2017;12(4):12-14. doi:10.21276/ijmrp.2017.3.4.003
30. Megiorni F, Mora B, Bonamico M, et al. HLA-DQ and risk gradient for celiac disease. Hum Immunol. 2009;70(1):55-59. doi:10.1016/j.humimm.2008.10.018
31. Clouzeau-Girard H, Rebouissoux L, Taupin JL, et al. HLA-DQ genotyping combined with serological markers for the diagnosis of celiac disease: Is intestinal biopsy still mandatory? J Pediatr Gastroenterol Nutr. 2011;52(6):729-733. doi:10.1097/MPG.0b013e31820a724d
32. Almeida LM, Gandolfi L, Pratesi R, et al. Presence of DQ2.2 associated with DQ2.5 increases the risk for celiac disease. Autoimmune Dis. 2016;2016. doi:10.1155/2016/5409 653
33. Martínez-Ojinaga E, Molina M, Polanco I, Urcelay E, Núñez C. HLA-DQ distribution and risk assessment of celiac disease in a spanish center. Rev Esp Enfermedades Dig. 2018;110(7):421-426. doi:10.17235/reed.2018.5399/2017
34. Murad H, Jazairi B, Khansaa I, Olabi D, Khouri L. HLA-DQ2 and -DQ8 genotype frequency in Syrian celiac disease children: HLA-DQ relative risks evaluation. BMC Gastroenterol. 2018;18(1). doi:10.1186/s12876-018-0802-2
35. Agrawal S, Gupta A, Yachha S, Müller-Myhsok B, Mehrotra P, Agarwal S. Association of human leucocyte-DR and DQ antigens in coeliac disease: A family study. J Gastroenterol Hepatol. 2000;15(7):771-774.
doi:10.1046/j.1440-1746.2000.02227.x
36. Kaur G, Sarkar N, Bhatnagar S, et al. Pediatric celiac disease in India is associated with multiple DR3-DQ2 haplotypes. Hum Immunol. 2002;63(8):677-682.
doi:10.1016/S0198-8859(02)00413-5
37. Kanga U, Vaidyanathan B, Jaini R, Menon PSN, Mehra NK. HLA haplotypes associated with type 1 diabetes mellitus in North Indian children. Hum Immunol. 2004;65(1):47-53. doi:10.1016/j.humimm.2003.10.013
38. Srivastava A, Yachha SK, Mathias A, Parveen F, Poddar U, Agrawal S. Prevalence, human leukocyte antigen typing and strategy for screening among Asian first-degree relatives of children with celiac disease. J Gastroenterol Hepatol. 2010;25(2):319-324. doi:10.1111/j. 1440-1746.2009.06044.x
39. Mishra A, Prakash S, Kaur G, et al. Prevalence of celiac disease among first-degree relatives of Indian celiac disease patients. Dig Liver Dis. 2016;48(3):255-259. doi:10.1016/j.dld. 2015.11.007
40. Singla S, Kumar P, Singh P, Kaur G, Rohtagi A, Choudhury M. HLA Profile of Celiac Disease among First-Degree Relatives from a Tertiary Care Center in North India. Indian J Pediatr. 2016;83(11):1248-1252. doi:10.1007/s12098-016-2146-7
41. Mills JR, Katzman BM, Ettore M, Murray JA, Gandhi MJ, Snyder MR. Exploring Associations Between Genotype and Serology in Celiac Disease. Vol 143. Oxford Academic; 2015. doi:10.1093/AJCP/143.SUPPL1.043
42. Ceylan GG. HLA Typing and Histopathologic Features of Patients with Celiac Disease-A Retrospective Study. J Clin Anal Med. 2016;7(3). doi:10.4328/jcam.2790
2. Esposito C, Caputo I, Troncone R, Esposito C, Caputo I, Troncone R. New Therapeutic Strategies for Coeliac Disease: Tissue Transglutaminase as a Target. Curr Med Chem. 2007;14(24):2572-2580. doi:10.2174/092986707782023343
3. Singh P, Arora A, Strand TA, et al. Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol. 2018;16(6):823-836.e2. doi:10.1016/j.cgh. 2017.06.037
4. Ramakrishna BS. Celiac disease: Can we avert the impending epidemic in India? Indian J Med Res. 2011;133(1):5-8.
5. Lomash A, Venkatakrishnan A, Bothra M, Dhingra B, Kumar P, Kapoor S. Coeliac disease presenting atypically: A much wider spectrum. Trop Doct. Published online February 11, 2021. doi:10.1177/0049475521991348
6. Mishra A, Prakash S, Kaur G, et al. Prevalence of celiac disease among first-degree relatives of Indian celiac disease patients. Dig Liver Dis. 2016;48(3):255-259. doi:10.1016/j.dld. 2015.11.007
7. Fasano A, Berti I, Gerarduzzi T, et al. Prevalence of Celiac Disease in At-Risk and Not-At-Risk Groups in the United States. Arch Intern Med. 2013;163:286-292.
8. Husby S, Koletzko S, Korponay-Szabó I, et al. European Society Paediatric Gastroenterology, Hepatology and Nutrition Guidelines for Diagnosing Coeliac Disease 2020. J Pediatr Gastroenterol Nutr. 2020;70(1):141-156. doi:10.1097/MPG.000000000000 2497
9. Van Der Windt DAWM, Jellema P, Mulder CJ, Kneepkens CMF, Van Der Horst HE. Diagnostic testing for celiac disease among patients with abdominal symptoms: A systematic review. JAMA - J Am Med Assoc. 2010;303(17):1738-1746. doi:10.1001/jama. 2010.549
10. Jain R, Kumar P, Kapoor S, Basu S, Lomash A, Rohatgi S. Reliability of coeliac serology in monitoring dietary adherence in children with coeliac disease on a gluten-free diet. Trop Doct. 2019;49(3):192-196. doi:10.1177/0049475519835732
11. Lomash A, Prasad A, Singh R, et al. Evaluation of the Utility of Amino Acid Citrulline as a Surrogate Metabolomic Biomarker for the Diagnosis of Celiac Disease. Nutr Metab Insights. 2021;14:117863882110606. doi:10.1177/11786388211060603
12. Brown NK, Guandalini S, Semrad C, Kupfer SS. A clinician’s guide to celiac disease HLA genetics. Am J Gastroenterol. 2019;114(10):1587-1592. doi:10.14309/ajg.0000000000000 310
13. Liu E, Rewers M, Eisenbarth GS. Genetic testing: Who should do the testing and what is the role of genetic testing in the setting of celiac disease? Gastroenterology. 2005;128(4 SUPPL. 1). doi:10.1053/j.gastro.2005.02.013
14. Dubé C, Rostom A, Sy R, et al. The prevalence of celiac disease in average-risk and at-risk Western European populations: A systematic review. Gastroenterology. 2005;128(4 SUPPL. 1):57-67. doi:10.1053/j.gastro.2005.02.014
15. Greco L, Romino R, Coto I, et al. The first large population based twin study of coeliac disease. Gut. 2002;50(5):624-628. doi:10.1136/gut.50.5.624
16. Bevan S, Popat S, Braegger CP, et al. Contribution of the MHC region to the familial risk of coeliac disease. J Med Genet. 1999;36(9):687-690. doi:10.1136/jmg.36.9.687
17. Lionetti E, Catassi C. Co-localization of gluten consumption and HLA-DQ2 and -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
18. Amarapurkar DN, Somani VS, Shah AS, Kankonkar SR. HLA - DQ genotyping in celiac disease in western India. Trop Gastroenterol. 2015;36(3):174-178. doi:10.7869/tg.279
19. Pallav K, Kabbani T, Tariq S, Vanga R, Kelly CP, Leffler DA. Clinical Utility of Celiac Disease-Associated HLA Testing. Dig Dis Sci. 2014;59(9):2199-2206.
doi:10.1007/ s10620-014-3143-1
20. Oberhuber G, Granditsch G, Vogelsang H. The histopathology of coeliac disease. Eur J Gastroenterol Hepatol. 1999;11(10):1185. doi:10.1097/00042737-199910000-00019
21. Ghatak S, Muthukumaran RB, Nachimuthu SK. A simple method of genomic DNA extraction from human samples for PCR-RFLP analysis. J Biomol Tech. 2013;24(4):224-231. doi:10.7171/jbt.13-2404-001
22. Olerup O, Aldener A, Fogdell A. HLA-DQB1 and -DQA1 typing by PCR amplification with sequence-specific primers (PCR-SSP) in 2 hours. Hum Immunol. 1993;36(1):57. doi:10.1016/0198-8859(93)90063-7
23. Doolan A, Donaghue K, Fairchild J, Wong M, Williams AJ. Use of HLA typing in diagnosing celiac disease in patients with type 1 diabetes. Diabetes Care. 2005;28(4):806-809. doi:10.2337/diacare.28.4.806
24. Scola L, Lio D, Candore G, et al. Analysis of HLA-DRB1,DQA1,DQB1 haplotypes in Sardinian centenarians. Exp Gerontol. 2008;43(2):114-118. doi:10.1016/j.exger.2007.06. 007
25. Rostami-Nejad M, Romanos J, Rostami K, et al. Allele and haplotype frequencies for HLA-DQ in Iranian celiac disease patients. World J Gastroenterol. 2014;20(20):6302-6308. doi:10.3748/wjg.v20.i20.6302
26. Uenishi RH, Gandolfi L, Almeida LM, et al. Screening for celiac disease in 1st degree relatives: A 10-year follow-up study. BMC Gastroenterol. 2014;14(1):1-5. doi:10.1186/ 1471-230X-14-36
27. Sood A, Midha V, Sood N, Kaushal V, Puri H. Increasing incidence of celiac disease in india. Am J Gastroenterol. 2001;96(9):2804-2805. doi:10.1111/j.1572-0241.2001.04150.x
28. Wessels MMS, de Rooij N, Roovers L, Verhage J, de Vries W, Mearin ML. Towards an individual screening strategy for first-degree relatives of celiac patients. Eur J Pediatr. 2018;177(11):1585-1592. doi:10.1007/S00431-018-3199-6
29. Subramanian R, Kumar Agrawal D, Agrawal R, Tanwar GS, Sethiya R. HLA Study Regarding the Prevalence of Celiac Disease in Type 1 Diabetes. Orig Res Artic. 2017;12(4):12-14. doi:10.21276/ijmrp.2017.3.4.003
30. Megiorni F, Mora B, Bonamico M, et al. HLA-DQ and risk gradient for celiac disease. Hum Immunol. 2009;70(1):55-59. doi:10.1016/j.humimm.2008.10.018
31. Clouzeau-Girard H, Rebouissoux L, Taupin JL, et al. HLA-DQ genotyping combined with serological markers for the diagnosis of celiac disease: Is intestinal biopsy still mandatory? J Pediatr Gastroenterol Nutr. 2011;52(6):729-733. doi:10.1097/MPG.0b013e31820a724d
32. Almeida LM, Gandolfi L, Pratesi R, et al. Presence of DQ2.2 associated with DQ2.5 increases the risk for celiac disease. Autoimmune Dis. 2016;2016. doi:10.1155/2016/5409 653
33. Martínez-Ojinaga E, Molina M, Polanco I, Urcelay E, Núñez C. HLA-DQ distribution and risk assessment of celiac disease in a spanish center. Rev Esp Enfermedades Dig. 2018;110(7):421-426. doi:10.17235/reed.2018.5399/2017
34. Murad H, Jazairi B, Khansaa I, Olabi D, Khouri L. HLA-DQ2 and -DQ8 genotype frequency in Syrian celiac disease children: HLA-DQ relative risks evaluation. BMC Gastroenterol. 2018;18(1). doi:10.1186/s12876-018-0802-2
35. Agrawal S, Gupta A, Yachha S, Müller-Myhsok B, Mehrotra P, Agarwal S. Association of human leucocyte-DR and DQ antigens in coeliac disease: A family study. J Gastroenterol Hepatol. 2000;15(7):771-774.
doi:10.1046/j.1440-1746.2000.02227.x
36. Kaur G, Sarkar N, Bhatnagar S, et al. Pediatric celiac disease in India is associated with multiple DR3-DQ2 haplotypes. Hum Immunol. 2002;63(8):677-682.
doi:10.1016/S0198-8859(02)00413-5
37. Kanga U, Vaidyanathan B, Jaini R, Menon PSN, Mehra NK. HLA haplotypes associated with type 1 diabetes mellitus in North Indian children. Hum Immunol. 2004;65(1):47-53. doi:10.1016/j.humimm.2003.10.013
38. Srivastava A, Yachha SK, Mathias A, Parveen F, Poddar U, Agrawal S. Prevalence, human leukocyte antigen typing and strategy for screening among Asian first-degree relatives of children with celiac disease. J Gastroenterol Hepatol. 2010;25(2):319-324. doi:10.1111/j. 1440-1746.2009.06044.x
39. Mishra A, Prakash S, Kaur G, et al. Prevalence of celiac disease among first-degree relatives of Indian celiac disease patients. Dig Liver Dis. 2016;48(3):255-259. doi:10.1016/j.dld. 2015.11.007
40. Singla S, Kumar P, Singh P, Kaur G, Rohtagi A, Choudhury M. HLA Profile of Celiac Disease among First-Degree Relatives from a Tertiary Care Center in North India. Indian J Pediatr. 2016;83(11):1248-1252. doi:10.1007/s12098-016-2146-7
41. Mills JR, Katzman BM, Ettore M, Murray JA, Gandhi MJ, Snyder MR. Exploring Associations Between Genotype and Serology in Celiac Disease. Vol 143. Oxford Academic; 2015. doi:10.1093/AJCP/143.SUPPL1.043
42. Ceylan GG. HLA Typing and Histopathologic Features of Patients with Celiac Disease-A Retrospective Study. J Clin Anal Med. 2016;7(3). doi:10.4328/jcam.2790