HLA-DQB1*0301 in Bullous Pemphigoid and Pemphigus Vulgaris: A Meta-Analysis
Keywords:HLA-DQB1 antigen, Pemphigus, Pemphigoid, Bullous, DQB1*0301, Bullous pemphigoid, Bullous pemphigus, Dermatology, Skin, Vesicles, Skin layer, Autoimmunity, Inflamation, Inflammatory syndrome, Pemphigoids, Skin disease, Vesiculobullous Skin Diseases, Autoimmune Diseases, Immune System Diseases
Background: The linkage of HLA-DQB1*0301 to autoimmune disorders is becoming more common in literature. Despite bullous pemphigoid (BP) and pemphigus vulgaris (PV) both having similar symptoms, such as blistering skin conditions, research has shown different relationships with HLAs.
Methods: In this systematic review, HLA-DQB1*0301 and the odds of developing BP and PV were explored. Google Scholar and Pubmed were consulted, and articles were included if living subjects were used, odds ratio was available or could be ascertained from the study, and if it was not a meta-analysis of other researcher’s works. MetaXL software was used to generate data for analysis and a forest plot was generated for each. Nine studies conducted between 1996 and 2021 met study selection criteria for the BP HLA-DQB1*0301 meta-analysis (1,340 patients and 6,673 controls) and five studies (247 patients and 2,435 controls) for PV.
Results: HLA-DQB1*0301 increased the odds of developing BP (OR= 1.64, 95% CI [1.44, 1.87], I2= 0%) yet decreased odds of PV (OR= 0.60, 95% CI [0.40, 0.89], I2= 34%).
Conclusion: Results suggest HLA-DQB1*0301 may serve opposite roles in BP and PV despite similarity in symptoms, finding higher odds for developing BP versus lower odds for developing PV. Understanding this HLA’s function in each requires further exploration. Limitations of the analysis included minor asymmetry in the PV Doi plot, suggesting publication bias. No funding was used; study protocol was not registered.
InStatPearls. Type II Hypersensitivity Reaction. Available from: https://www.ncbi.nlm.nih.gov/books/NBK563264/. Last Update: July 4, 2023.
Moro F, Fania L, Sinagra JL, Salemme A, Di Zenzo G. Bullous pemphigoid: trigger and predisposing factors. Biomolecules. 2020;10(10):1432. DOI: https://doi.org/10.3390/biom10101432
Di Lernia V, Casanova DM, Goldust M, Ricci C. Pemphigus vulgaris and bullous pemphigoid: update on diagnosis and treatment. Dermatol Pract Concept. 2020;10(3):e2020050. DOI: https://doi.org/10.5826/dpc.1003a50
Kershenovich R, Hodak E, Mimouni D. Diagnosis and classification of pemphigus and bullous pemphigoid. Autoimmun Rev. 2014;13(4-5):477-81. DOI: https://doi.org/10.1016/j.autrev.2014.01.011
Rabbani A, Abbasi F, Taghvaei M, Rabbani B, Moradi B, Shakiba Y, Rezaei N, Amirzargar A. HLA‐DRB,‐DQA, and DQB alleles and haplotypes in Iranian patients with diabetes mellitus type I. Pediatr Diabetes. 2013;14(5):366-71. DOI: https://doi.org/10.1111/j.1399-5448.2012.00869.x
Chouchane K, Di Zenzo G, Pitocco D, Calabrese L, De Simone C. Bullous pemphigoid in diabetic patients treated by gliptins: the other side of the coin. J Transl Med. 2021;19:1-0. DOI: https://doi.org/10.1186/s12967-021-03192-8
Fang H, Shen S, Zheng X, Dang E, Zhang J, Shao S, Qiao P, Li Q, Wang H, Li C, Sun L. Association of HLA class I and class II alleles with bullous pemphigoid in Chinese Hans. J Dermatol Sci. 2018;89(3):258-62. DOI: https://doi.org/10.1016/j.jdermsci.2017.11.014
Bateman AC, Turner SJ, Theaker JM, Howell WM. HLA‐DQB1* 0303 and* 0301 alleles influence susceptibility to and prognosis in cutaneous malignant melanoma in the British Caucasian population. Tissue Antigens. 1998;52(1):67-73. DOI: https://doi.org/10.1111/j.1399-0039.1998.tb03025.x
Gheorghe LM, Rugina S, Dumitru IM, Franciuc I, Martinescu A, Nastase V, Petcu LC, Constantinescu I. Association of HLA-DQB1 alleles with interferon/ribavirin therapy outcomes in a Romanian patient group infected with hepatitis C virus genotype 1b. J Cont Clin Pract. 2016;2(2):50-9. DOI: https://doi.org/10.18683/jccp.2016.1013
Alpsoy E, Akman-Karakas A, Uzun S. Geographic variations in epidemiology of two autoimmune bullous diseases: pemphigus and bullous pemphigoid. Archives of dermatological research. 2015;307:291-8. DOI: https://doi.org/10.1007/s00403-014-1531-1
Broussard KC, Leung TG, Moradi A, Thorne JE, Fine JD. Autoimmune bullous diseases with skin and eye involvement: Cicatricial pemphigoid, pemphigus vulgaris, and pemphigus paraneoplastica. Clin Dermatol. 2016;34(2):205-13. DOI: https://doi.org/10.1016/j.clindermatol.2015.11.006
Moher D, Altman DG, Tetzlaff J. PRISMA Preferred Reporting items for systematic reviews and Meta-Analyses. Guidelines for Reporting Health Research: A User’s Manual. 1996;1999:250.
Furuya-Kanamori L, Barendregt JJ, Doi SA. A new improved graphical and quantitative method for detecting bias in meta-analysis. JBI Evid. 2018;16(4):195-203. DOI: https://doi.org/10.1097/XEB.0000000000000141
National Heart, Lung, and Blood Institute. Study Quality Assessment Tools. Accessed: June 6, 2021. Available from: https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools. Accessed: May 4, 2021.
Barendregt JJ, Doi SA. MetaXL user guide, EpiGear International Pty Ltd, Sunrise Beach, Queensland, Australia; 2016.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88. DOI: https://doi.org/10.1016/0197-2456(86)90046-2
Schwarm C, Gola D, Holtsche MM, Dieterich A, Bhandari A, Freitag M, Nürnberg P, Toliat M, Lieb W, Wittig M, Franke A. Identification of two novel bullous pemphigoid-associated alleles, HLA-DQA1* 05: 05 and-DRB1* 07: 01, in Germans. Orphanet J Rare Dis. 2021;16(1):1-5. DOI: https://doi.org/10.1186/s13023-021-01863-9
Lindgren O, Varpuluoma O, Tuusa J, Ilonen J, Huilaja L, Kokkonen N, Tasanen K. Gliptin-associated Bullous Pemphigoid and the Expression of Dipeptidyl Peptidase-4/CD26 in Bullous Pemphigoid. Acta Derm Venereol. 2019;99(6):602-9. DOI: https://doi.org/10.2340/00015555-3166
Sun Y, Liu H, Wang Z, Wang C, Mi Z, Sun L, Bao F, Yu G, Zhou G, Zhang F. The HLA-DQB1* 03: 01 is associated with bullous pemphigoid in the Han Chinese population. J Invest Dermatol. 2018;138(8):1874-7. DOI: https://doi.org/10.1016/j.jid.2018.02.021
Ujiie H, Muramatsu K, Mushiroda T, Ozeki T, Miyoshi H, Iwata H, Nakamura A, Nomoto H, Cho KY, Sato N, Nishimura M. HLA-DQB1* 03: 01 as a biomarker for genetic susceptibility to bullous pemphigoid induced by DPP-4 inhibitors. J Invest Dermatol. 2018;138(5):1201-4. DOI: https://doi.org/10.1016/j.jid.2017.11.023
Esmaili N, Mortazavi H, Chams-Davatchi S, Daneshpazhoooh M, Rayati Damavandi M, Aryanian Z, Amirzargar AA. Association between HLA-DQB1* 03: 01 and Bullous pemphigoid in Iranian patients. Iran J Immunol. 2013;10(1):1-9.
Gao XH, Winsey S, Li G, Barnardo M, Zhu XJ, Chen HD, Song F, Zhai N, Fuggle S, Wojnarowska F. HLA‐DR and DQ polymorphisms in bullous pemphigoid from northern China. Clin Exp Dermatol. 2002;27(4):319-21. DOI: https://doi.org/10.1046/j.1365-2230.2002.01037.x
Okazaki A, Miyagawa S, Yamashina Y, Kitamura W, Shirai T. Polymorphisms of HLA‐DR and‐DQ genes in Japanese patients with bullous pemphigoid. J Dermatol. 2000;27(3):149-56. DOI: https://doi.org/10.1111/j.1346-8138.2000.tb02141.x
Delgado JC, Turbay D, Yunis EJ, Yunis JJ, Morton ED, Bhol K, Norman R, Alper CA, Good RA, Ahmed R. A common major histocompatibility complex class II allele HLA-DQB1* 0301 is present in clinical variants of pemphigoid. Proc Natl Acad Sci U S A. 1996;93(16):8569-71. DOI: https://doi.org/10.1073/pnas.93.16.8569
Chagury AA, Sennes LU, Gil JM, Kalil J, Rodrigues H, Rosales CB, Miziara ID. HLA-C* 17, DQB1* 03: 01, DQA1* 01: 03 and DQA1* 05: 05 alleles associated to bullous pemphigoid in Brazilian population. Ann Dermatol. 2018;30(1):8-12. DOI: https://doi.org/10.5021/ad.2018.30.1.8
Vuong TB, Do DM, Ong PT, Le TV. HLA-DRB1 and DQB1 genetic susceptibility to pemphigus vulgaris and pemphigus foliaceus in Vietnamese patients. Dermatol Reports. 2022;14(2):9286. DOI: https://doi.org/10.4081/dr.2021.9286
Lombardi ML, Mercuro O, Pirozzi G, Manzo C, Lombari V, Ruocco V, Schiavo AL, Guerrera V. Common human leukocyte antigen alleles in pemphigus vulgaris and pemphigus foliaceus Italian patients. Journal of investigative dermatology. 1999;113(1):107-10. DOI: https://doi.org/10.1046/j.1523-1747.1999.00626.x
Zivanovic D, Bojic S, Medenica L, Andric Z, Popadic D. Human leukocyte antigen class II (DRB1 and DQB1) alleles and haplotypes frequencies in patients with pemphigus vulgaris among the Serbian population. HLA. 2016;87(5):367-74. DOI: https://doi.org/10.1111/tan.12796
Párnická Z, Švecová D, Javor J, Shawkatová I, Buc M. High susceptibility to pemphigus vulgaris due to HLA‐DRB1* 14: 54 in the Slovak population. Int J Immunogenet. 2013;40(6):471-5. DOI: https://doi.org/10.1111/iji.12052
Sáenz‐Cantele AM, Fernández‐Mestre M, Montagnani S, Calebotta A, Balbas O, Layrisse Z. HLA‐DRB1* 0402 haplotypes without DQB1* 0302 in Venezuelan patients with pemphigus vulgaris. Tissue Antigens. 2007;69(4):318-25. DOI: https://doi.org/10.1111/j.1399-0039.2007.00826.x
Gil JM, Weber R, Rosales CB, Rodrigues H, Sennes LU, Kalil J, Chagury A, Miziara ID. Study of the association between human leukocyte antigens (HLA) and pemphigus vulgaris in Brazilian patients. Int J Dermatol. 2017;56(5):557-62. DOI: https://doi.org/10.1111/ijd.13577
Li S, Zhang Q, Wang P, Li J, Ni J, Wu J, Liang Y, Leng RX, Pan HF, Ye DQ. Association between HLA-DQB1 polymorphisms and pemphigus vulgaris: A meta-analysis. Immunol Invest. 2018;47(1):101-12. DOI: https://doi.org/10.1080/08820139.2017.1385622
Zivadinov, R., Uxa, L., Bratina, A., Bosco, A., Srinivasaraghavan, B., Minagar, A., Ukmar, M., yen Benedetto, S. and Zorzon, M., 2007. HLA‐DRB1* 1501,‐DQB1* 0301,‐DQB1* 0302,‐DQB1* 0602, and‐DQB1* 0603 alleles are associated with more severe disease outcome on MRI in patients with multiple sclerosis. Int Rev Neurobiol. 2007;79:521-35. DOI: https://doi.org/10.1016/S0074-7742(07)79023-2
Gorodezky C, Alaez C, Murguía A, Rodríguez A, Balladares S, Vazquez M, Flores H, Robles C. HLA and autoimmune diseases: Type 1 diabetes (T1D) as an example. Autoimmun Rev. 2006;5(3):187-94. DOI: https://doi.org/10.1016/j.autrev.2005.06.002
Kahaly GJ, Frommer L, Schuppan D. Celiac disease and endocrine autoimmunity–the genetic link. Autoimmun Rev. 2018;17(12):1169-75. DOI: https://doi.org/10.1016/j.autrev.2018.05.013
Lee JE, Reveille JD, Ross MI, Platsoucas CD. HLA‐DQB1* 0301 association with increased cutaneous melanoma risk. Int J Cancer. 1994;59(4):510-3. DOI: https://doi.org/10.1002/ijc.2910590413
Khalil I, Lepage V, Douay C, Morin L, Al-Daccak R, Wallach D, Binet O, Lemarchand F, Degos L, Hors J. HLA DQB1* 0301 allele is involved in the susceptibility to erythema multiforme. J Invest Dermatol. 1991;97(4):697-700. DOI: https://doi.org/10.1111/1523-1747.ep12484029
Chan LS, Hammerberg C, Cooper KD. Significantly increased occurrence of HLA-DQB1∗ 0301 allele in patients with ocular cicatricial pemphigoid. J Invest Dermatol. 1997;108(2):129-32. DOI: https://doi.org/10.1111/1523-1747.ep12332352
Setterfield J, Theron J, Vaughan RW, Welsh KI, Mallon E, Wojnarowska F, Challacombe SJ, Black MM. Mucous membrane pemphigoid: HLA‐DQB1* 0301 is associated with all clinical sites of involvement and may be linked to antibasement membrane IgG production. Br J Dermatol. 2001;145(3):406-14. DOI: https://doi.org/10.1046/j.1365-2133.2001.04380.x
Wu MS, Hsieh RP, Huang SP, Chang YT, Lin MT, Chang MC, Shun CT, Sheu JC, Lin JT. Association of HLA‐DQB1*0301 and HLA‐DQB1*0602 with Different Subtypes of Gastric Cancer in Taiwan. Jpn J Cancer Res. 2002;93(4):404-10. DOI: https://doi.org/10.1111/j.1349-7006.2002.tb01271.x
Duarte-Rey C, Pardo AL, Rodríguez-Velosa Y, Mantilla RD, Anaya JM, Rojas-Villarraga A. HLA class II association with autoimmune hepatitis in Latin America: a meta-analysis. Autoimmun Rev. 2009 Feb 1;8(4):325-31. DOI: https://doi.org/10.1016/j.autrev.2008.11.005
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