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Volume 21, Issue 3
  • ISSN: 1875-6921
  • E-ISSN: 1875-6913

Abstract

Diabetes mellitus (DM) is a complex and multifactorial metabolic disorder with a significant genetic component. The human leukocyte antigen (HLA) genes, specifically HLA-DQA1, HLA-DQB1, and HLA-DRB1, have been implicated in the susceptibility and pathogenesis of DM. This review delves into the intricate interplay of these HLA genes, seeking to unravel the genetic tapestry that contributes to the development and progression of diabetes. We begin by providing an overview of the HLA system and its critical role in immune regulation. Subsequently, we explore the current state of knowledge regarding the association between HLA-DQA1, HLA-DQB1, and HLA-DRB1 polymorphisms and susceptibility to both type 1 and type 2 diabetes. Emphasis is placed on recent advancements in genetic research methodologies, including genome-wide association studies and next-generation sequencing, that have provided deeper insights into the genetic architecture of DM. The review also scrutinizes the functional implications of specific HLA alleles in modulating immune responses and the potential mechanisms by which they contribute to the autoimmune processes observed in type 1 diabetes. Additionally, we examine the role of HLA genes in the context of insulin resistance and beta-cell dysfunction in type 2 diabetes, shedding light on the shared and distinct genetic underpinnings of these two major forms of DM. Furthermore, we discuss the clinical implications of HLA genotyping in predicting disease risk, prognosis, and personalized treatment strategies. The integration of genetic information into clinical practice holds promise for precision medicine approaches in diabetes management.

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2024-08-27
2025-01-30

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References

  1. Galicia-GarciaU. Benito-VicenteA. JebariS. Pathophysiology of type 2 diabetes mellitus.Int. J. Mol. Sci.20202117627510.3390/ijms21176275 32872570
     [Google Scholar]
  2. NobleJ.A. ValdesA.M. Genetics of the HLA region in the prediction of type 1 diabetes.Curr. Diab. Rep.201111653354210.1007/s11892‑011‑0223‑x 21912932
     [Google Scholar]
  3. RoepB.O. ThomaidouS. van TienhovenR. ZaldumbideA. Type 1 diabetes mellitus as a disease of the β-cell (do not blame the immune system?).Nat. Rev. Endocrinol.2020173150161
     [Google Scholar]
  4. PopoviciuM.S. KakaN. SethiY. PatelN. ChopraH. CavaluS. Type 1 diabetes mellitus and autoimmune diseases: A critical review of the association and the application of personalized medicine.J. Pers. Med.202313342210.3390/jpm13030422 36983604
     [Google Scholar]
  5. SimmondsM. GoughS. The HLA region and autoimmune disease: Associations and mechanisms of action.Curr. Genomics20078745346510.2174/138920207783591690 19412418
     [Google Scholar]
  6. MambiyaM. ShangM. WangY. The play of genes and non-genetic factors on type 2 diabetes.Front. Public Health2019734910.3389/fpubh.2019.00349 31803711
     [Google Scholar]
  7. Caillat-ZucmanS. Molecular mechanisms of HLA association with autoimmune diseases.Tissue Antigens200973118https://pubmed.ncbi.nlm.nih.gov/19017300/10.1111/j.1399‑0039.2008.01167.x 19017300
     [Google Scholar]
  8. JanA. SaeedM. AfridiM.H. KhudaF. ShabbirM. KhanH. Association of HLA-B gene polymorphisms with type 2 diabetes in pashtun ethnic population of Khyber Pakhtunkhwa, Pakistan.J. Diabetes Res.202120216669731
     [Google Scholar]
  9. AssociationAD Diagnosis and classification of diabetes mellitus.Diabetes Care200932Suppl 1)(Suppl. 1S62710.2337/dc09‑S062 19118289
     [Google Scholar]
  10. SteckA.K. RewersM.J. Genetics of type 1 diabetes.Clin. Chem.201157217618510.1373/clinchem.2010.148221 21205883
     [Google Scholar]
  11. MureaM. MaL. FreedmanB.I. Genetic and environmental factors associated with type 2 diabetes and diabetic vascular complications.Rev. Diabet. Stud.20129162210.1900/RDS.2012.9.6 22972441
     [Google Scholar]
  12. WuY. DingY. TanakaY. ZhangW. Risk factors contributing to type 2 diabetes and recent advances in the treatment and prevention.Int. J. Med. Sci.201411111185120010.7150/ijms.10001 25249787
     [Google Scholar]
  13. PrasadR. GroopL. Genetics of type 2 diabetes-pitfalls and possibilities.Genes (Basel)2015618712310.3390/genes6010087 25774817
     [Google Scholar]
  14. GomesM.B. PortoL.C. SilvaD.A. HLA Genotypes and type 1 diabetes and its relationship to reported race/skin color in their relatives: A brazilian multicenter study.Genes (Basel)2022136972https://pubmed.ncbi.nlm.nih.gov/35741734/10.3390/genes13060972 35741734
     [Google Scholar]
  15. KatteJ.C. McDonaldT.J. SobngwiE. JonesA.G. The phenotype of type 1 diabetes in sub-Saharan Africa.Front. Public Health202311101462610.3389/fpubh.2023.1014626 36778553
     [Google Scholar]
  16. LieB.A. ToddJ.A. PociotF. The predisposition to type 1 diabetes linked to the human leukocyte antigen complex includes at least one non-class II gene.Am. J. Hum. Genet.199964379380010.1086/302283 10053014
     [Google Scholar]
  17. SinghG. SinghU. SinghS.K. SinghS. Immunogenetic study of diabetes mellitus in relation to HLA DQ and DR.Indian J. Endocrinol. Metab.202024432533210.4103/ijem.IJEM_564_19 33088755
     [Google Scholar]
  18. MosaadY.M. Clinical role of human leukocyte antigen in health and disease.Scand. J. Immunol.2015824283306https://onlinelibrary.wiley.com/doi/full/10.1111/sji.1232910.1111/sji.12329 26099424
     [Google Scholar]
  19. ChooS.Y. The HLA system: Genetics, immunology, clinical testing, and clinical implications.Yonsei Med. J.2007481112310.3349/ymj.2007.48.1.11 17326240
     [Google Scholar]
  20. DilworthL. FaceyA. OmoruyiF. Diabetes mellitus and its metabolic complications: The role of adipose tissues.Int. J. Mol. Sci.20212214764410.3390/ijms22147644 34299261
     [Google Scholar]
  21. BurrackA.L. MartinovT. FifeB.T. T cell-mediated beta cell destruction: Autoimmunity and alloimmunity in the context of type 1 diabetes.Front. Endocrinol. (Lausanne)20178DEC34310.3389/fendo.2017.00343 29259578
     [Google Scholar]
  22. CernaM. Epigenetic regulation in etiology of type 1 diabetes mellitus.Int. J. Mol. Sci.20192113610.3390/ijms21010036 31861649
     [Google Scholar]
  23. FarinaF. PicasciaS. PisapiaL. HLA-DQA1 and HLA-DQB1 alleles, conferring susceptibility to celiac disease and type 1 diabetes, are more expressed than non-predisposing alleles and are coordinately regulated.Cells20198775110.3390/cells8070751 31331105
     [Google Scholar]
  24. StichtJ. Álvaro-BenitoM. KonigorskiS. Type 1 diabetes and the HLA region: Genetic association besides classical HLA class II genes.Front. Genet.20211268394610.3389/fgene.2021.683946 34220961
     [Google Scholar]
  25. DashtiM. NizamR. JacobS. Association between alleles, haplotypes, and amino acid variations in HLA class II genes and type 1 diabetes in Kuwaiti children.Front. Immunol.202314123826910.3389/fimmu.2023.1238269 37638053
     [Google Scholar]
  26. Muñiz-CastrilloS. VogrigA. HonnoratJ. Associations between HLA and autoimmune neurological diseases with autoantibodies.Auto Immun. Highlights2020111210.1186/s13317‑019‑0124‑6 32127039
     [Google Scholar]
  27. CruxN.B. ElahiS. Human leukocyte antigen (hla) and immune regulation: How do classical and non-classical hla alleles modulate immune response to human immunodeficiency virus and hepatitis c virus infections?Front. Immunol.201787832
     [Google Scholar]
  28. ZhaoL.P. PapadopoulosG.K. MoustakasA.K. Nine residues in HLA-DQ molecules determine with susceptibility and resistance to type 1 diabetes among young children in Sweden.Sci. Rep.2021111882110.1038/s41598‑021‑86229‑8 33893332
     [Google Scholar]
  29. KinneyJ.W. BemillerS.M. MurtishawA.S. LeisgangA.M. SalazarA.M. LambB.T. Inflammation as a central mechanism in Alzheimer’s disease.Alzheimers Dement. (N. Y.)20184157559010.1016/j.trci.2018.06.014 30406177
     [Google Scholar]
  30. AlowaisS.A. AlghamdiS.S. AlsuhebanyN. Revolutionizing healthcare: The role of artificial intelligence in clinical practice.BMC Med. Educ.202323168910.1186/s12909‑023‑04698‑z 37740191
     [Google Scholar]
  31. MorranM.P. VonbergA. KhadraA. PietropaoloM. Immunogenetics of type 1 diabetes mellitus.Mol. Aspects Med.201542426010.1016/j.mam.2014.12.004 25579746
     [Google Scholar]
  32. ZhangM. LinS. YuanX. LinZ. HuangZ. HLA-DQB1 and HLA-DRB1 variants confer susceptibility to latent autoimmune diabetes in adults: Relative predispositional effects among allele groups.Genes (Basel)201910971010.3390/genes10090710 31540313
     [Google Scholar]
  33. AisagbonhiO. MorrisG.P. Human leukocyte antigens in pregnancy and preeclampsia.Front. Genet.20221388427510.3389/fgene.2022.884275 35571013
     [Google Scholar]
  34. AngumF. KhanT. KalerJ. SiddiquiL. HussainA. The prevalence of autoimmune disorders in women: A narrative review.Cureus2020125e809410.7759/cureus.8094 32542149
     [Google Scholar]
  35. GorisA. ListonA. The immunogenetic architecture of autoimmune disease.Cold Spring Harb. Perspect. Biol.201243a00726010.1101/cshperspect.a007260 22383754
     [Google Scholar]
  36. Zaborek-ŁyczbaM. ŁyczbaJ. MertowskaP. The HLA-G immune checkpoint plays a pivotal role in the regulation of immune response in autoimmune diseases.Int. J. Mol. Sci.202122241334810.3390/ijms222413348 34948145
     [Google Scholar]
  37. GregersenP.K. BehrensT.W. Genetics of autoimmune diseases — disorders of immune homeostasis.Nat. Rev. Genet.200671291792810.1038/nrg1944 17139323
     [Google Scholar]
  38. HockingA.M. BucknerJ.H. Genetic basis of defects in immune tolerance underlying the development of autoimmunity.Front. Immunol.20221397212110.3389/fimmu.2022.972121 35979360
     [Google Scholar]
  39. GregersenP.K. OlssonL.M. Recent advances in the genetics of autoimmune disease.Annu. Rev. Immunol.200927136339110.1146/annurev.immunol.021908.132653 19302045
     [Google Scholar]
  40. WangL. WangF.S. GershwinM.E. Human autoimmune diseases: A comprehensive update.J. Intern. Med.2015278436939510.1111/joim.12395 26212387
     [Google Scholar]
  41. Sanchez-MazasA. A review of HLA allele and SNP associations with highly prevalent infectious diseases in human populations.Swiss Med. Wkly.2020150w2021410.4414/smw.2020.20214 32297957
     [Google Scholar]
  42. TamouzaR. KrishnamoorthyR. LeboyerM. Understanding the genetic contribution of the human leukocyte antigen system to common major psychiatric disorders in a world pandemic context.Brain Behav. Immun.20219173173910.1016/j.bbi.2020.09.033 33031918
     [Google Scholar]
  43. LintasC. Linking genetics to epigenetics: The role of folate and folate‐related pathways in neurodevelopmental disorders.Clin. Genet.201995224125210.1111/cge.13421 30047142
     [Google Scholar]
  44. NageetaF.N.U. WaqarF. AllahiI. Precision medicine approaches to diabetic kidney disease: Personalized interventions on the horizon.Cureus2023159e4557510.7759/cureus.45575 37868402
     [Google Scholar]
  45. BowmanP FlanaganSE HattersleyAT Future roadmaps for precision medicine applied to diabetes: Rising to the challenge of heterogeneity.J Diabetes Res20182018
     [Google Scholar]
  46. SugandhF.N.U. ChandioM. RaveenaF.N.U. Advances in the management of diabetes mellitus: A focus on personalized medicine.Cureus2023158e4369710.7759/cureus.43697 37724233
     [Google Scholar]
  47. HarrisonJ.W. TallapragadaD.S.P. BaptistA. Type 1 diabetes genetic risk score is discriminative of diabetes in non-Europeans: Evidence from a study in India.Sci. Rep.2020101945010.1038/s41598‑020‑65317‑1 32528078
     [Google Scholar]
  48. TaylorR. Insulin resistance and type 2 diabetes.Diabetes201261477877910.2337/db12‑0073 22442298
     [Google Scholar]
  49. LuW. HuC. Molecular biomarkers for gestational diabetes mellitus and postpartum diabetes.Chin. Med. J. (Engl.)2022135161940195110.1097/CM9.0000000000002160 36148588
     [Google Scholar]
  50. MaZ.J. SunP. GuoG. ZhangR. ChenL.M. Association of the HLA-DQA1 and HLA-DQB1 alleles in type 2 diabetes mellitus and diabetic nephropathy in the han ethnicity of China.J. Diabetes Res.20132013452537
     [Google Scholar]
  51. NobleJ.A. ErlichH.A. Genetics of type 1 diabetes.Cold Spring Harb. Perspect. Med.201221a00773210.1101/cshperspect.a007732 22315720
     [Google Scholar]
  52. ColeJ.B. FlorezJ.C. Genetics of diabetes mellitus and diabetes complications.Nat. Rev. Nephrol.202016737739010.1038/s41581‑020‑0278‑5 32398868
     [Google Scholar]
  53. El NahasR. Al-AghbarM.A. HerreroL. van PanhuysN. Espino-GuarchM. Applications of genome-editing technologies for type 1 diabetes.Int. J. Mol. Sci.202325134410.3390/ijms25010344 38203514
     [Google Scholar]
  54. NobleJ.A. ValdesA.M. BugawanT.L. AppleR.J. ThomsonG. ErlichH.A. The HLA class I A locus affects susceptibility to type 1 diabetes.Hum. Immunol.200263865766410.1016/S0198‑8859(02)00421‑4 12121673
     [Google Scholar]
  55. AkilA.A.S. YassinE. Al-MaraghiA. AliyevE. Al-MalkiK. FakhroK.A. Diagnosis and treatment of type 1 diabetes at the dawn of the personalized medicine era.J. Transl. Med.202119113710.1186/s12967‑021‑02778‑6 33794915
     [Google Scholar]
  56. ZhaoR. LuZ. YangJ. ZhangL. LiY. ZhangX. Drug delivery system in the treatment of diabetes mellitus.Front. Bioeng. Biotechnol.2020888010.3389/fbioe.2020.00880 32850735
     [Google Scholar]
  57. FuggerL. JensenL.T. RossjohnJ. Challenges, progress, and prospects of developing therapies to treat autoimmune diseases.Cell20201811638010.1016/j.cell.2020.03.007 32243797
     [Google Scholar]
  58. FrenetE.M. ScaradavouA. Human Leukocyte Antigens. In: Transfusion Medicine and Hemostasis.Third EditionElsevier2019191197
     [Google Scholar]
  59. PisetskyD.S. Pathogenesis of autoimmune disease.Nat. Rev. Nephrol.202319850952410.1038/s41581‑023‑00720‑1 37165096
     [Google Scholar]
  60. BalboaD. PrasadR.B. GroopL. OtonkoskiT. Genome editing of human pancreatic beta cell models: Problems, possibilities and outlook.Diabetologia20196281329133610.1007/s00125‑019‑4908‑z 31161346
     [Google Scholar]
  61. MartinovT. FifeB.T. Type 1 diabetes pathogenesis and the role of inhibitory receptors in islet tolerance.Ann. N. Y. Acad. Sci.2020146117310310.1111/nyas.14106 31025378
     [Google Scholar]
  62. RothschildJ. Ethical considerations of gene editing and genetic selection.J. Gen. Fam. Med.2020213374710.1002/jgf2.321 32489755
     [Google Scholar]
  63. GootjesC. ZwagingaJ.J. RoepB.O. NikolicT. Functional impact of risk gene variants on the autoimmune responses in type 1 diabetes.Front. Immunol.20221388673610.3389/fimmu.2022.886736 35603161
     [Google Scholar]
  64. TremblayJ. HametP. Environmental and genetic contributions to diabetes.Metabolism201910015395210.1016/j.metabol.2019.153952 31610851
     [Google Scholar]
  65. HoodK.K. HilliardM. PiattG. Ievers-LandisC.E. Effective strategies for encouraging behavior change in people with diabetes.Diabetes Manag. (Lond.)20155649951010.2217/dmt.15.43 30100925
     [Google Scholar]
  66. LiH. YangY. HongW. HuangM. WuM. ZhaoX. Applications of genome editing technology in the targeted therapy of human diseases: Mechanisms, advances and prospects.Signal Transduct. Target. Ther.20205112310.1038/s41392‑019‑0089‑y 32296011
     [Google Scholar]
  67. KarpovD.S. SosnovtsevaA.O. PylinaS.V. Challenges of CRISPR/Cas-based cell therapy for type 1 diabetes: How not to engineer a Trojan Horse.Int. J. Mol. Sci.202324241732010.3390/ijms242417320 38139149
     [Google Scholar]
  68. CarrollD. Genome engineering with zinc-finger nucleases.Genetics2011188477378210.1534/genetics.111.131433 21828278
     [Google Scholar]
  69. SunN. ZhaoH. Transcription activator‐like effector nucleases (TALENs): A highly efficient and versatile tool for genome editing.Biotechnol. Bioeng.201311071811182110.1002/bit.24890 23508559
     [Google Scholar]
  70. KantorA. McClementsM. MacLarenR. CRISPR-Cas9 DNA Base-Editing and Prime-Editing.Int. J. Mol. Sci.20202117624010.3390/ijms21176240 32872311
     [Google Scholar]
  71. FuY. HeX. GaoX.D. Prime editing: Current advances and therapeutic opportunities in human diseases.Sci. Bull. (Beijing)202368243278329110.1016/j.scib.2023.11.015 37973465
     [Google Scholar]
  72. MöllerL. AirdE.J. SchröderM.S. Recursive Editing improves homology-directed repair through retargeting of undesired outcomes.Nat. Commun.2022131455010.1038/s41467‑022‑31944‑7 35931681
     [Google Scholar]
  73. RodgersK. McveyM. Error-prone repair of DNA double-strand breaks.J. Cell. Physiol.201623111524
     [Google Scholar]
  74. KangH. GaY.J. KimS.H. Small interfering RNA (siRNA)-based therapeutic applications against viruses: Principles, potential, and challenges.J. Biomed. Sci.20233018810.1186/s12929‑023‑00981‑9 37845731
     [Google Scholar]
  75. MentzerA.J. O’ConnorD. BibiS. Human leukocyte antigen alleles associate with COVID-19 vaccine immunogenicity and risk of breakthrough infection.Nat. Med.202329114715710.1038/s41591‑022‑02078‑6 36228659
     [Google Scholar]
  76. BakayM. PandeyR. HakonarsonH. Genes involved in type 1 diabetes: An update.Genes (Basel)20134349952110.3390/genes4030499 24705215
     [Google Scholar]
  77. MerinoJ. FlorezJ.C. Precision medicine in diabetes: An opportunity for clinical translation.Ann. N. Y. Acad. Sci.20181411114015210.1111/nyas.13588 29377200
     [Google Scholar]
  78. SatamH. JoshiK. MangroliaU. Next-generation sequencing technology: Current trends and advancements.Biology (Basel)202312799710.3390/biology12070997 37508427
     [Google Scholar]
  79. LiM. JiangY. ZhangY. ZhuH. Medical image analysis using deep learning algorithms.Front. Public Health202311127325310.3389/fpubh.2023.1273253 38026291
     [Google Scholar]
  80. RaguramanR. SrivastavaA. MunshiA. RameshR. Therapeutic approaches targeting molecular signaling pathways common to diabetes, lung diseases and cancer.Adv. Drug Deliv. Rev.202117811391810.1016/j.addr.2021.113918 34375681
     [Google Scholar]
  81. TobiasD.K. MerinoJ. AhmadA. Second international consensus report on gaps and opportunities for the clinical translation of precision diabetes medicine.Nat. Med.202329102438245710.1038/s41591‑023‑02502‑5 37794253
     [Google Scholar]
/content/journals/cppm/10.2174/0118756921310081240821065036
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Deciphering the Genetic Landscape: Exploring the Relationship Between HLA-DQA1, HLA-DQB1, and HLA-DRB1 Genes in Diabetes Mellitus
Current Pharmacogenomics and Personalized Medicine (Formerly Current Pharmacogenomics) 21, 125 (2024); https://doi.org/10.2174/0118756921310081240821065036
/content/journals/cppm/10.2174/0118756921310081240821065036
/content/journals/cppm/10.2174/0118756921310081240821065036
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  • Article Type:     Review Article
Keyword(s): beta-cell function; Diabetes mellitus; genetic predisposition; human leukocyte antigen; immune response; polymorphisms
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