Top

Published in:

06-05-2022 | Myasthenia Gravis | Original Article

HLA-DQB105:02, 05:03, and *03:01 alleles as risk factors for myasthenia gravis in a Spanish cohort

Authors: Maria Salvado, Jose Luis Caro, Cecilia Garcia, Francesc Rudilla, Laura Zalba-Jadraque, Eva Lopez, Elia Sanjuan, Josep Gamez, Jose Manuel Vidal-Taboada

Published in: Neurological Sciences | Issue 8/2022

Abstract

Background

Myasthenia gravis (MG) is a very heterogenic chronic autoimmune disease caused by the failure of neuromuscular transmission. The HLA gene complex has conventionally been recognized as its main genetic risk and phenotype modifying factor. Our aim was to investigate the prevalence of HLA class I and II alleles and to identify possible risk factors for sporadic MG in a Spanish cohort.

Methods

We designed a clinical case–control study comparing HLA alleles and haplotype frequencies in a cohort of 234 patients with sporadic autoimmune MG with data from a group of 492 randomly selected healthy subjects. Using a high-resolution next-generation sequencing (NGS)–based HLA genotyping assay, we investigated the contribution of HLA genotypes and haplotypes in the resulting phenotype, especially, the age at onset, sex, onset MGFA class, thymic histopathology, and serological status.

Results

We found that the DQB1*05:02 and DQB1*05:03 alleles could be novel risk factors for Spanish MG cases. The HLA alleles A*01:01, B*08:01, DRB1*03:01, DRB1*14:54, and DQB1*02:01 were also risk factors for the disease. DQB1*03:01 acted as a risk factor for EOMG in women with AChR-positive antibodies and thymus hyperplasia. Additionally, several alleles were identified as potential phenotype-modifying factors that could exert a protective effect: HLA-B*35:08, DRB1*13:01, and DQB1*06:03 in MG; HLA-A*24:02 in women and DRB1*07:01 and DQB1*02:02 for early onset. HLA-C*07:01 and haplotype A1-B8-C7-DR3-DQ2 were associated with an early-onset phenotype.

Available only for authorised users

Namba T, Brunner NG, Brown SB et al (1971) Familial myasthenia gravis: report of 27 patients in 12 families and review of 164 patients in 73 families. Arch Neurol 25:49–60. https://doi.org/10.1001/archneur.1971.00490010059009CrossRefPubMed

Marrie RA, Sahlas DJ, Bray GM (2000) Familial autoimmune myasthenia gravis: four patients involving three generations. Can J Neurol Sci 27:307–310. https://doi.org/10.1017/S0317167100001050CrossRefPubMed

Chen Y, Wang W, Wei D, Yang L (2012) Three cases of myasthenia gravis from one family with variations in clinical features and serum antibodies. Neuromuscul Disord 22:286–288. https://doi.org/10.1016/j.nmd.2011.10.004CrossRefPubMed

Koneczny I, Herbst R (2019) Myasthenia gravis: pathogenic effects of autoantibodies on neuromuscular architecture. Cells 8(7):671. https://doi.org/10.3390/cells8070671CrossRefPubMedCentral

Lazaridis K, Tzartos SJ (2020) Autoantibody specificities in myasthenia gravis; implications for improved diagnostics and therapeutics. Front Immunol 14(11):212. https://doi.org/10.3389/fimmu.2020.00212CrossRef

Meriggioli MN, Sanders DB (2009) Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. Lancet Neurol 8:475–490. https://doi.org/10.1016/S1474-4422(09)70063-8CrossRefPubMedPubMedCentral

Giraud M, Vandiedonck C, Garchon HJ (2008) Genetic factors in autoimmune myasthenia gravis. Ann N Y Acad Sci 1132:180–192. https://doi.org/10.1196/annals.1405.027CrossRefPubMed

Zhong H, Zhao C, Luo S (2019) HLA in myasthenia gravis: from superficial correlation to underlying mechanism. Autoimmun Rev 18(9):102349. https://doi.org/10.1016/j.autrev.2019.102349CrossRefPubMed

Muñiz-Castrillo S, Vogrig A, Honnorat J (2020) Associations between HLA and autoimmune neurological diseases with autoantibodies. Autoimmun Highlights 11(1):2. https://doi.org/10.1186/s13317-019-0124-6CrossRef

10.

Larsen CE, Alper CA (2004) The genetics of HLA-associated disease. Curr Opin Immunol 16:660–667. https://doi.org/10.1016/j.coi.2004.07.014CrossRefPubMed

11.

Naeim F, Keesey JC, Herrmann C et al (1978) Association of HLA—B8, DRw3, and anti-acetylcholine receptor antibodies in myasthenia gravis. Tissue Antigens 12:381–386. https://doi.org/10.1111/j.1399-0039.1978.tb01347.xCrossRefPubMed

12.

Ryder LP, Svejgaard A, Dausset J (2003) Genetics of HLA disease association. Annu Rev Genet 15:169–187. https://doi.org/10.1146/annurev.ge.15.120181.001125CrossRef

13.

Svejgaard A, Ryder LP (1994) HLA and disease associations: detecting the strongest association. Tissue Antigens 43:18–27. https://doi.org/10.1111/j.1399-0039.1994.tb02291.xCrossRefPubMed

14.

(IMSGC) TIMSGC, (WTCCC2) WTCCC 2, Sawcer S, et al (2012) Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature 476:214–219. https://doi.org/10.1038/nature10251.Genetic

15.

Moutsianas L, Jostins L, Beecham AH et al (2015) Class II HLA interactions modulate genetic risk for multiple sclerosis. Nat Genet 47(10):1107–1113. https://doi.org/10.1038/ng.3395CrossRefPubMedPubMedCentral

16.

Saruhan-Direskeneli G, Hughes T, Yilmaz V et al (2016) Genetic heterogeneity within the HLA region in three distinct clinical subgroups of myasthenia gravis. Clin Immunol 166–167:81–88. https://doi.org/10.1016/j.clim.2016.05.003CrossRefPubMed

17.

Gamez J, Salvadó M, Carmona F et al (2019) Intravenous immunoglobulin to prevent myasthenic crisis after thymectomy and other procedures can be omitted in patients with well-controlled myasthenia gravis. Ther Adv Neurol Disord 383:118–122. https://doi.org/10.1177/1756286419864497CrossRef

18.

Jaretzki A, Barohn RJ, Ernstoff RM et al (2000) Myasthenia gravis: recommendations for clinical research standards. Neurology 55:16–23. https://doi.org/10.1212/wnl.55.1.16CrossRefPubMed

19.

Enrich E, Campos E, Martorell L et al (2019) HLA-A, -B, -C, -DRB1, and -DQB1 allele and haplotype frequencies: an analysis of umbilical cord blood units at the Barcelona Cord Blood Bank. HLA 94(4):347–359. https://doi.org/10.1111/tan.13644CrossRefPubMed

20.

Alkhawajah NM, Oger J (2013) Late-onset myasthenia gravis: a review when incidence in older adults keeps increasing. Muscle Nerve 48:705–710. https://doi.org/10.1002/mus.23964CrossRefPubMed

21.

Pappas DJ, Marin W, Hollenbach JA, Mack SJ (2016) Bridging ImmunoGenomic Data Analysis Workflow Gaps (BIGDAWG): an integrated case-control analysis pipeline. Hum Immunol 77:283–287. https://doi.org/10.1016/j.humimm.2015.12.006CrossRefPubMed

22.

Gauderman WJ (2002) Sample size requirements for matched case-control studies of gene-environment interaction. Stat Med 21(1):35-50. https://doi.org/10.1002/sim.973

23.

Yousefipour GA, Salami Z, Farjadian S (2009) Association of HLADQA1* 0101/2 and DQB1*0502 with myasthenia gravis in southern Iranian patients. Iran J Immunol 6(2):99–102. https://iji.sums.ac.ir/?sid=Entrez:PubMed&id=pmid:19561379&key=2009.6.2.99, https://iji.sums.ac.ir/articl_17080_31d1b7a151ba8b666a264d0cc96d90c5.pdf

24.

Saruhan-Direskeneli G, Kiliç A, Parman Y et al (2006) HLA-DQ polymorphism in Turkish patients with myasthenia gravis. Hum Immunol 67:352–358. https://doi.org/10.1016/j.humimm.2006.02.039CrossRefPubMed

25.

Testi M, Terracciano C, Guagnano A et al (2012) Association of HLA-DQB1*05:02 and DRB1*16 alleles with late-onset, nonthymomatous. AChR-Ab-positive myasthenia gravis Autoimmune Dis 1:541760. https://doi.org/10.1155/2012/541760CrossRef

26.

Yang H, Hao J, Peng X et al (2012) The association of HLA-DQA1*0401 and DQB1*0604 with thymomatous myasthenia gravis in northern Chinese patients. J Neurol Sci 312:57–61. https://doi.org/10.1016/j.jns.2011.08.023CrossRefPubMed

27.

Horiki T, Inoko H, Moriuchi J et al (1994) Combinations of HLA-DPBl and HLA-DQB1 alleles determine susceptibility to early-onset myasthenia gravis in Japan. Autoimmunity 19:49–54. https://doi.org/10.3109/08916939409008008CrossRefPubMed

28.

Xie YC, Qu Y, Sun L et al (2011) Association between HLA-DRB1 and myasthenia gravis in a northern Han Chinese population. J Clin Neurosci 18:1524–1527. https://doi.org/10.1016/j.jocn.2011.05.002CrossRefPubMed

29.

Giraud M, Beaurain G, Yamamoto AM et al (2001) Linkage of HLA to myasthenia gravis and genetic heterogeneity depending on anti-titin antibodies. Neurology 57:1555–1560. https://doi.org/10.1212/WNL.57.9.1555CrossRefPubMed

30.

Ling CS, Shen ML, Wang Y et al (2020) The associations of HLA-DRB1 gene polymorphisms with late-onset myasthenia gravis: a meta-analysis. Neurol Sci 41(5):1041–1049. https://doi.org/10.1007/s10072-019-04213-7CrossRefPubMed

31.

Maniaol AH, Elsais A, Lorentzen ÅR, et al (2012) Late onset myasthenia gravis is associated with HLA DRB1*15:01 in the norwegian population. PLoS One 7(5) https://doi.org/10.1371/journal.pone.0036603

32.

Fritze D, Naeim F, Herrman C et al (1974) HL-A antigens in myasthenia gravis. Lancet 303:240–243. https://doi.org/10.1016/S0140-6736(74)92548-3CrossRef

33.

Vieira M, Caillat-Zucman S, Gajdos P et al (1993) Identification by genomic typing of non-DR3 HLA class II genes associated with myasthenia gravis. J Neuroimmunol 47:115–122. https://doi.org/10.1016/0165-5728(93)90021-PCrossRefPubMed

34.

Hjelmström P, Giscombe R, Lefvert AK et al (1995) Different HLA-DQ are positively and negatively associated in Swedish patients with myasthenia gravis. Autoimmunity 22:59–65. https://doi.org/10.3109/08916939508995300CrossRefPubMed

35.

Spagni G, Todi L, Monte G et al (2021) Human leukocyte antigen class II associations in late-onset myasthenia gravis. Ann Clin Transl Neurol 8(3):656–665. https://doi.org/10.1002/acn3.51309CrossRefPubMedPubMedCentral

36.

Gregersen PK, Kosoy R, Lee AT et al (2012) Risk for myasthenia gravis maps to a 151Pro→Ala change in TNIP1 and to human leukocyte antigen-B*08. Ann Neurol 72:927–935. https://doi.org/10.1002/ana.23691CrossRefPubMedPubMedCentral

37.

Compston DAS, Vincent A, Newsom-davis J, Batchelor JR (1980) Clinical, pathological, HLA antigen and immunological evidence for disease heterogeneity in myasthenia gravis. Brain 103:579–601. https://doi.org/10.1093/brain/103.3.579CrossRefPubMed

38.

Spurkland A, Gilhus NE, Rønningen KS et al (1991) Myasthenia gravis patients with thymus hyperplasia and myasthenia gravis patients with thymoma display different HLA associations. Tissue Antigens 37:90–93. https://doi.org/10.1111/j.1399-0039.1991.tb01851.xCrossRefPubMed

39.

Zhu W-H, Lu J-H, Lin J et al (2012) HLA-DQA1*03:02/DQB1*03:03:02 is strongly associated with susceptibility to childhood-onset ocular myasthenia gravis in Southern Han Chinese. J Neuroimmunol 247:81–85. https://doi.org/10.1016/j.jneuroim.2012.03.018CrossRefPubMed

40.

Ehsan S, Amirzargar A, Yekaninejad MS et al (2015) Association of HLA class II (DRB1, DQA1, DQB1) alleles and haplotypes with myasthenia gravis and its subgroups in the Iranian population. J Neurol Sci 359:335–342. https://doi.org/10.1016/j.jns.2015.11.021CrossRefPubMed

Title: HLA-DQB1*05:02, *05:03, and *03:01 alleles as risk factors for myasthenia gravis in a Spanish cohort
Authors: Maria Salvado
Jose Luis Caro
Cecilia Garcia
Francesc Rudilla
Laura Zalba-Jadraque
Eva Lopez
Elia Sanjuan
Josep Gamez
Jose Manuel Vidal-Taboada
Publication date: 06-05-2022
Publisher: Springer International Publishing
Keywords: Myasthenia Gravis
Thymoma
Thymoma
Published in: Neurological Sciences / Issue 8/2022
Print ISSN: 1590-1874
Electronic ISSN: 1590-3478
DOI: https://doi.org/10.1007/s10072-022-06102-y

Keynote webinar | Spotlight on medication adherence

Springer Medicine

HLA-DQB105:02, 05:03, and *03:01 alleles as risk factors for myasthenia gravis in a Spanish cohort

Abstract

Background

Methods

Results

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Please log in to get access to this content

Other articles of this Issue 8/2022

Paraneoplastic autoimmune autonomic ganglionopathy as the first symptom of bladder cancer: a case report and review of literature

A snapshot of emergency neurology management in the Lombardy Region, Italy

Neural underpinnings of the slowness of information processing in patients with traumatic brain injury: insights from tract-based spatial statistics

Comparison of pain-provoked versus standard 40-min tilt table test for the conformation of vasovagal syncope

Dolichoectasia: a brain arterial disease with an elusive treatment

The prediction effects of thyroid function in the severity of Guillain-Barré syndrome