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The associations of HLA-DRB1 gene polymorphisms with late-onset myasthenia gravis: a meta-analysis

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Abstract

Background

Late-onset myasthenia gravis (LOMG) is one of the major subgroups of the MG. Intensive evidence suggested that polymorphisms in HLA-DRB1 gene were associated with LOMG risk, but the results remained inconsistent. Therefore, a meta-analysis is conducted to make a more precise evaluation between HLA-DRB1 alleles and LOMG.

Methods

The PubMed, EMBASE, Cochrane library, Chinese National Knowledge Infrastructure (CNKI), and Wan Fang and Technology of Chongqing (VIP) Database were searched for eligible studies. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were applied to assess the association between HLA-DRB1 alleles and LOMG.

Results

A total of 11 studies involving 5513 people were included in our meta-analysis. The results showed that DRB1 07 and 0403 alleles were risk factors for LOMG (1.83 [1.12, 2.98], P = 0.02; 7.05 [2.62, 18.92], P = 0.0001, respectively), while DRB1 0301 and 1301 alleles were identified as protective factors for LOMG (0.44 [0.31, 0.62], P < 0.00001; 0.38 [0.23, 0.62], P = 0.0001, respectively). As for the HLA-DRB1 04 and 14 alleles, our subgroup analysis showed that there were significant associations between these alleles and LOMG in Caucasians (2.21 [1.14, 4.27], P = 0.02; 2.82 [1.29, 6.14], P = 0.009, respectively).

Conclusions

These results confirmed the association of DRB1 alleles (0301, 04, 0403, 07, 1301, and 14) and LOMG, which might provide potential promising biomarkers for prediction of LOMG risk.

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References

  1. Chen L , Xie W , Zheng D , et al.  Early extubation after thymectomy is good for the patients with myasthenia gravis[J].Neurological Sciences, 2019, 40(10):2125–2132

  2. Gilhus NE, Skeie GO, Romi F, Lazaridis K, Zisimopoulou P, Tzartos S (2016) Myasthenia gravis—autoantibody characteristics and their implications for therapy[J]. Nat Rev Neurol 12(5):259–268

    Article  CAS  Google Scholar 

  3. Santos E, Bettencourt A, Da SA et al (2017) HLA and age of onset in myasthenia gravis[J]. Neuromuscul Disord 27(7):S0960896617300603

    Article  Google Scholar 

  4. Meriggioli MN, Sanders DB (2009) Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity[J]. Lancet Neurol 8(5):475–490

    Article  CAS  Google Scholar 

  5. Somnier FE (2005) Increasing incidence of late-onset anti-AChR antibody-seropositive myasthenia gravis[J]. Neurology 65(6):928–930

    Article  CAS  Google Scholar 

  6. Casetta I, Groppo E, Gennaro RD et al (2010) Myasthenia gravis: a changing pattern of incidence[J]. J Neurol 257(12):2015–2019

    Article  CAS  Google Scholar 

  7. Pallaver F, Riviera AP, Piffer S, Ricciardi R, Roni R, Orrico D, Bonifati DM (2011) Change in myasthenia gravis epidemiology in Trento, Italy, after twenty years. Neuroepidemiology 36(4):282–287

    Article  Google Scholar 

  8. Popperud TH, Viken MK, Kerty E et al (2017) Juvenile myasthenia gravis in Norway: HLA-DRB1*04:04 is positively associated with prepubertal onset.[J]. Plos One 12(10):e0186383

    Article  CAS  Google Scholar 

  9. Avidan N, Le PR, Berrih-Aknin S et al (2014) Genetic basis of myasthenia gravis - a comprehensive review[J]. J Autoimmun 52:146–153

    Article  CAS  Google Scholar 

  10. Imanishi T, Akaza T, Kimura A, Tokunaga K, Gojyobori T (1992) Allele and haplotype frequencies for HLA and complement loci in various ethnic group, HLA 1991. Oxford: Oxford Press 1:1063–1220

  11. Suzuki S, Utsugisawa K, Nagane Y et al (2011) Clinical and immunological differences between early and late-onset myasthenia gravis in Japan[J]. J Neuroimmunol 230(1):148–152

    Article  CAS  Google Scholar 

  12. Xie YC, Qu Y, Sun L et al (2011) Association between HLA-DRB1 and myasthenia gravis in a northern Han Chinese population[J]. J Clin Neurosci 18(11):1527

    Article  Google Scholar 

  13. 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[J]. Autoimmune Dis 2012(1):541760

    PubMed  PubMed Central  Google Scholar 

  14. Ehsan S, Amirzargar A, Yekaninejad MS, Mahmoudi M, Mehravar S, Moradi B, Nafissi S (2015) Association of HLA class II (DRB1, DQA1, DQB1) alleles and haplotypes with myasthenia gravis and its subgroups in the Iranian population[J]. J Neurol Sci 359(1–2):335–342

    Article  CAS  Google Scholar 

  15. Baggi F, Antozzi C, Andreetta F et al (2010) Identification of a novel HLA class II association with DQB1*0502 in an Italian myasthenic population.[J]. Ann N Y Acad Sci 841(1):355–359

    Google Scholar 

  16. Fekihmrissa N, Klai S, Zaouali J et al (2013) Association of HLA-DR/DQ polymorphism with myasthenia gravis in Tunisian patients.[J]. Clin Neurol Neurosurg 115(1):32–36

    Article  Google Scholar 

  17. Maniaol AH, Elsais A, Lorentzen ÅR et al (2012) Late onset myasthenia gravis is associated with HLA DRB1*15:01 in the Norwegian population[J]. PLoS One 7:e36603

    Article  CAS  Google Scholar 

  18. Seldin MF, Alkhairy OK, Lee AT et al (2015) Genome-wide association study of late-onset myasthenia gravis: confirmation of TNFRSF11A, and identification of ZBTB10 and three distinct HLA associations[J]. Mol Med 21(1):769–781

    Article  CAS  Google Scholar 

  19. Hui-yu F , Li-xuan Y , Wei-bin L , Xin H., Li Q , Yan L.The HLA-B*4601-DRB1*0901 haplotype is positively correlated with juvenile ocular myasthenia gravis in a southern Chinese Han population[J]. Neurological Sciences, 2015, 36(7):1135–1140

  20. Massa R, Greco G, Testi M et al (2019) Thymomatous myasthenia gravis: novel association with HLA DQB1*05:01 and strengthened evidence of high clinical and serological severity[J]. J Neurol 266:982–989

    Article  Google Scholar 

  21. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses[J]. Eur J Epidemiol 25(9):603–605

    Article  Google Scholar 

  22. Reny J, Combescure C, Daali Y, Fontana P, PON1 Meta-Analysis Group (2012) Influence of the paraoxonase-1 Q192R genetic variant on clopidogrel responsiveness and recurrent cardiovascular events: a systematic review and meta-analysis. J Thromb Haemost 10(7):1242–1251

    Article  CAS  Google Scholar 

  23. Compston DA, 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

    Article  CAS  Google Scholar 

  24. Evoli A, Batocchi AP, Minisci C, Di Schino C, Tonali P (2000) Clinical characteristics and prognosis of myasthenia gravis in older people. J Am Geriatr Soc 48:1442–1448

    Article  CAS  Google Scholar 

  25. Akaishi T et al (2014) Insights into the classification of myasthenia gravis. PLoS One 9:e106757

    Article  Google Scholar 

  26. Janer M, Cowland A, Picard J, Campbell D, Pontarotti P, Newsom-Davis J, Bunce M, Welsh K, Demaine A, Wilson AG, Willcox N (1999) A susceptibility region for myasthenia gravis extending into the HLA-class I sector telomeric to HLA-C. Hum Immunol 60:909–917

    Article  CAS  Google Scholar 

  27. Tremolizzo L, Giopato F, Piatti ML, Rigamonti A, Ferrarese C, Appollonio I.Myasthenia gravis mimicking stroke: a case series with sudden onset dysarthria[J]. Neurological Sciences, 2015, 36(6):895–898

  28. Giraud M, Beaurain G, Yamamoto AM, Eymard B, Tranchant C, Gajdos P, Garchon HJ (2001) Linkage of HLA to myasthenia gravis and genetic heterogeneity depending on anti-titin antibodies[J]. Neurology 57(9):1555–1560

    Article  CAS  Google Scholar 

  29. Romi F, Skeie GO, Aarli JA, Gilhus NE (2000) The severity of myasthenia gravis correlates with the serum concentration of titin and ryanodine receptor antibodies[J]. Arch Neurol 57(11):1596–1600

    Article  CAS  Google Scholar 

  30. Yamamoto AM, Gajdos P, Eymard B, Tranchant C, Warter JM, Gomez L, Bourquin C, Bach JF, Garchon HJ (2001) Anti-titin antibodies in myasthenia gravis: tight association with thymoma and heterogeneity of nonthymoma patients[J]. Arch Neurol 58(6):885–890

    Article  CAS  Google Scholar 

  31. Suzuki S, Utsugisawa K, Nagane Y, Satoh T, Terayama Y, Suzuki N, Kuwana M (2007) Classification of myasthenia gravis based on autoantibody status[J]. Arch Neurol 64(8):1121–1124

    Article  Google Scholar 

  32. Romi F, Gilhus NE, Varhaug JE et al (2010) Thymectomy and antimuscle antibodies in nonthymomatous myasthenia gravis.[J]. Ann N Y Acad Sci 998(1):481–490

    Article  Google Scholar 

  33. Evoli A, Antonini G, Antozzi C et al (2019) Italian recommendations for the diagnosis and treatment of myasthenia gravis[J]. Neurol Sci 40:1111–1124

    Article  Google Scholar 

  34. Abdelhafidh H, Almawi Wassim Y, Mouna S et al (2019) Association of HLA-DRB1 and -DQB1 alleles with type 1 (autoimmune) diabetes in African Arabs: systematic review and meta-analysis.[J]. Immunol Investig 48:130–146

    Article  Google Scholar 

  35. Hong Y, Li HF, Romi F et al (2018) HLA and MuSK-positive myasthenia gravis: a systemic review and meta-analysis.[J]. Acta Neurol Scand:138(3)

  36. Voight BF, Cotsapas C (2012) Human genetics offers an emerging picture of common pathways and mechanisms in autoimmunity [J]. Curr Opin Immunol 24(5):552–557

    Article  CAS  Google Scholar 

  37. Parkes M, Cortes A, Heel DAV et al (2013) Genetic insights into common pathways and complex relationships among immune-mediated diseases[J]. Nat Rev Genet 14(9):661–673

    Article  CAS  Google Scholar 

  38. Mahmoodi M, Nahvi H, Mahmoudi M, Kasaian A, Mohagheghi MA, Divsalar K, Nahavandian B, Jafari A, Ansarpour B, Moradi B, Aghamohammadi A, Amirzargar A (2012) HLA-DRB1,-DQA1 and -DQB1 allele and haplotype frequencies in female patients with early onset breast cancer[J]. Pathology & Oncology Research 18(1):49–55

    Article  CAS  Google Scholar 

  39. Oksenberg JR, Barcellos LF, Cree BA, Baranzini SE, Bugawan TL, Khan O, Lincoln RR, Swerdlin A, Mignot E, Lin L, Goodin D, Erlich HA, Schmidt S, Thomson G, Reich DE, Pericak-Vance MA, Haines JL, Hauser SL (2004) Mapping multiple sclerosis susceptibility to the HLA-DR locus in African Americans.[J]. Am J Hum Genet 74(1):160–167

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by grants from the National Science Foundation of China (Nos. 81460560 and 81960664) and the Applied Basic Research Program of Yunnan Province of China (No. 2017FB134).

Author information

Author notes

  1. Cai-Se Ling, Ming-Li Shen and Yi Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Pharmacy, 920th Hospital of Joint Logistics Support Force, 212 Daguan Rd, Kunming, 650032, China

    Cai-Se Ling, Ming-Li Shen, Qian Huang & Gong-Hao He

  2. Kunming Medical University, Kunming, 650032, China

    Cai-Se Ling

  3. Department of Orthopaedics, 920th Hospital of Joint Logistics Support Force, Kunming, 650032, China

    Yi Wang

  4. Department of Cardio-Thoracic Surgery, 920th Hospital of Joint Logistics Support Force, Kunming, 650032, China

    Wen-Ke Cai

  5. Department of Phase I Clinical Trial, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, Fujian, People’s Republic of China

    Xiao-Qian Lin

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Contributions

ML Shen and Y Wang reviewed the topic-related literature and performed the study concept and analysis design. CS Ling performed the data collection, wrote the first draft, analyzed, and interpreted the data. CS Ling, MLShen, Y Wang, WK Cai, XQ Lin, Q Huang, and GH He edited and GH He revised the manuscript. All authors checked interpreted results and approved the final version.

Corresponding author

Correspondence to Gong-Hao He.

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All results and analyses were based on previous ethically-approved studies, thus no further ethical approval and patient consent are required.

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ESM 1

a Forest plots for association between HLA-DRB1 01 allele and LOMG in random model. b Forest plots for association between HLA-DRB1 1501 allele and LOMG in random model (TIF 1494 kb)

High Resolution (PNG 48 kb)

ESM 2

Forrest plots for association between HLA-DRB1 alleles and LOMG in six different alleles: a HLA-DRB1 03 allele. b HLA-DRB1 0701 allele. c HLA-DRB1 08 allele. d HLA-DRB1 09 allele. e HLA-DRB1 0901 allele. f HLA-DRB1 10 allele (TIF 3807 kb)

High Resolution (PNG 136 kb)

ESM 3

Forrest plots for association between HLA-DRB1 alleles and LOMG in six different alleles: a HLA-DRB1 11 allele. b HLA-DRB1 12 allele. c HLA-DRB1 13 allele. d HLA-DRB1 1302 allele. e HLA-DRB1 15 allele. f HLA-DRB1 16 (TIF 3879 kb)

High Resolution (PNG 154 kb)

ESM 4

Forest plots for association between HLA-DRB1 alleles and LOMG according to the ethnicity in four different alleles: a HLA-DRB1 01 allele. b HLA-DRB1 03 allele. c HLA-DRB1 08 allele. d HLA-DRB1 09 allele (TIF 4853 kb)

High Resolution (PNG 168 kb)

ESM 5

Forest plots for association between HLA-DRB1 alleles and LOMG according to the ethnicity in three different alleles: a HLA-DRB1 10 allele. b HLA-DRB1 11 allele. c HLA-DRB1 12 allele (TIF 3726 kb)

High Resolution (PNG 131 kb)

ESM 6

Forest plots for association between HLA-DRB1 alleles and LOMG according to the ethnicity in three different alleles: a HLA-DRB1 13 allele. b HLA-DRB1 15 allele. c HLA-DRB1 16 allele (TIF 3664 kb)

High Resolution (PNG 123 kb)

ESM 7

(DOCX 16 kb)

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

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