Skip to main content
SpringerLink
Log in

Common genetic variants in PRRC2A are associated with both neuromyelitis optica spectrum disorder and multiple sclerosis in Han Chinese population

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

Background

The proline-rich coiled-coil 2A (PRRC2A) gene has been reported to underlie risk of various autoimmune diseases. However, no data reveal the risk susceptibility of PRRC2A to neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS) so far.

Objectives

To explore the association between PRRC2A variants and NMOSD and MS susceptibility in Han Chinese population.

Methods

Totally, 207 NMOSD (98 AQP4+ and 109 AQP4−) patients, 141 MS and 196 healthy controls (HC) were enrolled. Candidate tagging single nucleotide polymorphisms (tag-SNPs) were selected from the 1000G database based on the Chinese data. SNP genotyping was performed using MassArray and Sanger sequencing.

Results

PRRC2A variants rs2736171, rs2736157, rs2844470 alter susceptibility to AQP4+ NMOSD, while rs2242659 to MS. Genotype AT of rs2844470 and AG of rs2242659 increased risk susceptibility for AQP4+ NMOSD and MS, respectively. AQP4+ NMOSD exhibited a higher frequency of genotype AG of rs2736157 compared with AQP4− NMOSD. Haplotype TCAAGGTAG was conferred risk susceptibility to AQP4+ NMOSD and haplotype TTAGAGTAG had a protective effect on both AQP4+ and AQP4− NMOSD. Further, we identified various gene expression levels in disease-related regions that are significantly modulated by three cis-eQTL SNPs rs2736157, rs2736171 and rs2242659 (p < 1.05 × 10–4).

Conclusions

PRRC2A variants are first reported to be associated with NMOSD and MS. The identified PRRC2A variants may shed light on the pathogenesis of NMOSD and MS and potentially lead to an individualized therapeutic approach for both distinct disease entities.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Papadopoulos MC, Bennett JL, Verkman AS (2014) Treatment of neuromyelitis optica: state-of-the-art and emerging therapies. Nat Rev Neurol 10:493–506. https://doi.org/10.1038/nrneurol.2014.141

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG (2007) The spectrum of neuromyelitis optica. Lancet Neurol 6:805–815. https://doi.org/10.1016/S1474-4422(07)70216-8

    Article  CAS  PubMed  Google Scholar 

  3. Reich DS, Lucchinetti CF, Calabresi PA (2018) Multiple Sclerosis. N Engl J Med 378:169–180. https://doi.org/10.1056/NEJMra1401483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Willer CJ, Dyment DA, Risch NJ, Sadovnick AD, Ebers GC, Canadian Collaborative Study Group (2003) Twin concordance and sibling recurrence rates in multiple sclerosis. Proc Natl Acad Sci 100:12877–12882. https://doi.org/10.1073/pnas.1932604100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Ebers GC, Sadovnick AD, Risch NJ (1995) A genetic basis for familial aggregation in multiple sclerosis. Nature 377:150–151. https://doi.org/10.1038/377150a0

    Article  CAS  PubMed  Google Scholar 

  6. Matiello M, Kim HJ, Kim W et al (2010) Familial neuromyelitis optica. Neurology 75:310–315. https://doi.org/10.1212/WNL.0b013e3181ea9f15

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. The MHC sequencing consortium (1999) Complete sequence and gene map of a human major histocompatibility complex. Nature 401:921–923. https://doi.org/10.1038/44853

    Article  Google Scholar 

  8. Lessard CJ, Ice JA, Adrianto I et al (2012) The genomics of autoimmune disease in the era of genome-wide association studies and beyond. Autoimmun Rev 11:267–275. https://doi.org/10.1016/j.autrev.2011.10.003

    Article  CAS  PubMed  Google Scholar 

  9. Campbell RD, Trowsdale L (1993) Map of the human MHC. Immunol Today 14:349–352. https://doi.org/10.1016/0167-5699(93)90234-C

    Article  CAS  PubMed  Google Scholar 

  10. Ogawa K, Okuno T, Hosomichi K et al (2019) Next-generation sequencing identifies contribution of both class I and II HLA genes on susceptibility of multiple sclerosis in Japanese. J Ne-uroinflammation 16:162. https://doi.org/10.1186/s12974-019-1551-z

    Article  CAS  Google Scholar 

  11. Wang H, Dai Y, Qiu W et al (2011) HLA-DPB1 0501 is associated with susceptibility to anti-aquaporin-4 antibodies positive neuromyelitis optica in southern Han Chinese. J Neuroimmunol 233:181–184. https://doi.org/10.1016/j.jneuroim.2010.11.004

    Article  CAS  PubMed  Google Scholar 

  12. Estrada K, Whelan CW, Zhao F et al (2018) A whole-genome sequence study identifies geneti-c risk factors for neuromyelitis optica. Nat Commun 9:1929. https://doi.org/10.1038/s41467-018-04332-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Terao C, Brynedal B, Chen Z et al (2019) Distinct HLA associations with rheumatoid arthritis subsets defined by serological subphenotype. Am J Hum Genet 105:616–624. https://doi.org/10.1016/j.ajhg.2019.08.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Diakite M, Clark TG, Auburn S et al (2009) A genetic association study in the Gambia using tagging polymorphisms in the major histocompatibility complex class III region implicates a HLA-B associated transcript 2 polymorphism in severe malaria susceptibility. Hum Genet 125:105–109. https://doi.org/10.1007/s00439-008-0597-2

    Article  CAS  PubMed  Google Scholar 

  15. Singal DP, Li J, Zhu Y (2000) HLA class III region and susceptibility to rheumatoid arthritis. Clin Exp Rheumatol 18:485–491

    CAS  PubMed  Google Scholar 

  16. Tarassi K, Carthy D, Papasteriades C et al (1998) HLA-TNF haplotype heterogeneity in Greek SLE patients. Clin Exp Rheumatol 16:66–68

    CAS  PubMed  Google Scholar 

  17. Ratanachaiyavong S, Demaine AG, Campbell RD, McGregor AM (1991) Heat shock protein 70 (HSP70) and complement C4 genotypes in patients with hyperthyroid Graves’s disease. Clin Exp Immunol 84:48–52

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Singal DP, Li J, Zhu Y (1999) Genetic basis for rheumatoid arthritis. Arch Immunol Ther Exp 47:307–311

    CAS  Google Scholar 

  19. Singal DP, Li J, Lei K (1999) Genetics of rheumatoid arthritis (RA): two separate regions in the major histocompatibility complex contribute to susceptibility to RA. Immunol Lett 69:301–306. https://doi.org/10.1016/s0165-2478(99)00108-x

    Article  CAS  PubMed  Google Scholar 

  20. Wu R, Li A, Sun B et al (2019) A novel m6A reader Prrc2a controls oligodendroglial specification and myelination. Cell Res 29:23–41. https://doi.org/10.1038/s41422-018-0113-8

    Article  CAS  PubMed  Google Scholar 

  21. Wingerchuk DM, Banwell B, Bennett JL et al (2015) International consensus diagnostic criteri-a for neuromyelitis optica spectrum disorders. Neurology 85:177–189. https://doi.org/10.1212/WNL.0000000000001729

    Article  PubMed  PubMed Central  Google Scholar 

  22. Thompson AJ, Banwell BL, Barkhof F et al (2018) Diagnosis of multiple sclerosis: 2017 revisions of the McDonald Criteria. Lancet Neurol 17:162–173. https://doi.org/10.1016/S1474-4422(17)30470-2

    Article  PubMed  Google Scholar 

  23. Piras IS, Angius A, Andreani M et al (2014) BAT2 and BAT3 polymorphisms as a novel genetic risk factors for rejection after HLA-related SCT. Bone Marrow Transplant 49:1400–1404. https://doi.org/10.1038/bmt.2014.177

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Yoshimura S, Isobe N, Matsushita T et al (2013) Distinct genetic and infectious profiles in Ja-panese neuromyelitis optica patients according to anti-aquaporin 4 antibody status. J Neurol Neurosurg Psychiatry 84:29–34. https://doi.org/10.1136/jnnp-2012-302925

    Article  PubMed  Google Scholar 

  25. Hafler DA, Compston A, International Multiple Sclerosis Genetics Consortium et al (2007) Ris-k alleles for multiple sclerosis identified by a genomewide study. N Engl J Med 357:851–862. https://doi.org/10.1056/NEJMoa073493

    Article  CAS  PubMed  Google Scholar 

  26. Dyment DA, Ebers GC, Sadovnick AD (2004) Genetics of multiple sclerosis. Lancet Neurol 3:104–110. https://doi.org/10.1016/s1474-4422(03)00663-x

    Article  CAS  PubMed  Google Scholar 

  27. Patsopoulos NA, Bayer Pharma MS Genetics Working Group, Steering Committees of Studies Evaluating IFNβ-1b, and CCR1-Antagonist et al (2011) Genome-wide meta-analysis identifies n-ovel multiple sclerosis susceptibility loci. Ann Neurol 70:897–912. https://doi.org/10.1002/ana.22609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yamasaki K, Horiuchi I, Minohara M et al (1999) HLA-DPB1*0501-associated opticospinal m-ultiple sclerosis: clinical, neuroimaging and immunogenetic studies. Brain 122:1689–1696. https://doi.org/10.1093/brain/122.9.1689

    Article  PubMed  Google Scholar 

  29. Liu QB, Li ZX, Zhao GX, Yu H, Wu ZY (2014) No association between identified multiple sclerosis non-MHC risk loci and neuromyelitis optica. Neurosci Bull 30:1036–1044. https://doi.org/10.1007/s12264-013-1457-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We sincerely thank the participants for their willingness to participate in this study.

Funding

This study was supported by the research foundation for distinguished scholar of Zhejiang University to Zhi-Ying Wu (188020-193810101/089).

Author information

Authors and Affiliations

  1. Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, 88 Jiefang Road, Hangzhou, 310009, China

    Juan Zhang, Mei-Jiao Chen, Hong-Fu Li, Lei Wu, Yong-Feng Xu & Zhi-Ying Wu

  2. Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China

    Gui-Xian Zhao

  3. Department of Neurology, First Affiliated Hospital, Fujian Medical University, Fuzhou, China

    Gui-Xian Zhao

  4. The Brain Science Center, Beijing Institute of Basic Medical Sciences, Beijing, 100850, China

    Yajin Liao & Zengqiang Yuan

Authors
  1. Juan Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mei-Jiao Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gui-Xian Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hong-Fu Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Lei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yong-Feng Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yajin Liao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Zengqiang Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Zhi-Ying Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Zhi-Ying Wu.

Ethics declarations

Conflicts of interest

The authors declare that they have no competing interests.

Ethical approval

This study was approved by the ethics committee of Second Affiliated Hospital of Zhejiang University School of Medicine, Huashan Hospital of Fudan University and First Affiliated Hospital of Fujian Medical University.

Informed consent

Informed consent was obtained from each participant.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, J., Chen, MJ., Zhao, GX. et al. Common genetic variants in PRRC2A are associated with both neuromyelitis optica spectrum disorder and multiple sclerosis in Han Chinese population. J Neurol 268, 506–515 (2021). https://doi.org/10.1007/s00415-020-10184-z

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-020-10184-z

Keywords

Search

Navigation