Genetics

Chapter

Abstract

Extensive studies revealed more than 70 strong candidate regions for susceptibility genes to systemic lupus erythematosus (SLE), and efforts to identify the causative variants in each candidate region are under way. The list of candidate genes points to the crucial pathways that play a role in the development of SLE, such as HLA and immune system signaling, upregulated type I interferon and nucleic acids response, and defective clearance of dying cells. Among these pathways, type I interferon pathway may be particularly relevant to neuropsychiatric SLE (NPSLE), because Aicardi-Goutières syndrome (AGS), a group of single gene diseases with enhanced type I IFN response and exhibits severe central nervous system symptoms, has some similarities with SLE. In fact, variants in some of the genes responsible for AGS are also reported in familial and sporadic patients with SLE. On the other hand, the efforts to identify NPSLE associated genes using case-case association analysis have not been very successful thus far. In the future, large-scale case-case association analysis, not limited to the genes associated with overall SLE, may be necessary in order to identify variants associated with clinical subphenotypes including neuropsychiatric manifestations.

Keywords

Genetics Systemic Lupus Erythematosus Neuropsychiatric Type I interferon TREX1 

References

  1. 1.
    Alarcon-Segovia D, et al. Familial aggregation of systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus patients from the GLADEL cohort. Arthritis Rheum. 2005;52:1138–47.CrossRefPubMedGoogle Scholar
  2. 2.
    Deapen D, et al. A revised estimate of twin concordance in systemic lupus erythematosus. Arthritis Rheum. 1992;35:311–8.CrossRefPubMedGoogle Scholar
  3. 3.
    Rees F, et al. The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies. Rheumatology. 2017;56:1945–61.CrossRefPubMedGoogle Scholar
  4. 4.
    Langefeld CD, et al. Transancestral mapping and genetic load in systemic lupus erythematosus. Nat Commun. 2017;8:16021.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Sun C, et al. High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry. Nat Genet. 2016;48:323–30.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Morris DL, et al. Genome-wide association meta-analysis in Chinese and European individuals identifies ten new loci associated with systemic lupus erythematosus. Nat Genet. 2016;48:940–6.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Deng Y, Updates in Lupus Genetics TBP. Curr Rheumatol Rep. 2017;19:68.CrossRefPubMedGoogle Scholar
  8. 8.
    Raj P, et al. Regulatory polymorphisms modulate the expression of HLA class II molecules and promote autoimmunity. Elife. 2016; 5. pii: e12089.Google Scholar
  9. 9.
    Taylor KE, et al. Risk alleles for systemic lupus erythematosus in a large case-control collection and associations with clinical subphenotypes. PLoS Genet. 2011;7:e1001311.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Graham RR, et al. Visualizing human leukocyte antigen class II risk haplotypes in human systemic lupus erythematosus. Am J Hum Genet. 2002;71:543–53.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Furukawa H, et al. Human leukocyte antigens and systemic lupus erythematosus: a protective role for the HLA-DR6 alleles DRB1*13:02 and *14:03. PLoS One. 2014;9:e87792.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Sirikong M, et al. Association of HLA-DRB1*1502-DQB1*0501 haplotype with susceptibility to systemic lupus erythematosus in Thais. Tissue Antigens. 2002;59:113–7.CrossRefPubMedGoogle Scholar
  13. 13.
    Lu LY, et al. Molecular analysis of major histocompatibility complex allelic associations with systemic lupus erythematosus in Taiwan. Arthritis Rheum. 1997;40:1138–45.CrossRefPubMedGoogle Scholar
  14. 14.
    Oka S, et al. Protective effect of the HLA-DRB1*13:02 allele in Japanese rheumatoid arthritis patients. PLoS One. 2014;9:e99453.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Kawasaki A, et al. Protective role of HLA-DRB1*13:02 against microscopic Polyangiitis and MPO-ANCA-positive Vasculitides in a Japanese population: a case-control study. PLoS One. 2016;11:e0154393.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Furukawa H, et al. Human leukocyte antigen and systemic sclerosis in Japanese: the sign of the four independent protective alleles, DRB1*13:02, DRB1*14:06, DQB1*03:01, and DPB1*02:01. PLoS One. 2016;11:e0154255.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Furuya T, et al. Immunogenetic features in 120 Japanese patients with idiopathic inflammatory myopathy. J Rheumatol. 2004;31:1768–74.PubMedGoogle Scholar
  18. 18.
    Furukawa H, et al. The role of common protective alleles HLA-DRB1*13 among systemic autoimmune diseases. Genes Immun. 2017;18:1–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Hachiya Y, et al. Association of HLA-G 3' untranslated region polymorphisms with systemic lupus erythematosus in a Japanese population: a case-control association study. PLoS One. 2016;11:e0158065.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Fernando MM, et al. Transancestral mapping of the MHC region in systemic lupus erythematosus identifies new independent and interacting loci at MSH5, HLA-DPB1 and HLA-G. Ann Rheum Dis. 2012;71:777–84.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Lintner KE, et al. Early components of the complement classical activation pathway in human systemic autoimmune diseases. Front Immunol. 2016;7:36.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Kim K, et al. The HLA-DRbeta1 amino acid positions 11-13-26 explain the majority of SLE-MHC associations. Nat Commun. 2014;5:5902.CrossRefPubMedGoogle Scholar
  23. 23.
    Bennett L, et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J Exp Med. 2003;197:711–23.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Baechler EC, et al. Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A. 2003;100:2610–5.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Kawasaki A, et al. Association of IRF5 polymorphisms with systemic lupus erythematosus in a Japanese population: support for a crucial role of intron 1 polymorphisms. Arthritis Rheum. 2008;58:826–34.CrossRefPubMedGoogle Scholar
  26. 26.
    Graham RR, et al. Three functional variants of IFN regulatory factor 5 (IRF5) define risk and protective haplotypes for human lupus. Proc Natl Acad Sci U S A. 2007;104:6758–63.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kawasaki A, et al. TLR7 single-nucleotide polymorphisms in the 3′ untranslated region and intron 2 independently contribute to systemic lupus erythematosus in Japanese women: a case-control association study. Arthritis Res Ther. 2011;13:R41.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Shen N, et al. Sex-specific association of X-linked toll-like receptor 7 (TLR7) with male systemic lupus erythematosus. Proc Natl Acad Sci U S A. 2010;107:15838–43.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Cunninghame Graham DS, et al. Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus. PLoS Genet. 2011;7:e1002341.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Bronson PG, et al. The genetics of type I interferon in systemic lupus erythematosus. Curr Opin Immunol. 2012;24:530–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Crow YJ, Manel N. Aicardi-Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol. 2015;15:429–40.CrossRefPubMedGoogle Scholar
  32. 32.
    Cuadrado E, et al. Aicardi–Goutières syndrome harbours abundant systemic and brain-reactive autoantibodies. Ann Rheum Dis. 2015;74:1931–9.CrossRefPubMedGoogle Scholar
  33. 33.
    Abe J, et al. A nationwide survey of Aicardi-Goutieres syndrome patients identifies a strong association between dominant TREX1 mutations and chilblain lesions: Japanese cohort study. Rheumatology. 2014;53:448–58.CrossRefPubMedGoogle Scholar
  34. 34.
    Shiozawa S, et al. Interferon-alpha in lupus psychosis. Arthritis Rheum. 1992;35:417–22.CrossRefPubMedGoogle Scholar
  35. 35.
    Oda H, et al. Aicardi-Goutieres syndrome is caused by IFIH1 mutations. Am J Hum Genet. 2014;95:121–5.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Costa-Reis P, Sullivan KE. Monogenic lupus: it's all new. Curr Opin Immunol. 2017;49:87–95.CrossRefPubMedGoogle Scholar
  37. 37.
    Ellyard JI, et al. Identification of a pathogenic variant in TREX1 in early-onset cerebral systemic lupus erythematosus by whole-exome sequencing. Arthritis Rheumatol. 2014;66:3382–6.CrossRefPubMedGoogle Scholar
  38. 38.
    de Vries B, et al. TREX1 gene variant in neuropsychiatric systemic lupus erythematosus. Ann Rheum Dis. 2010;69:1886–7.CrossRefPubMedGoogle Scholar
  39. 39.
    Lee-Kirsch MA, et al. Mutations in the gene encoding the 3′-5' DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet. 2007;39:1065–7.CrossRefPubMedGoogle Scholar
  40. 40.
    Mistry P, Kaplan MJ. Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis. Clin Immunol. 2017;185:59–73.CrossRefPubMedGoogle Scholar
  41. 41.
    Macedo AC, Isaac L. Systemic lupus erythematosus and deficiencies of early components of the complement classical pathway. Front Immunol. 2016;7:55.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Sisirak V, et al. Digestion of chromatin in apoptotic cell microparticles prevents autoimmunity. Cell. 2016;166:88–101.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Yasutomo K, et al. Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet. 2001;28:313–4.CrossRefPubMedGoogle Scholar
  44. 44.
    Graham RR, et al. Genetic variants near TNFAIP3 on 6q23 are associated with systemic lupus erythematosus. Nat Genet. 2008;40:1059–61.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Kawasaki A, et al. Association of TNFAIP3 interacting protein 1, TNIP1 with systemic lupus erythematosus in a Japanese population: a case-control association study. Arthritis Res Ther. 2010;12:R174.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Sandling JK, Garnier S, Sigurdsson S, Wang C, Nordmark G, Gunnarsson I, et al. A candidate gene study of the type I interferon pathway implicates IKBKE and IL8 as risk loci for SLE. Eur J Hum Genet. 2011;1(9):479–84.CrossRefGoogle Scholar
  47. 47.
    Lewis MJ, et al. UBE2L3 polymorphism amplifies NF-kappaB activation and promotes plasma cell development, linking linear ubiquitination to multiple autoimmune diseases. Am J Hum Genet. 2015;96:221–34.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Wu YY, et al. Concordance of increased B1 cell subset and lupus phenotypes in mice and humans is dependent on BLK expression levels. J Immunol. 2015;194:5692–702.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Samuelson EM, et al. Reduced B lymphoid kinase (Blk) expression enhances proinflammatory cytokine production and induces nephrosis in C57BL/6-lpr/lpr mice. PLoS One. 2014;9:e92054.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Ito I, et al. Replication of the association between the C8orf13-BLK region and systemic lupus erythematosus in a Japanese population. Arthritis Rheum. 2009;60:553–8.CrossRefPubMedGoogle Scholar
  51. 51.
    Hom G, et al. Association of systemic lupus erythematosus with C8orf13-BLK and ITGAM-ITGAX. N Engl J Med. 2008;358:900–9.CrossRefPubMedGoogle Scholar
  52. 52.
    Kawasaki A, et al. Role of STAT4 polymorphisms in systemic lupus erythematosus in a Japanese population: a case-control association study of the STAT1-STAT4 region. Arthritis Res Ther. 2008;10:R113.CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Zhao J, et al. A missense variant in NCF1 is associated with susceptibility to multiple autoimmune diseases. Nat Genet. 2017;49:433–7.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Fredi M, et al. Typing TREX1 gene in patients with systemic lupus erythematosus. Reumatismo. 2015;67:1–7.CrossRefPubMedGoogle Scholar
  55. 55.
    Ho RC, et al. Genetic variants that are associated with neuropsychiatric systemic lupus erythematosus. J Rheumatol. 2016;43:541–51.CrossRefPubMedGoogle Scholar
  56. 56.
    Ota Y, et al. Single nucleotide polymorphisms of CD244 gene predispose to renal and neuropsychiatric manifestations with systemic lupus erythematosus. Mod Rheumatol. 2010;20:427–31.CrossRefPubMedGoogle Scholar
  57. 57.
    Pullmann R Jr, et al. Apolipoprotein E polymorphism in patients with neuropsychiatric SLE. Clin Rheumatol. 2004;23:97–101.CrossRefPubMedGoogle Scholar
  58. 58.
    Ruiz-Larranaga O, et al. Genetic association study of systemic lupus erythematosus and disease subphenotypes in European populations. Clin Rheumatol. 2016;35:1161–8.CrossRefPubMedGoogle Scholar
  59. 59.
    Taha S, et al. Vascular endothelial growth factor G1612A (rs10434) gene polymorphism and neuropsychiatric manifestations in systemic lupus erythematosus patients. Rev Bras Reumatol Engl Ed. 2017;57:149–53.CrossRefPubMedGoogle Scholar
  60. 60.
    Ramirez GA, et al. TRPC6 gene variants and neuropsychiatric lupus. J Neuroimmunol. 2015;288:21–4.CrossRefPubMedGoogle Scholar
  61. 61.
    Sandrin-Garcia P, et al. Functional single-nucleotide polymorphisms in the DEFB1 gene are associated with systemic lupus erythematosus in southern Brazilians. Lupus. 2012;21:625–31.CrossRefPubMedGoogle Scholar
  62. 62.
    Kisiel BM, et al. Differential association of juvenile and adult systemic lupus erythematosus with genetic variants of oestrogen receptors alpha and beta. Lupus. 2011;20:85–9.CrossRefPubMedGoogle Scholar
  63. 63.
    Yang W, et al. ITGAM is associated with disease susceptibility and renal nephritis of systemic lupus erythematosus in Hong Kong Chinese and Thai. Hum Mol Genet. 2009;18:2063–70.CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Bassi C, et al. Efficiency of the DNA repair and polymorphisms of the XRCC1, XRCC3 and XRCC4 DNA repair genes in systemic lupus erythematosus. Lupus. 2008;17:988–95.CrossRefPubMedGoogle Scholar
  65. 65.
    Oroszi G, et al. The Met66 allele of the functional Val66Met polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in systemic lupus erythematosus. Ann Rheum Dis. 2006;65:1330–5.CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Liao CH, et al. Polymorphisms in the promoter region of RANTES and the regulatory region of monocyte chemoattractant protein-1 among Chinese children with systemic lupus erythematosus. J Rheumatol. 2004;31:2062–7.PubMedGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Molecular and Genetic Epidemiology Laboratory, Faculty of MedicineUniversity of TsukubaTsukubaJapan

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