Genomics & Informatics

Korea Genome Organization (한국유전체학회)
권호 표지
DOI QR코드

DOI QR Code

Identifying pathogenic variants related to systemic lupus erythematosus by integrating genomic databases and a bioinformatic approach

  • Received : 2023.01.12
  • Accepted : 2023.08.09
  • Published : 2023.09.30
Download PDF
⟨ Previous Next ⟩

Abstract

Systemic lupus erythematosus (SLE) is an inflammatory-autoimmune disease with a complex multi-organ pathogenesis, and it is known to be associated with significant morbidity and mortality. Various genetic, immunological, endocrine, and environmental factors contribute to SLE. Genomic variants have been identified as potential contributors to SLE susceptibility across multiple continents. However, the specific pathogenic variants that drive SLE remain largely undefined. In this study, we sought to identify these pathogenic variants across various continents using genomic and bioinformatic-based methodologies. We found that the variants rs35677470, rs34536443, rs17849502, and rs13306575 are likely damaging in SLE. Furthermore, these four variants appear to affect the gene expression of NCF2, TYK2, and DNASE1L3 in whole blood tissue. Our findings suggest that these genomic variants warrant further research for validation in functional studies and clinical trials involving SLE patients. We conclude that the integration of genomic and bioinformatic-based databases could enhance our understanding of disease susceptibility, including that of SLE.

Keywords

References

  1. Shuoshan X, Changjuan X, Honglin Z, Qinghua Z, Shaxi O, Qi W, et al. Genetic variants related to systemic lupus erythematosus revealed using bioinformatics. Eur J Inflamm 2022 Mar 4 [Epub]. https://doi.org/10.1177/20587392211070407.
  2. Rees F, Doherty M, Grainge MJ, Lanyon P, Zhang W. The worldwide incidence and prevalence of systemic lupus erythematosus: a systematic review of epidemiological studies. Rheumatology (Oxford) 2017;56:1945-1961. https://doi.org/10.1093/rheumatology/kex260
  3. Ahearn JM, Liu CC, Kao AH, Manzi S. Biomarkers for systemic lupus erythematosus. Transl Res 2012;159:326-342. https://doi.org/10.1016/j.trsl.2012.01.021
  4. Greenan-Barrett J, Doolan G, Shah D, Virdee S, Robinson GA, Choida V, et al. Biomarkers associated with organ-specific involvement in juvenile systemic lupus erythematosus. Int J Mol Sci 2021;22:7619.
  5. Buniello A, MacArthur JA, Cerezo M, Harris LW, Hayhurst J, Malangone C, et al. The NHGRI-EBI GWAS catalog of published genome-wide association studies, targeted arrays and summary statistics 2019. Nucleic Acids Res 2019;47:D1005-D1012. https://doi.org/10.1093/nar/gky1120
  6. Pe'er I, Yelensky R, Altshuler D, Daly MJ. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet Epidemiol 2008;32:381-385. https://doi.org/10.1002/gepi.20303
  7. Fadista J, Manning AK, Florez JC, Groop L. The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants. Eur J Hum Genet 2016;24:1202-1205. https://doi.org/10.1038/ejhg.2015.269
  8. Oscanoa J, Sivapalan L, Gadaleta E, Dayem Ullah AZ, Lemoine NR, Chelala C. SNPnexus: a web server for functional annotation of human genome sequence variation (2020 update). Nucleic Acids Res 2020;48:W185-W192. https://doi.org/10.1093/nar/gkaa420
  9. Dayem Ullah AZ, Oscanoa J, Wang J, Nagano A, Lemoine NR, Chelala C. SNPnexus: assessing the functional relevance of genetic variation to facilitate the promise of precision medicine. Nucleic Acids Res 2018;46:W109-W113. https://doi.org/10.1093/nar/gky399
  10. Dayem Ullah AZ, Lemoine NR, Chelala C. A practical guide for the functional annotation of genetic variations using SNPnexus. Brief Bioinform 2013;14:437-447. https://doi.org/10.1093/bib/bbt004
  11. Dayem Ullah AZ, Lemoine NR, Chelala C. SNPnexus: a web server for functional annotation of novel and publicly known genetic variants (2012 update). Nucleic Acids Res 2012;40:W65-W70. https://doi.org/10.1093/nar/gks364
  12. Chelala C, Khan A, Lemoine NR. SNPnexus: a web database for functional annotation of newly discovered and public domain single nucleotide polymorphisms. Bioinformatics 2009;25:655-661. https://doi.org/10.1093/bioinformatics/btn653
  13. Puspitaningrum AN, Perwitasari DA, Adikusuma W, Djalilah GN, Dania H, Maliza R, et al. Integration of genomic databases and bioinformatic approach to identify genomic variants for sjogren's syndrome on multiple continents. Media Farm J Ilmu Farm 2022;19:71-81. https://doi.org/10.12928/mf.v19i2.23706
  14. Irham LM, Adikusuma W, Lolita L, Puspitaningrum AN, Afief AR, Sarasmita MA, et al. Investigation of susceptibility genes for chickenpox disease across multiple continents. Biochem Biophys Rep 2023;33:101419.
  15. Bakutenko IY, Haurylchyk ID, Nikitchenko NV, Sechko EV, Kozyro IA, Tchitchko AM, et al. Neutrophil cytosolic factor 2 (NCF2) gene polymorphism is associated with juvenile-onset systemic lupus erythematosus, but probably not with other autoimmune rheumatic diseases in children. Mol Genet Genomic Med 2022;10:e1859.
  16. Cachat J, Deffert C, Hugues S, Krause KH. Phagocyte NADPH oxidase and specific immunity. Clin Sci (Lond) 2015;128:635-648. https://doi.org/10.1042/CS20140635
  17. Arnold DE, Heimall JR. A review of chronic granulomatous disease. Adv Ther 2017;34:2543-2557. https://doi.org/10.1007/s12325-017-0636-2
  18. Jordan MA, Baxter AG. Genetic predisposition, humans. In: The Autoimmune Diseases (Rose NR, Mackay IR, eds.). 6th ed. San Diego: Academic Press, 2020. pp. 383-418.
  19. O'Neill S, Brault J, Stasia MJ, Knaus UG. Genetic disorders coupled to ROS deficiency. Redox Biol 2015;6:135-156. https://doi.org/10.1016/j.redox.2015.07.009
  20. Jacob CO, Eisenstein M, Dinauer MC, Ming W, Liu Q, John S, et al. Lupus-associated causal mutation in neutrophil cytosolic factor 2 (NCF2) brings unique insights to the structure and function of NADPH oxidase. Proc Natl Acad Sci U S A 2012;109:E59-E67. https://doi.org/10.1073/pnas.1113251108
  21. Armstrong DL, Eisenstein M, Zidovetzki R, Jacob CO. Systemic lupus erythematosus-associated neutrophil cytosolic factor 2 mutation affects the structure of NADPH oxidase complex. J Biol Chem 2015;290:12595-12602. https://doi.org/10.1074/jbc.M115.639021
  22. Ohl K, Tenbrock K. Oxidative stress in SLE T cells, is NRF2 really the target to treat? Front Immunol 2021;12:633845.
  23. Lee YH, Bae SC. Association between TYK2 polymorphisms and susceptibility to autoimmune rheumatic diseases: a meta-analysis. Lupus 2016;25:1307-1314. https://doi.org/10.1177/0961203316638933
  24. Pellenz FM, Dieter C, Lemos NE, Bauer AC, Souza BM, Crispim D. Association of TYK2 polymorphisms with autoimmune diseases: a comprehensive and updated systematic review with meta-analysis. Genet Mol Biol 2021;44:e20200425.
  25. Shao WH, Cohen PL. The role of tyrosine kinases in systemic lupus erythematosus and their potential as therapeutic targets. Expert Rev Clin Immunol 2014;10:573-582. https://doi.org/10.1586/1744666X.2014.893827
  26. Ronnblom L, Alm GV. Systemic lupus erythematosus and the type I interferon system. Arthritis Res Ther 2003;5:68-75. https://doi.org/10.1186/ar625
  27. Faezi ST, Soltani S, Akbarian M, Aslani S, Hamzeh E, Jamshidi A, et al. Association of TYK2 rs34536443 polymorphism with susceptibility to systemic lupus erythematous in the Iranian population. Rheumatol Res 2018;3:151-159. https://doi.org/10.22631/rr.2018.69997.1057
  28. Gorman JA, Hundhausen C, Kinsman M, Arkatkar T, Allenspach EJ, Clough C, et al. The TYK2-P1104A autoimmune protective variant limits coordinate signals required to generate specialized T cell subsets. Front Immunol 2019;10:44.
  29. Couturier N, Bucciarelli F, Nurtdinov RN, Debouverie M, Lebrun-Frenay C, Defer G, et al. Tyrosine kinase 2 variant influences T lymphocyte polarization and multiple sclerosis susceptibility. Brain 2011;134:693-703. https://doi.org/10.1093/brain/awr010
  30. Diogo D, Bastarache L, Liao KP, Graham RR, Fulton RS, Greenberg JD, et al. TYK2 protein-coding variants protect against rheumatoid arthritis and autoimmunity, with no evidence of major pleiotropic effects on non-autoimmune complex traits. PLoS One 2015;10:e0122271.
  31. Contreras-Cubas C, Garcia-Ortiz H, Velazquez-Cruz R, Barajas-Olmos F, Baca P, Martinez-Hernandez A, et al. Catalytically impaired TYK2 variants are protective against childhood- and adult-onset systemic lupus erythematosus in Mexicans. Sci Rep 2019;9:12165.
  32. Ghoreschi K, Augustin M, Baraliakos X, Kronke G, Schneider M, Schreiber S, et al. TYK2 inhibition and its potential in the treatment of chronic inflammatory immune diseases. J Dtsch Dermatol Ges 2021;19:1409-1420. https://doi.org/10.1111/ddg.14585
  33. Sisirak V, Sally B, D'Agati V, Martinez-Ortiz W, Ozcakar ZB, David J, et al. Digestion of chromatin in apoptotic cell mMicroparticles prevents autoimmunity. Cell 2016;166:88-101. https://doi.org/10.1016/j.cell.2016.05.034
  34. Shi G, Abbott KN, Wu W, Salter RD, Keyel PA. Dnase1L3 regulates inflammasome-dependent cytokine secretion. Front Immunol 2017;8:522.
  35. Al-Mayouf SM, Sunker A, Abdwani R, Abrawi SA, Almurshedi F, Alhashmi N, et al. Loss-of-function variant in DNASE1L3 causes a familial form of systemic lupus erythematosus. Nat Genet 2011;43:1186-1188. https://doi.org/10.1038/ng.975
  36. Yu Y, Gomez-Banuelos E, Li J, Cashman KS, Paz M, Trejo-Zambrano MI, et al. Neutralizing anti-DNase1L3 antibodies derive from autoreactive VH4-34+-B cells and associate with the interferon signature in SLE. Preprint at: https://doi.org/11.1101/2021.06.07.21258180 (2021). 101/2021.06.07.21258180()
  37. Zervou MI, Andreou A, Matalliotakis M, Spandidos DA, Goulielmos GN, Eliopoulos EE. Association of the DNASE1L3 rs35677470 polymorphism with systemic lupus erythematosus, rheumatoid arthritis and systemic sclerosis: structural biological insights. Mol Med Rep 2020;22:4492-4498. https://doi.org/10.3892/mmr.2020.11547
  38. Coke LN, Wen H, Comeau M, Ghanem MH, Shih A, Metz CN, et al. Arg206Cys substitution in DNASE1L3 causes a defect in DNASE1L3 protein secretion that confers risk of systemic lupus erythematosus. Ann Rheum Dis 2021;80:782-787. https://doi.org/10.1136/annrheumdis-2020-218810
  39. Yap DY, Chan TM. Lupus nephritis in Asia: clinical features and management. Kidney Dis (Basel) 2015;1:100-109. https://doi.org/10.1159/000430458
  40. Stojan G, Petri M. Epidemiology of systemic lupus erythematosus: an update. Curr Opin Rheumatol 2018;30:144-150. https://doi.org/10.1097/BOR.0000000000000480
  41. Ueki M, Takeshita H, Fujihara J, Iida R, Yuasa I, Kato H, et al. Caucasian-specific allele in non-synonymous single nucleotide polymorphisms of the gene encoding deoxyribonuclease I-like 3, potentially relevant to autoimmunity, produces an inactive enzyme. Clin Chim Acta 2009;407:20-24. https://doi.org/10.1016/j.cca.2009.06.022
  42. Li Z, Rotival M, Patin E, Michel F, Pellegrini S. Two common disease-associated TYK2 variants impact exon splicing and TYK2 dosage. PLoS One 2020;15:e0225289.
  43. Kim-Howard X, Sun C, Molineros JE, Maiti AK, Chandru H, Adler A, et al. Allelic heterogeneity in NCF2 associated with systemic lupus erythematosus (SLE) susceptibility across four ethnic populations. Hum Mol Genet 2014;23:1656-1668. https://doi.org/10.1093/hmg/ddt532
  44. Reid S, Alexsson A, Frodlund M, Morris D, Sandling JK, Bolin K, et al. High genetic risk score is associated with early disease onset, damage accrual and decreased survival in systemic lupus erythematosus. Ann Rheum Dis 2020;79:363-369. https://doi.org/10.1136/annrheumdis-2019-216227
  45. Sonawane AR, Platig J, Fagny M, Chen CY, Paulson JN, Lopes-Ramos CM, et al. Understanding tissue-specific gene regulation. Cell Rep 2017;21:1077-1088. https://doi.org/10.1016/j.celrep.2017.10.001
  46. Human Protein Atlas. The Human Protein Atlas - NCF2 2023. Stockholm: Human Protein Atlas, 2023. Accessed 2023 Jan 12. Available from: https://www.proteinatlas.org/ENSG00000116701-NCF2/tissue.
  47. Human Protein Atlas. The Human Protein Atlas - TYK2 2023. Stockholm: Human Protein Atlas, 2023. Accessed 2023 Jan 12. Available from: https://www.proteinatlas.org/ENSG00000105397-TYK2/tissue.
  48. Human Protein Atlas. The Human Protein Atlas - DNASE1L3 2023. Stockholm: Human Protein Atlas, 2023. Accessed 2023 Jan 12. Available from: https://www.proteinatlas.org/ENSG00000163687-DNASE1L3/tissue.
  49. Chan RW, Serpas L, Ni M, Volpi S, Hiraki LT, Tam LS, et al. Plasma DNA profile associated with DNASE1L3 gene mutations: clinical observations, relationships to nuclease substrate preference, and in vivo correction. Am J Hum Genet 2020;107:882-894. https://doi.org/10.1016/j.ajhg.2020.09.006
  50. Hromadova D, Elewaut D, Inman RD, Strobl B, Gracey E. From science to success? Targeting tyrosine kinase 2 in spondyloarthritis and related chronic inflammatory diseases. Front Genet 2021;12:685280.
  51. Li B, Ge YZ, Yan WW, Gong B, Cao K, Zhao R, et al. DNASE1L3 inhibits proliferation, invasion and metastasis of hepatocellular carcinoma by interacting with beta-catenin to promote its ubiquitin degradation pathway. Cell Prolif 2022;55:e13273.
  52. Binatti E, Gerussi A, Barisani D, Invernizzi P. The role of macrophages in liver fibrosis: new therapeutic opportunities. Int J Mol Sci 2022;23:6649.
  53. Fernald GH, Capriotti E, Daneshjou R, Karczewski KJ, Altman RB. Bioinformatics challenges for personalized medicine. Bioinformatics 2011;27:1741-1748. https://doi.org/10.1093/bioinformatics/btr295