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The 3′-UTR (CA)n microsatellite on CD40LG gene as a possible genetic marker for rheumatoid arthritis in Mexican population: impact on CD40LG mRNA expression

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Abstract

The objective of this study was to determine the association of the CD40LG 3′-UTR (CA)n microsatellite with rheumatoid arthritis (RA) and CD40LG mRNA levels in females from western Mexico. A case-control study with 219 RA patients and 175 control subjects (CS) was conducted. Genotyping was performed by polymerase chain reaction (PCR), X 2 test was used to compare genotype and allele frequencies, and odds ratios and 95% confidence intervals were calculated to evaluate the association between RA and the microsatellite. CD40LG mRNA expression was assessed by real-time quantitative PCR. For comparisons between groups, Kruskal-Wallis or Mann-Whitney U tests for non-parametric data and ANOVA test for parametric data were performed. Among the 13 different alleles identified, CA25 was the most represented (45.4% RA and 46.3% CS). Stratification according to CA repeats as <CA25, CA25, and >CA25 showed a tendency towards a higher frequency of >CA25 alleles in RA patients (29%) compared to CS (23.4%). There was no association between any genotype and the clinical parameters of RA patients. According to the 2-∆∆Cq method, CD40LG mRNA expression in RA patients was 4.5-fold higher compared to CS; this difference was significant when assessed by the 2-∆Cq method (p = 0.028). Compared to carriers of the CA25/CA25 genotype, CS carrying the <CA25/<CA25 genotypes showed greater CD40LG mRNA expression (9.97-fold), unlike RA patients, where expression was 2.55-fold higher for >CA25/>CA25 carriers. The 3′-UTR CD40LG (CA)n microsatellite is not a genetic marker for RA in western Mexican population; however, results suggest that it plays a role in the CD40LG mRNA expression.

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References

  1. McInnes IB, Schett G (2011) The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205–2219

    Article  CAS  PubMed  Google Scholar 

  2. Arend WP, Firestein GS (2012) Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis. Nat Rev Rheumatol 8:573–586

    Article  CAS  PubMed  Google Scholar 

  3. Kurkó J, Besenyei T, Laki J, Glant TT, Mikecz K, Szekanecz Z (2013) Genetics of rheumatoid arthritis—a comprehensive review. Clinl Rev Allergy Immunol 45:170–179

    Article  Google Scholar 

  4. Elgueta R, Benson MJ, de Vries VC, Wasiuk A, Guo Y, Noelle RJ (2009) Molecular mechanism and function of CD40/CD40L engagement in the immune system. Immunol Rev 229:152–172

    Article  CAS  PubMed  Google Scholar 

  5. Korthäuer U, Graf D, Mages HW, Brière F, Padayachee M, Malcolm S et al (1993) Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature 36:539–541

    Article  Google Scholar 

  6. Peters AL, Stunz LL, Bishop GA (2009) CD40 and autoimmunity: the dark side of a great activator. Semin Immunol 21:293–300

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Mälarstig A, Lindahl B, Wallentin L, Siegbahn A (2006) Soluble CD40L levels are regulated by the -3459 A>G polymorphism and predict myocardial infarction and the efficacy of antithrombotic treatment in non-ST elevation acute coronary syndrome. Arterioscler Thromb Vasc Biol 26:1667–1673

    Article  PubMed  Google Scholar 

  8. García-Bermúdez M, González-Juanatey C, López-Mejías R, Teruel M, Corrales A, Miranda-Filloy JA et al (2012) Study of association of CD40-CD154 gene polymorphisms with disease susceptibility and cardiovascular risk in Spanish rheumatoid arthritis patients. PLoS One 7:e49214

    Article  PubMed  PubMed Central  Google Scholar 

  9. Lee SH, Lee EB, Shin ES, Lee JE, Cho SH, Min KU et al (2014) The interaction between allelic variants of CD86 and CD40lg: a common risk factor of allergic asthma and rheumatoid arthritis. Allergy Asthma Immunol Res 6:137–141

    Article  PubMed  Google Scholar 

  10. Dai Y, Masterman T, Huang W, Hillert J (2002) Analysis of a CD40 ligand dinucleotide microsatellite in multiple sclerosis. Eur J Immunogenet 29:81–85

    Article  CAS  PubMed  Google Scholar 

  11. Citores MJ, Rua-Figueroa I, Rodriguez-Gallego C, Durántez A, García-Laorden MI, Rodríguez-Lozano C et al (2004) The dinucleotide repeat polymorphism in the 3’UTR of the CD154 gene has a functional role on protein expression and is associated with systemic lupus erythematosus. Ann Rheum Dis 63:310–317

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Martin-Donaire T, Losada-Fernandez I, Perez-Chacon G, Rua-Figueroa I, Erausquin C, Naranjo-Hernandez A et al (2007) Association of the microsatellite in the 3′ untranslated region of the CD154 gene with rheumatoid arthritis in females from a Spanish cohort: a case-control study. Arthritis Res Ther 9:R89

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hamilton BJ, Wang XW, Collins J, Bloch D, Bergeron A, Henry B et al (2008) Separate cis-trans pathways post-transcriptionally regulate murine CD154 (CD40 Ligand) expression: a novel function for CA repeats in the 3′-untranslated region. J Biol Chem 283:25606–25616

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Citores MJ, Pérez-Aciego P, Rodríguez-Gallego C, Contreras-Martín B, García-Laorden I, Durántez A (2000) CD154 polymorphism in Spanish populations. Differences in the allelic distribution between Canary Islanders and Peninsulars. Eur J Immunogenet 27:141–144

    Article  CAS  PubMed  Google Scholar 

  16. Chomczynski P, Sacchi N (1987) Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 162:156–159

    Article  CAS  PubMed  Google Scholar 

  17. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2^-ΔΔCT method. Methods 25:402–408

    Article  CAS  PubMed  Google Scholar 

  18. Schmittgen TD, Livak KJ (2008) Analyzing real-time PCR data by the comparative CT method. Nat Protoc 3:1101–1108

    Article  CAS  PubMed  Google Scholar 

  19. Raychaudhuri S, Remmers EF, Lee AT, Hackett R, Guiducci C, Burtt NP et al (2008) Common variants at CD40 and other loci confer risk of rheumatoid arthritis. Nat Genet 40:1216–1223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Plant D, Flynn E, Mbarek H, Dieudé P, Cornelis F, Arlestig L et al (2010) Investigation of potential non-HLA rheumatoid arthritis susceptibility loci in a European cohort increases the evidence for nine markers. Ann Rheum Dis 69:1548–1553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP et al (2010) Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet 42:508–514

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Reparon-Schuijt CC, van Esch WJ, van Kooten C, Schellekens GA, de Jong BA, van Venrooij WJ et al (2001) Secretion of anti-citrulline-containing peptide antibody by B lymphocytes in rheumatoid arthritis. Arthritis Rheum 44:41–47

    Article  CAS  PubMed  Google Scholar 

  23. Yellin MJ, Winikoff S, Fortune SM, Baum D, Crow MK, Lederman S et al (1995) Ligation of CD40 on fibroblasts induces CD54 (ICAM-1) and CD106 (VCAM-1) up-regulation and IL-6 production and proliferation. J Leukoc Biol 58:209–216

    Article  CAS  PubMed  Google Scholar 

  24. Kitagawa M, Mitsui H, Nakamura H, Yoshino S, Miyakawa S, Ochiai N et al (1999) Differential regulation of rheumatoid synovial cell interleukin-12 production by tumor necrosis factor alpha and CD40 signals. Arthritis Rheum 42:1917–1926

    Article  CAS  PubMed  Google Scholar 

  25. Möttönen M, Isomäki P, Luukkainen R, Lassila O (2002) Regulation of CD154-induced interleukin-12 production in synovial fluid macrophages. Arthritis Res 4:R9

    Article  PubMed  PubMed Central  Google Scholar 

  26. Cho ML, Yoon CH, Hwang SY, Park MK, Min SY, Lee SH et al (2004) Effector function of type II collagen-stimulated T cells from rheumatoid arthritis patients: cross-talk between T cells and synovial fibroblasts. Arthritis Rheum 50:776–784

    Article  CAS  PubMed  Google Scholar 

  27. Lee HY, Jeon HS, Song EK, Han MK, Park SI, Lee SI et al (2006) CD40 ligation of rheumatoid synovial fibroblasts regulates RANKL-mediated osteoclastogenesis: evidence of NF-kappaB-dependent, CD40-mediated bone destruction in rheumatoid arthritis. Arthritis Rheum 54:1747–1758

    Article  CAS  PubMed  Google Scholar 

  28. Berner B, Wolf G, Hummel KM, Müller GA, Reuss-Borst MA (2000) Increased expression of CD40 ligand (CD154) on CD4+ T cells as a marker of disease activity in rheumatoid arthritis. Ann Rheum Dis 59:190–195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Liu MF, Chao SC, Wang CR, Lei HY (2001) Expression of CD40 and CD40 ligand among cell populations within rheumatoid synovial compartment. Autoimmunity 34:107–113

    Article  CAS  PubMed  Google Scholar 

  30. Tamura N, Kobayashi S, Kato K, Bando H, Haruta K, Oyanagi M et al (2001) Soluble CD154 in rheumatoid arthritis: elevated plasma levels in cases with vasculitis. J Rheumatol 28:2583–2590

    CAS  PubMed  Google Scholar 

  31. Aloui C, Sut C, Prigent A, Fagan J, Cognasse F, Granados-Herbepin V et al (2014) Are polymorphisms of the immunoregulatory factor CD40LG implicated in acute transfusion reactions? Sci Rep 4:7239

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Martínez-Cortés G, Salazar-Flores J, Fernández-Rodríguez LG, Rubi-Castellanos R, Rodríguez-Loya C, Velarde-Félix JS et al (2012) Admixture and population structure in Mexican-Mestizos based on paternal lineages. J Hum Genet 57:568–574

    Article  PubMed  Google Scholar 

  33. Kochi Y, Suzuki A, Yamada R, Yamamoto K (2010) Ethnogenetic heterogeneity of rheumatoid arthritis-implications for pathogenesis. Nat Rev Rheumatol 6:290–295

    Article  CAS  PubMed  Google Scholar 

  34. McInnes IB, Schett G (2007) Cytokines in the pathogenesis of rheumatoid arthritis. Nat Rev Immunol 7:429–442

    Article  CAS  PubMed  Google Scholar 

  35. Barrett LW, Fletcher S, Wilton SD (2012) Regulation of eukaryotic gene expression by the untranslated gene regions and other non-coding elements. Cell Mol Life Sci 69:3613–3634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hui J, Reither G, Bindereif A (2003) Novel functional role of CA repeats and hnRNP L in RNA stability. RNA 9:931–936

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cheli Y, Kunicki TJ (2006) hnRNP L regulates differences in expression of mouse integrin α2β1. Blood 107:4391–4398

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Liao J, Liang G, Xie S, Zhao H, Zuo X, Li F et al (2012) CD40L demethylation in CD4+ T cells from women with rheumatoid arthritis. Clin Immunol 145:13–18

    Article  CAS  PubMed  Google Scholar 

  39. Ford GS, Barnhart B, Shone S, Covey LR (1999) Regulation of CD154 (CD40 ligand) mRNA stability during T cell activation. J Immunol 162:4037–4044

    CAS  PubMed  Google Scholar 

  40. Guo Y, Xiao P, Lei S, Deng F, Xiao GG, Liu Y et al (2008) How is mRNA expression predictive for protein expression? A correlation study on human circulating monocytes. Acta Biochim Biophys Sin 40:426–436

    Article  CAS  PubMed  Google Scholar 

  41. Rigby WF, Waugh MG, Hamilton BJ (1999) Characterization of RNA binding proteins associated with CD40 ligand (CD154) mRNA turnover in human T lymphocytes. J Immunol 163:4199–4206

    CAS  PubMed  Google Scholar 

  42. Barnhart B, Kosinski PA, Wang Z, Ford GS, Kiledjian M, Covey LR (2000) Identification of a complex that binds to the CD154 3′ untranslated region: implications for a role in message stability during T cell activation. J Immunol 165:4478–4486

    Article  CAS  PubMed  Google Scholar 

  43. Schubert LA, Cron RQ, Cleary AM, Brunner M, Song A, Lu LS et al (2002) A T cell-specific enhancer of the human CD40 ligand gene. J Biol Chem 277:7386–7395

    Article  CAS  PubMed  Google Scholar 

  44. Hamilton BJ, Genin A, Cron RQ, Rigby WF (2003) Delineation of a novel pathway that regulates CD154 (CD40 ligand) expression. Mol Cell Biol 23:510–525

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Brooks WH, Renaudineau Y (2015) Epigenetics and autoimmune diseases: the X chromosome-nucleolus nexus. Front Genet 6:22

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by funding from the National Council of Science and Technology (CONACYT, grant no. 180663), CONACYT-México-Universidad de Guadalajara, awarded to Muñoz-Valle JF. The funding source had no involvement in any phase of the study.

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Authors and Affiliations

  1. Instituto de Investigación en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico

    I. V. Román-Fernández, G. A. Sánchez-Zuno, J. R. Padilla-Gutiérrez, J. Hernández-Bello, Y. Valle & J. F. Muñoz-Valle

  2. Servicio de Reumatología, O.P.D. Hospital Civil de Guadalajara “Fray Antonio Alcalde”, Guadalajara, Jalisco, Mexico

    S. Cerpa-Cruz

  3. Laboratorio de Inmunología, Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico

    M. G. Ramírez-Dueñas

  4. Instituto de Investigación en Enfermedades Crónico Degenerativas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico

    C. Carrillo

  5. Insurgentes 244-1, Lomas de Atemajac, 45178, Zapopan, Jalisco, Mexico

    J. F. Muñoz-Valle

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  1. I. V. Román-Fernández
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  6. Y. Valle
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Correspondence to J. F. Muñoz-Valle.

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All subjects signed a written informed consent form prior enrollment and the guidelines of the declaration of Helsinki were considered. The study was approved by the ethics committees of Hospital Civil “Fray Antonio Alcalde” and Universidad de Guadalajara.

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Román-Fernández, I.V., Sánchez-Zuno, G.A., Padilla-Gutiérrez, J.R. et al. The 3′-UTR (CA)n microsatellite on CD40LG gene as a possible genetic marker for rheumatoid arthritis in Mexican population: impact on CD40LG mRNA expression. Clin Rheumatol 37, 345–353 (2018). https://doi.org/10.1007/s10067-017-3853-9

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  • DOI: https://doi.org/10.1007/s10067-017-3853-9

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