MOLECULAR-GENETIC CHARACTERISTICS OF EARLY RHEUMATOID ARTHRITIS

DOI: https://doi.org/None

I.A. Guseva (1), N.V. Demidova (1), N.E. Soroka (2), E.L. Luchikhina (1), G.V. Lukina (1), E.V. Fedorenko (1), E.S. Aronova (1), E.Yu. Samarkina (1), D.Yu. Trofimov (2), D.E. Karateev (1), E.L. Nasonov (1) 1 -Research Institute of Rheumatology named after V.A. Nasonova, Kashirskoe shosse, 34A, Moscow, 115522, Russian Federation; 2 -Company DNA-Technology, Varshavskoe shosse, 125Zh, Bld. 6, fl. 5, Moscow, 117587, Russian Federation

Objective. To study the distribution of PTPN22, TNFAIP3, CTLA4, TNFA, IL-6, IL-6R, IL-10, MCP-1, ICAM1 alleles and genotypes in early rheumatoid arthritis (eRA) patients and controls, and assess their value as potential molecular-genetic markers of predisposition to RA. Materials and methods. The study was conducted within framework of «Early arthritis: diagnostics, outcomes, criteria, active treatment (RADICAL – Russian acronym)» program. 122 patients with confirmed by АСR 1987 criteria RA lasting less than 2 years were included into prospective study, in 73 (59,8%) out of them the follow up was initiated during first 6 month from the onset/manifestation of first symptoms. 314 healthy blood donors made the control group. The distribution of polymorphic alleles PTPN22 (+1858 C >T, rs2476601), TNFAIP3 (rs675520, rs6920220, rs10499194), CTLA-4 (+49A>G, rs231775 ), TNFА(-308A>G, rs1800629), IL-6 (-174G>C, rs1800795), IL6R (+358A>C, rs8192284), IL-10 (-592A>C, rs1800872, -1082 A>G, rs1800896), MCP-1 /CCL2 (+2518A>G, rs1024611), ICAM1 (721G>A, rs1799969) in patients and controls was studied by real time PCR. Results. The analysis identified the association between polymorphisms PTPN22 (+1858 C >T, rs2476601), TNFAIP3 (rs675520, rs10499194) and eRA (OR =1,5 [1,0–2,3], р=0,05, OR=1,5 [1,1–2,0], p=0,02, OR=0,5 [0,4–0,8], p=0,01, respectively). Moreover, theanalysis also established a trend to the positive correlation between rs6920220 polymorphism in TNFAIP3 gene, and rs8192284 polymorphism in IL6R gene and susceptibility to RA (р=0,056). Meanwhile polymorphisms of IL-6( rs1800795), IL-10 (rs1800872, rs1800896), MCP-1 /CCL2 (rs1024611), and of ICAM1 (rs1799969) genes were not associated with RA risks. Conclusion. The results obtained indicate that polymorphisms of genes participating in immune and auto-immune reactions, such as PTPN22 (rs2476601), TNFAIP3 (rs675520, rs10499194) and IL-6R (rs8192284) contribute to RA pathogenesis. At the same time polymorphisms of IL-6 (rs1800795), IL-10 (rs1800872, rs1800896), MCP-1 /CCL2 (rs1024611), and ICAM1 (rs1799969) genes were not associated with eRA risk.
Keywords: 
rheumatoid arthritis, early rheumatoid arthritis, gene polymorphisms, single nucleotide polymorphism, SNP
Список литературы: 
  1. Nasonov E.L., Nasonova V.A., redaktory. Revmatologiya: Nacional`noe rukovodstvo. M.: GE`OTAR-MEDIA, 2008. [Nasonov E.L., Nasonova V.A., redaktoryi. Revmatologiya: Natsionalnoe rukovodstvo. M.: GEOTAR-MEDIA; 2008 (in Russian)]
  2. Nasonov E.L., Guseva I.A., Aleksandrova E.N. Problemy personificirovannoy terapii revmatoidnogo artrita genno-inzhenernymi biologicheskimi preparatami. V knige: E.L.Nasonov, redaktor. Genno-inzhenernye biologicheskie preparaty v lechenii revmatoidnogo artrita. M.: IMA-PRESS, 2013; 489–509.[Nasonov E.L., Guseva I.A., Aleksandrova E.N. Problemyi personifitsirovannoy terapii revmatoidnogo artrita genno-inzhenernyimi biologicheskimi preparatami. V knige: E.L.Nasonov, redaktor. Genno-inzhenernyie biologicheskie preparatyi v lechenii revmatoidnogo artrita. Moskva: IMA-PRESS, 2013; 489–509 (in Russian)]
  3. Begovich A.B., Carlton V.E., Honigberg L.A., Schrodi S.J., Chokkalingam A.P., Alexander H.C., Ardlie K.G., Huang Q., Smith A.M., Spoerke J.M., Conn M.T., Chang M., Chang S.Y., Saiki R.K., Catanese J.J., Leong D.U., Garcia V.E., McAllister L.B., Jeffery D.A., Lee A.T., Batliwalla F., Remmers E., Criswell L.A., Seldin M.F., Kastner D.L., Amos C.I., Sninsky J.J., Gregersen P.K. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. Am. J. Hum. Genet. 2004; 75 (2): 330–7.
  4. Plenge R.M., Padyukov L., Remmers E.F., Purcell S., Lee A.T., Karlson E.W., Wolfe F., Kastner D.L., Alfredsson L., Altshuler D., Gregersen P.K., Klareskog L., Rioux J.D. Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. Am. J. Hum. Genet. 2005; 77 (6): 1044–60.
  5. Barton A., Bowes J., Eyre S., Spreckley K., Hinks A., John S., Worthington J. A functional haplotype of the PADI4 gene associated with rheumatoid arthritis in a Japanese population is not associated in a United Kingdom population. Arthritis Rheum. 2004; 50 (4): 1117–21.
  6. Kochi Y., Yamada R., Suzuki A., Harley J.B., Shirasawa S., Sawada T., Bae S.C., Tokuhiro S., Chang X., Sekine A., Takahashi A., Tsunoda T., Ohnishi Y., Kaufman K.M., Kang C.P., Kang C., Otsubo S., Yumura W., Mimori A., Koike T., Nakamura Y., Sasazuki T., Yamamoto K. A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities. Nat Genet. 2005; 37 (5): 478–85.
  7. Guseva I.A., Demidova N.V., Soroka N.E., Luchihina E.L., Lukina G.V., Fedorenko E.V., Aronova E.F., Samarkina E.Yu., Trofimov V.Yu., Karateev D.E., Nasonov E.L. Immunogeneticheskie aspekty rannego revmatoidnogo artrita. Vestnik Rossiyskoy Akademii Medicinskih nauk. 2013; 4: 36–43.[Guseva I.A., Demidova N.V., Soroka N.E., Novikov A.A., Luchikhina E.L., Aleksandrova E.N., Lukina G.V., Fedorenko E.V., Aronova E.S., Samarkina E.Iu, Boldyreva M.N., Trofimov D.Iu, Karateev D.E., Nasonov E.L. [Immunogenetic aspects of early rheumatoid arthritis]. Vestn Ross Akad Med Nauk. 2013; 4: 36–43 (in Russian)]
  8. Kofiadi I.A., Rebrikov D.V. Metody detekcii odnonukleotidnyh polimorfizmov: allel`-specificheskaya PCR i gibridizaciya s oligonukleotidnoy proboy. Genetika. 2006; 42: 22–32.[Kofiadi I.A., Rebrikov D.V. Metodyi detektsii odnonukleotidnyih polimorfizmov: allel-spetsificheskaya PTsR i gibridizatsiya s oligonukleotidnoy proboy. Genetika. 2006; 42: 22–32 (in Russian)]
  9. Totaro M.C., Tolusso B., Napolioni V., Faustini F., Canestri S., Mannocci A., Gremese E., Bosello S.L., Alivernini S., Ferraccioli G. PTPN22 1858C>T polymorphism distribution in Europe and association with rheumatoid arthritis: case-control study and meta-analysis. PLoS One. 2011; 6 (9): e24292.
  10. Lee Y.H., Bae S.C., Choi S.J., Ji J.D., Song G.G. The association between the PTPN22 C1858T polymorphism and rheumatoid arthritis: a meta-analysis update. Mol. Biol. Rep. 2012; 39 (4): 3453–60.
  11. Lee Y.H., Rho Y.H., Choi S.J., Ji .JD., Song G.G., Nath S.K., Harley J.B. The PTPN22 C1858T functional polymorphism and autoimmune diseases--a meta-analysis. Rheumatology (Oxford). 2007; 46 (1): 49–56.
  12. Yu X., Sun J.P., He Y., Guo X., Liu S., Zhou B., Hudmon A., Zhang Z.Y. Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific tyrosine phosphatase implicated in autoimmune diseases. Proc Natl Acad Sci USA. 2007; 104 (50): 19767–72.
  13. Chang H.H., Tai T.S., Lu B., Iannaccone C., Cernadas M., Weinblatt M., Shadick N., Miaw S.C., Ho I.C. PTPN22.6, a dominant negative isoform of PTPN22 and potential biomarker of rheumatoid arthritis. PLoS One. 2012; 7 (3): e33067.
  14. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007; 447 (7145): 661–78.
  15. Plenge R.M., Cotsapas C., Davies L., Price A.L., de Bakker P.I., Maller J., Pe’er I., Burtt N.P., Blumenstiel B., DeFelice M., Parkin M., Barry R., Winslow W., Healy C., Graham R.R., Neale B.M., Izmailova E., Roubenoff R., Parker A.N., Glass R., Karlson E.W., Maher N., Hafler D.A., Lee D.M., Seldin M.F., Remmers E.F., Lee A.T., Padyukov L., Alfredsson L., Coblyn J., Weinblatt M.E., Gabriel S.B., Purcell S., Klareskog L., Gregersen P.K., Shadick N.A., Daly M.J., Altshuler D. Two independent alleles at 6q23 associated with risk of rheumatoid arthritis. Nat Genet. 2007; 39 (12): 1477–82.
  16. Dieguez-Gonzalez R., Calaza M., Perez-Pampin E., Balsa A., Blanco F.J., Cañete J.D., Caliz R., Carreño L., de la Serna A.R., Fernandez-Gutierrez B., Ortiz A.M., Herrero-Beaumont G., Pablos J.L., Narvaez J., Navarro F., Marenco J.L., Gomez-Reino J.J., Gonzalez A. Analysis of TNFAIP3, a feedback inhibitor of nuclear factor-kappaB and the neighbor intergenic 6q23 region in rheumatoid arthritis susceptibility. Arthritis Res Ther. 2009; 11 (2): R42.
  17. Lee E.G., Boone D.L., Chai S., Libby S.L., Chien M., Lodolce J.P., Ma A. Failure to regulate TNF-induced NF-kappaB and cell death responses in A20-deficient mice. Science. 2000; 289 (5488): 2350–4.
  18. Matmati M., Jacques P., Maelfait J., Verheugen E., Kool M., Sze M., Geboes L., Louagie E., Mc Guire C., Vereecke L., Chu Y., Boon L., Staelens S., Matthys P., Lambrecht B.N., Schmidt-Supprian M., Pasparakis M., Elewaut D., Beyaert R., van Loo G. A20 (TNFAIP3) deficiency in myeloid cells triggers erosive polyarthritis resembling rheumatoid arthritis. Nat Genet. 2011; 43 (9): 908–12.
  19. Plant D., Farragher T., Flynn E., Martin P., Eyre S., Bunn D., Worthington J., Symmons D., Barton A., Thomson W.. A genetic marker at the OLIG3/TNFAIP3 locus associates with methotrexate continuation in early inflammatory polyarthritis: results from the Norfolk Arthritis Register. Pharmacogenomics J. 2012; 12 (2): 128–33.
  20. Guseva I., Soroka N., Devyataykina A. TNFAIP3 rs675520 variant may predict response to rituximab treatment in rheumatoid arthritis Ann Rheum Dis. 2012; 71 (3): 669.
  21. Guseva I.A., Panasyuk E.Yu., Soroka N.E. i dr. Associativnaya vzaimosvyaz` geneticheskih markerov s e`ffektivnost`yu lecheniya revmatoidnogo artrita tocilizumabom. Nauchno-prakticheskaya revmatologiya. 2013; 4 (51): 377–82.[Guseva I.A., Panasyuk E.Yu., Soroka N.E., Avdeeva A.S., Aleksandrova E.N., Luchihina E.L., Gubar E.E., Fedorenko E.V., Gavva T.N., Tsvetkova E.S., Logino-va E.Yu., Samarkina E.Yu., Lukina G.V., Trofimov D.Yu., Nasonov E.L. Assotsiativnaya vzaimosvyaz geneticheskih markerov s effektivnostyu lecheniya revmatoidnogo artrita totsilizumabom. Nauchno-prakticheskaya revmatologiya, 2013; 4 (51): 377–82 (in Russian)]
  22. Marinou I., Walters K., Winfield J., Bax D.E., Wilson A.G. A gain of function polymorphism in the interleukin 6 receptor influences RA susceptibility. Ann Rheum Dis. 2010; 69 (6): 1191–4.
  23. Hingorani A.D., Casas J.P. Interleukin-6 Receptor Mendelian Randomisation Analysis (IL6R MR) Consortium. The interleukin-6 receptor as a target for prevention of coronary heart disease: a mendelian randomisation analysis. Lancet. 2012; 379 (9822): 1214–24.
  24. Sarwar N., Butterworth A.S., Freitag D.F. IL6R Genetics Consortium Emerging Risk Factors Collaboration. Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies. Lancet. 2012; 379 (9822): 1205–13.