Title: Role of HLA-DRB1, PTPN22, CTLA4 Gene Polymorphisms in Susceptibility to Rheumatoid Arthritis
Authors: Vasanth Konda Mohan, Nalini Ganesan, Rajasekhar Gopalakrishnan, Vasanthi Pallinti, Vettriselvi Venkatesan
DOI: http://dx.doi.org/10.18535/jmscr/v4i7.58
Background and AIM: The genetic and environmental factors are believed to play an important role in the pathogenesis of rheumatoid arthritis (RA), the precise etiology is still uncertain. Regarding its genetic components, the strongest genetic association with RA is that found for certain alleles of HLA-DRB1. Recent studies have revealed that the single‐nucleotide polymorphism (SNP) of non-HLA PTPN22 and CTLA4 gene were associated with RA. The associations of HLA, PTPN22 and CTLA4 polymorphisms with RA risk have been less well replicated. Thus, the current study was undertaken to investigate the effects of HLA-DRB1, PTPN22, CTLA4 gene polymorphisms and autoantibodies in susceptibility to RA. Methods: A total of 200 patients fulfilled the criteria for RA and 200 healthy individuals were included in the study. Anti-cyclic citrullinated peptide (anti-CCP) antibodies and rheumatoid factor (RF) were measured by enzyme-linked immunosorbent assay (ELISA). HLA-DRB1 alleles were determined by polymerase chain reaction-sequence specific primer (PCR-SSP) method. Samples were genotyped for PTPN22 1858C/T (rs2476601) and CTLA4 CT60 (rs3087243) variants using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Results: In RA patients 88% and 82% were positive for anti-CCP and RF autoantibodies, respectively. A significant increase in the frequency of HLA-DRB1*01, HLA-DRB1*04, HLA-DRB1*10, HLA-DRB1*14 shared epitope (SE) alleles were identified in RA patients, whereas in healthy subjects, they were HLA-DRB1*03, HLA-DRB1*07, HLA-DRB1*11, HLA-DRB1*13. There was no association of the PTPN22 1858T variant with RA and it seems to be independent of MHC associations. The frequency of CTLA4 CT60 A allele carriers was significantly higher in RA patients and also it is preferentially in SE-positive RA patients. Conclusion: Our results confirmed the previously reported HLA-DRB1 SE alleles associations with RA. The CTLA4 polymorphism appears to interfere with HLA-DRB1 susceptibility to RA. On the other hand, we failed to provide evidence for the association of the PTPN22 SNP with RA. Keywords: HLA-DRB1; PTPN22; CTLA4; rheumatoid arthritis; polymorphism. 1. Prasannavar DJ, Yeola A, Pradhan V, Patwardhan M, Rajadhyaksha A, Ghosh K. Distribution of HLA-DRβ1 alleles among well-characterized rheumatoid arthritis patients from Western India. Rheumatol Int. 2014;34: 705-8. 2. Chou CT, Liao HT, Chen CH, Chen WS, Wang HP, Su KY. The Clinical Application of Anti-CCP in Rheumatoid Arthritis and Other Rheumatic Diseases. Biomark Insights 2007;2:165-71. 3. Bax M, van Heemst J, Huizinga TW, Toes RE. Genetics of rheumatoid arthritis: what have we learned? Immunogenetics 2011;63:459-66. 4. Louzada-Junior P, Freitas MVC, Oliveira RDR, Deghaide NHS, Conde RA, Bertolo MB. et al. A majority of Brazilian patients with rheumatoid arthritis HLA-DRB1 alleles carry both the HLA-DRB1 shared epitope and anti-citrunillated peptide antibodies. Braz J Med Biol Res. 2008;41:493-9. 5. Gibert M, Balandraud N, Touinssi M, Mercier P, Roudier J, Reviron D. Functional categorization of HLA-DRB1 alleles in rheumatoid arthritis: the protective effect. Hum Immunol. 2003;64:930-5. 6. Mourad J, Monem F. HLA-DRB1 allele association with rheumatoid arthritis susceptibility and severity in Syria. Rev Bras Reumatol. 2013;53:47-56. 7. Kremer JM, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med. 2003;349:1907-15. 8. Vang T, Congia M, Macis MD, Musumeci L, Orru V, Zavattare P. et al. Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. Nat Genet. 2005;37:1317-9. 9. Kokkonen H, Johansson M, Innala L, Jidell E, Rantapää-Dahlqvist S. The PTPN22 1858C/T polymorphism is associated with anti-cyclic citrullinated peptide-positive early rheumatoid arthritis in northern Sweden. Arthritis Res Ther. 2007;9:R56. 10. Nistico L, Buzzetti R, Pritchard LE, Van der Auwera B, Giovannini C, Bosi E. et al. The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Hum Mol Genet. 1996;5:1075-80. 11. Yanagawa T, Hidaka Y, Guimaraes V, Soliman M, DeGroot LJ. CTLA-4 gene polymorphism associated with Graves’ disease in a Caucasian population. J Clin Endocrinol Metab. 1995;80:41-5. 12. Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO III. et al. 2010 Rheumatoid Arthritis Classification Criteria. Arthritis & Rheum. 2010;62:1580-88 13. Sambrook J, Fritsch EF, Maniatis T. Molecular Cloning: a laboratory manual. 2nd ed. Vol. 3. Cold Spring Harbor Laboratory Press; 1989. pp.E3–E4. 14. Sambrook J. The Condensed Protocols from Molecular Cloning: a laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York; 2006. 15. Rani R, Israni N, Kumar A, Vasudevan S, Singh J. Association of Protein Tyrosine Phosphatase Non-receptor, Type 22 (PTPN22) C1858T Polymorphism with Type 1 Diabetes in North India: A Replication Study. J Diabetes Metab. 2014;5:342. 16. Wang L, Li D, Fu Z, Li H, Jiang W, Li D. Association of CTLA-4 gene polymorphisms with sporadic breast cancer in Chinese Han population. BMC Cancer 2007;7:173. 17. Kinikli G, Ates A, Turgay M, Akay G, Kinikli S, Tokgoz G. HLADRB1 genes and disease severity in rheumatoid arthritis in Turkey. Scand J Rheumatol. 2003;32, 277-80. 18. Bongi SM, Porfirio B, Rombola G, Palasciano A, Beneforti E, Bianucci G. Shared-epitope HLA-DRB1 alleles and sex ratio in Italian patients with rheumatoid arthritis. Joint Bone Spine 2004;71;24-8. 19. Laivoranta-Nyman S, Möttönen T, Hermann R, Tuokko J, Luukkainen R, Hakala M. et al. HLA-DR-DQ haplotypes and genotypes in Finnish patients with rheumatoid arthritis. Ann Rheum Dis 2004;63:1406-12 20. Al-Timimi DJ, Rasool MT, Sulaiman DM. HLA-DR/DQ Genotypes in Kurd Patients with Rheumatoid Arthritis: Relation to Disease Activity. J Clin Diagn Res. 2014;8:CC01-4. 21. Naqi N, Ahmed TA, Malik JM, Ahmed M, Bashir MM. HLA DRb1 Alleles in Pakistani Patients with Rheumatoid Arthritis. J Coll Physicians Surg Pak. 2011;21:727-30. 22. Castro F, Acevedo E, Ciusani E, Angulo JA, Wollheim FA, Sandberg-Wollheim M. Tumour necrosis factor microsatellites and HLADRB1*, HLA-DQA1*, and HLA-DQB1* alleles in Peruvian patients with rheumatoid arthritis. Ann Rheum Dis. 2001;60:791-5. 23. del Rincon I, Escalante A. HLA-DRB1 alleles associated with susceptibility or resistance to rheumatoid arthritis, articular deformities, and disability in Mexican Americans. Arthritis Rheum 1999;42:1329-38. 24. Griffiths B, Situnayake RD, Clark B, Tennant A, Salmon M, Emery P. Racial origin and its effect on disease expression and HLA-DRB1 types in patients with rheumatoid arthritis: a matched cross-sectional study. Rheumatology (Oxford) 2000;39:857-64. 25. Stark K, Rovensky J, Blazickova S, Grosse-Wilde H, Ferencik S, Hengstenberg C. et al. Association of common polymorphisms in known susceptibility genes with rheumatoid arthritis in a Slovak population using osteoarthritis patients as controls. Arthritis Res Ther. 2009;11:R70. 26. Carlton VE, Hu X, Chokkalingam AP, Schrodi SJ, Brandon R, Alexander HC. et al. PTPN22 genetic variation: evidence for multiple variants associated with rheumatoid arthritis. Am J Hum Genet. 2005;77:567-81. 27. Pierer M, Kaltenhauser S, Arnold S, Wahle M, Baerwald C, Hantzschel H. et al. Association of PTPN22 1858 single nucleotide polymorphism with rheumatoid arthritis in a German cohort: higher frequency of the risk allele in male compared to female patients. Arthritis Res Ther. 2006;8:R75. 28. Ikari K, Momohara S, Inoue E, Tomatsu T, Hara M, Yamanaka H. et al. Haplotype analysis revealed no association between the PTPN22 gene and RA in a Japanese population. Rheumatology 2006;45:1345-8. 29. Ahmed YAT, Hameed MJ, Mohammed HA. Saleh AW. Genetic polymorphism in protein tyrosine phosphatase non-receptor 22 (PTPN22) gene in Iraqi patients with rheumatoid arthritis. WJPR 2016; 5:340-50. 30. Maritz NG, Gerber AJ, Greyling SJ, Sanda BB. The rheumatoid wrist in black South African patients. J Hand Surg Br. 2003; 28:373-5. 31. Mori M, Yamada R, Kobayashi K, Kawaida R, Yamamoto K. Ethnic differences in allele frequency of autoimmune‐disease associated SNPs. J Hum Genet. 2005;50:264-6. 32. Li X, Zhang C, Zhang J, Zhang Y, Wu Z, Yang L, Xiang Z, Qi Z, Zhang X, Xiao X. Polymorphisms in the CTLA-4 gene and rheumatoid arthritis susceptibility: a meta-analysis. J Clin Immunol. 2012;32:530-9.Abstract
References