PTPN22 rs2488457C˃G and TRAF1-C5 rs10818488A˃G and rs3761847G˃A variants in Mexican mestizo women with Systemic Lupus Erythematosus
Main Article Content
Abstract
Introduction: Systemic lupus erythematosus is an autoimmune disease with higher prevalence in women. Single nucleotide variants in genes involved in the regulation of autoreactive cells, such as PTPN22 rs2488457C˃G, and TRAF1-C5 rs10818488A˃G and rs3761847G˃A, have been associated with the disease in some populations; however, little is known about these variants in the Mexican mestizo population. Aim: We analyzed whether these variants are associated with lupus in women from Central Mexico and Yucatan. Methods: DNA samples from two hundred female patients with lupus (100 from Yucatan and 100 from Central Mexico) and 200 female healthy controls (100 from Yucatan and 100 from Central Mexico) were genotyped. Allelic and genotypic frequencies of variants were calculated and their association with lupus was analyzed. Results: Distribution of risk allele PTPN22 rs2488457G ranged 36% to 48%, while TRAF1-C5 rs10818488A and rs3761847G ranged from 34% to 40%. Heterozygous C/G was the most frequent for PTPN22 rs2488457 in all studied groups, while TRAF1-C5 heterozygous genotype was the most frequent in cases of Yucatan and controls from Central Mexico. However, we did not find significant differences in allelic and genotypic frequencies of PTPN22 and TRAF1-C5 variants, neither its haplotypes between cases and controls, suggesting a lack of association for lupus in the two Mexican populations. Conclusion: The PTPN22 rs2488457C˃G and TRAF1-C5 rs10818488A˃G and rs3761847G˃A variants do not confer susceptibility with the development of lupus in both studiedpopulations. However, the strong linkage disequilibrium observed in the TRAF1-C5 haplotypes suggests that they are co-inherited together and could be involved in the development of the disease in association with other genes or risk factors, as well as the Caucasian influence.
Keywords:
Systemic lupus erythematosus, PTPN22, TRAF1-C5, Variants, Yucatan, Mexico Central
Article Details
How to Cite
JIMÉNEZ-BECERRA, Eduardo D. et al.
PTPN22 rs2488457C˃G and TRAF1-C5 rs10818488A˃G and rs3761847G˃A variants in Mexican mestizo women with Systemic Lupus Erythematosus.
Medical Research Archives, [S.l.], v. 12, n. 6, june 2024.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/5520>. Date accessed: 26 dec. 2024.
doi: https://doi.org/10.18103/mra.v12i6.5520.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Tsokos GC. Systemic lupus erythematosus. N Engl J Med. 2011;365(22):2110-2121. Doi:10.1056/NEJMra1100359.
2. Tsokos GC, Lo MS, Costa Reis P, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheu-matol. 2016;12(12):716-730. Doi:10.1038/nrrheum.2016.186.
3. Pieterse E, van der Vlag J. Breaking immuno-logical tolerance in systemic lupus erythemato-sus. Front Immunol. 2014; 5:164. Doi:10.3389/fimmu.2014.00164
4. Reefman E, Horst G, Nijk MT, Limburg PC, Kal-lenberg CG, Bijl M. Opsonization of late apop¬totic cells by systemic lupus erythematosus au¬toantibodies inhibits their uptake via an Fc-gamma receptor-dependent mechanism. Arthri¬tis Rheum. 2007;56(10):3399-3411. Doi:10.1002/art.22947.
5. Rees F, Doherty M, Grainge MJ, Lanyon P, Zhang W. The worldwide incidence and preva¬lence of systemic lupus erythematosus: a system¬atic review of epidemiological studies. Rheuma¬tology (Oxford). 2017;56(11):1945-1961. Doi:10.1093/rheumatology/kex260.
6. Weckerle CE, Niewold TB. The unexplained fe¬male predominance of systemic lupus erythe¬matosus: clues from genetic and cytokine stud¬ies. Clin Rev Allergy Immunol. 2011;40(1):42-49. Doi:10.1007/s12016-009-8192-4
7. McCarty DJ, Manzi S, Medsger TA Jr, Ramsey-Goldman R, LaPorte RE, Kwoh CK. Incidence of systemic lupus erythematosus. Race and gender differences. Arthritis Rheum. 1995;38(9):1260-1270. Doi:10.1002/art.1780380914
8. Ameer MA, Chaudhry H, Mushtaq J, et al. An Overview of Systemic Lupus Erythematosus (SLE) Pathogenesis, Classification, and Man-agement. Cureus. 2022;14(10):e30330. Pub-lished 2022 Oct 15. Doi:10.7759/cu-reus.30330
9. Alvarez-Nemegyei J, Peláez-Ballestas I, Sanin LH, Cardiel MH, Ramírez-Angulo A, Goy-cochea-Robles MV. Prevalence of musculoskel-etal pain and rheumatic diseases in the south-eastern region of Mexico. A COPCORD-based community survey. J Rheumatol Suppl. 2011;86:21-25. Doi:10.3899/jrheum.100954
10. Peláez-Ballestas I, Sanin LH, Moreno-Montoya J, et al. Epidemiology of the rheumatic diseases in Mexico. A study of 5 regions based on the COPCORD methodology. J Rheumatol Suppl. 2011 Mar;38(3):585]. J Rheumatol Suppl. 2011;86:3-8. Doi:10.3899/jrheum.100951
11. Deng Y, Tsao BP. Genetics of human SLE. Du-bois' Lupus Erythematosus and Related Syn-dromes (Ninth Edition). Wallace DJ, Hahn BH (ed): Elsevier, London; 2019. 54-68. 10.1016/B978-0-323-47927-1.00005-0
12. Armstrong DL, Zidovetzki R, Alarcón-Riquelme ME, et al. GWAS identifies novel SLE suscepti-bility genes and explains the association of the HLA region. Genes Immun. 2014;15(6):347-354. Doi:10.1038/gene.2014.23
13. Deng Y, Tsao BP. Genetic susceptibility to sys-temic lupus erythematosus in the genomic era. Nat Rev Rheumatol. 2010;6(12):683-692. Doi:10.1038/nrrheum.2010.176
14. Burn GL, Svensson L, Sanchez-Blanco C, Saini M, Cope AP. Why is PTPN22 a good candidate susceptibility gene for autoimmune disease?. FEBS Lett. 2011;585(23):3689-3698. Doi:10.1016/j.febslet.2011.04.032
15. Román-Fernández IV, Machado-Contreras JR, Muñoz-Valle JF, Cruz A, Salazar-Camarena DC, Palafox-Sánchez CA. Altered PTPN22 and IL10 mRNA Expression Is Associated with Dis¬ease Activity and Renal Involvement in Systemic Lupus Erythematosus. Diagnostics (Basel). 2022;12(11):2859. Published 2022 Nov 18. Doi:10.3390/diagnostics12112859
16. Stanford SM, Bottini N. PTPN22: the archetypal non-HLA autoimmunity gene. Nat Rev Rheu¬matol. 2014;10(10):602-611. Doi:10.1038/nrrheum.2014.109
17. Siminovitch KA. PTPN22 and autoimmune dis-ease. Nat Genet. 2004;36(12):1248-1249. Doi:10.1038/ng1204-1248.
18. Wu H, Cantor RM, Graham DS, et al. Associa-tion analysis of the R620W polymorphism of protein tyrosine phosphatase PTPN22 in sys-temic lupus erythematosus families: increased T allele frequency in systemic lupus erythemato-sus patients with autoimmune thyroid disease. Arthritis Rheum. 2005;52(8):2396-2402. Doi:10.1002/art.21223
19. Bottini N, Musumeci L, Alonso A, et al. A func-tional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004;36(4):337-338. Doi:10.1038/ng1323
20. Tizaoui K, Shin JI, Jeong GH, et al. Genetic Pol¬ymorphism of PTPN22 in Autoimmune Diseases: A Comprehensive Review. Medicina (Kaunas). 2022;58(8):1034. Published 2022 Aug 2. Doi:10.3390/medicina58081034
21. Kawasaki E, Awata T, Ikegami H, et al. System¬atic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter pol¬ymorphism and type 1 diabetes in Asian popu¬lations [published correction appears in Am J Med Genet A. 2007 Aug 1;143(15):18212-3. Uga, Mho [corrected to Uga, Miho]]. Am J Med Genet A. 2006;140(6):586-593. Doi:10.1002/ajmg.a.31124
22. Feng X, Li YZ, Zhang Y, et al. Association of the PTPN22 gene (-1123G > C) polymorphism with rheumatoid arthritis in Chinese patients. Tissue Antigens. 2010;76(4):297-300. Doi:10.1111/j.1399-0039.2010.01521.x
23. Fan ZD, Wang FF, Huang H, et al. STAT4 rs7574865 G/T and PTPN22 rs2488457 G/C polymorphisms influence the risk of developing juvenile idiopathic arthritis in Han Chinese pa-tients. PLoS One. 2015;10(3):e0117389. Pub-lished 2015 Mar 17. Doi:10.1371/jour-nal.pone.0117389
24. Liu F, Liu J, Zheng TS, et al. The -1123G>C var¬iant of PTPN22 gene promoter is associated with latent autoimmune diabetes in adult Chi¬nese Hans. Cell Biochem Biophys. 2012;62(2):273-279. Doi:10.1007/s12013-011-9291-4
25. Machado-Contreras JR, Muñoz-Valle JF, Cruz A, Salazar-Camarena DC, Marín-Rosales M, Palafox-Sánchez CA. Distribution of PTPN22 polymorphisms in SLE from western Mexico: cor¬relation with mRNA expression and disease ac¬tivity. Clin Exp Med. 2016;16(3):399-406. Doi:10.1007/s10238-015-0359-0
26. Kurreeman FA, Goulielmos GN, Alizadeh BZ, et al. The TRAF1-C5 region on chromosome 9q33 is associated with multiple autoimmune dis¬eases. Ann Rheum Dis. 2010;69(4):696-699. Doi:10.1136/ard.2008.106567
27. Albers HM, Kurreeman FA, Houwing-Duister-maat JJ, et al. The TRAF1/C5 region is a risk factor for polyarthritis in juvenile idiopathic ar¬thritis. Ann Rheum Dis. 2008;67(11):1578-1580. Doi:10.1136/ard.2008.089060
28. Behrens EM, Finkel TH, Bradfield JP, et al. Asso¬ciation of the TRAF1-C5 locus on chromosome 9 with juvenile idiopathic arthritis. Arthritis Rheum. 2008;58(7):2206-2207. Doi:10.1002/art.23603
29. Zervou MI, Vazgiourakis VM, Yilmaz N, et al. TRAF1/C5, eNOS, C1q, but not STAT4 and PTPN22 gene polymorphisms are associated with genetic susceptibility to systemic lupus ery¬thematosus in Turkey. Hum Immunol. 2011;72(12):1210-1213. Doi:10.1016/j.humimm.2011.09.003
30. Bradley JR, Pober JS. Tumor necrosis factor re-ceptor-associated factors (TRAFs). Oncogene. 2001;20(44):6482-6491. Doi:10.1038/sj.onc.1204788
31. Wajant H, Henkler F, Scheurich P. The TNF-re-ceptor-associated factor family: scaffold mole-cules for cytokine receptors, kinases and their regulators. Cell Signal. 2001;13(6):389-400. Doi:10.1016/s0898-6568(01)00160-7
32. So T, Nagashima H, Ishii N. TNF Receptor-Asso¬ciated Factor (TRAF) Signaling Network in CD4(+) T-Lymphocytes. Tohoku J Exp Med. 2015;236(2):139-154. Doi:10.1620/tjem.236.139
33. Lalani AI, Zhu S, Gokhale S, Jin J, Xie P. TRAF molecules in inflammation and inflammatory diseases. Curr Pharmacol Rep. 2018;4(1):64-90. Doi:10.1007/s40495-017-0117-y
34. Schmidt RE, Gessner JE. Fc receptors and their interaction with complement in autoimmunity. Immunol Lett. 2005;100(1):56-67. Doi:10.1016/j.imlet.2005.06.022
35. Weinstein A, Alexander RV, Zack DJ. A Review of Complement Activation in SLE. Curr Rheu-matol Rep. 2021;23(3):16. Published 2021 Feb 10. Doi:10.1007/s11926-021-00984-1
36. Plenge RM, Seielstad M, Padyukov L, et al. TRAF1-C5 as a risk locus for rheumatoid arthri-tis--a genomewide study. N Engl J Med. 2007;357(12):1199-1209. Doi:10.1056/NEJMoa073491
37. Abdul-Sater AA, Edilova MI, Clouthier DL, Mbanwi A, Kremmer E, Watts TH. The signaling adaptor TRAF1 negatively regulates Toll-like receptor signaling and this underlies its role in rheumatic disease. Nat Immunol. 2017;18(1):26-35. Doi:10.1038/ni.3618
38. González-Herrera L, Sosa-Escalante JE, López-González PN, et al. Ancestral proportions based on 22 autosomal STRs of an admixed population (Mestizos) from the Península of Yu¬catán, México. Forensic Science International: Genetics Supplement Series 7, 2019; 429-31. https://doi.org/10.1016/j.fsigss.2019.10.063
39. Welsh K, Bunce M. Molecular typing for the MHC with PCR-SSP. Rev Immunogenet. 1999;1(2):157-76
40. Tan EM, Cohen AS, Fries JF, et al. The 1982 re¬vised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25(11):1271-1277. Doi:10.1002/art.1780251101
41. Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of associ¬ation studies. Bioinformatics. 2006;22(15): 1928-1929.
Doi:10.1093/bioin¬formatics/btl268
42. Tzeng J, Lu HH, Li WH. Multidimensional scaling for large genomic data sets. BMC Bioinformat¬ics. 2008;9:179. Published 2008 Apr 4. Doi:10.1186/1471-2105-9-179
43. Xu K, Peng H, Zhou M, et al. Association study of TRAF1/C5 polymorphism (rs10818488) with susceptibility to rheumatoid arthritis and sys¬temic lupus erythematosus: a meta-analysis. Gene. 2013;517(1):46-54. Doi:10.1016/j.gene.2012.12.092
44. Nishimoto K, Kochi Y, Ikari K, et al. Association study of TRAF1-C5 polymorphisms with suscep-tibility to rheumatoid arthritis and systemic lupus erythematosus in Japanese. Ann Rheum Dis. 2010;69(2):368-373. Doi:10.1136/ard.2008.104315
45. Sarantopoulos A, Theodorou I and Boura P. TRAF1-C5 rs3761847 SNP is associated with severe pattern of rheumatoid arthritis in Greek Patients. Open Journal of Rheumatology and Autoimmune Diseases. 2016 Feb; 6: 10-2. Doi: http://dx.doi.org/10.4236/ojra.2016.61002.
46. Palomino-Morales RJ, Rojas-Villarraga A, Gon¬zález CI, Ramírez G, Anaya JM, Martín J. STAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and sys¬temic lupus erythematosus in Colombians. Genes Immun. 2008;9(4):379-382. Doi:10.1038/gene.2008.30
47. Moez P, Soliman E. Association of PTPN22 gene polymorphism and systemic lupus erythemato¬sus in a cohort of Egyptian patients: impact on clinical and laboratory results. Rheumatol Int. 2012;32(9):2753-2758. Doi:10.1007/s00296-011-2063-z.
48. Kyogoku C, Langefeld CD, Ortmann WA, et al. Genetic association of the R620W polymor¬phism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet. 2004;75(3):504-507. Doi:10.1086/423790
49. Kaufman KM, Kelly JA, Herring BJ, et al. Evalu¬ation of the genetic association of the PTPN22 R620W polymorphism in familial and sporadic systemic lupus erythematosus. Arthritis Rheum. 2006;54(8):2533-2540. Doi:10.1002/art.21963
50. Salmond RJ, Brownlie RJ, Zamoyska R. Multi-functional roles of the autoimmune disease-as-sociated tyrosine phosphatase PTPN22 in reg-ulating T cell homeostasis. Cell Cycle. 2015;14(5):705-711. Doi:10.1080/15384101.2015.1007018
51. Menard L, Saadoun D, Isnardi I, et al. The PTPN22 allele encoding an R620W variant in¬terferes with the removal of developing auto¬reactive B cells in humans. J Clin Invest. 2011;121(9):3635-3644. Doi:10.1172/JCI45790
52. Schrezenmeier E, Weißenberg SY, Stefanski AL, et al. Postactivated B cells in systemic lupus er¬ythematosus: update on translational aspects and therapeutic considerations. Curr Opin Rheu¬matol. 2019;31(2):175-184. Doi:10.1097/BOR.0000000000000576
53. Chang HH, Dwivedi N, Nicholas AP, Ho IC. The W620 Polymorphism in PTPN22 Disrupts Its In-teraction With Peptidylarginine Deiminase Type 4 and Enhances Citrullination and NETosis. Arthritis Rheumatol. 2015;67(9):2323-2334. Doi:10.1002/art.39215
54. Wang Y, Shaked I, Stanford SM, et al. The au¬toimmunity-associated gene PTPN22 potenti¬ates toll-like receptor-driven, type 1 interferon-dependent immunity. Immunity. 2013;39(1):111-122. Doi:10.1016/j.im-muni.2013.06.013
55. López-Cano DJ, Cadena-Sandoval D, Beltrán-Ramírez O, et al. The PTPN22 R263Q polymor¬phism confers protection against systemic lupus erythematosus and rheumatoid arthritis, while PTPN22 R620W confers susceptibility to Graves' disease in a Mexican population. In¬flamm Res. 2017;66(9):775-781. Doi:10.1007/s00011-017-1056-0
56. Begovich AB, Carlton VE, Honigberg LA, et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthri¬tis. Am J Hum Genet. 2004;75(2):330-337. Doi:10.1086/422827
57. Velaga MR, Wilson V, Jennings CE, et al. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major de¬terminant of Graves' disease. J Clin Endocrinol Metab. 2004;89(11):5862-5865. Doi:10.1210/jc.2004-1108
58. Kariuki SN, Crow MK, Niewold TB. The PTPN22 C1858T polymorphism is associated with skew¬ing of cytokine profiles toward high interferon-alpha activity and low tumor necrosis factor al¬pha levels in patients with lupus. Arthritis Rheum. 2008;58(9):2818-2823. Doi:10.1002/art.23728
59. Begovich AB, Carlton VE, Honigberg LA, et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthri¬tis. Am J Hum Genet. 2004;75(2):330-337. Doi:10.1086/422827
60. Heneberg P, Malá M, Yorifuji T, et al. Low Fre¬quencies of Autoimmunity-Associated PTPN22 Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoanti¬bodies. Int Arch Allergy Immunol. 2015;166(3):189-198. Doi:10.1159/000380853
61. Huraib GB, Harthi FA, Arfin M, et al. The Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) Gene Polymorphism and Susceptibil¬ity to Autoimmune Diseases. In The Recent Topics in Genetic Polymorphisms; Mahmut Çalı¸skan, O.E., Gül, Ö., Eds.; IntechOpen: London, UK, 2020.
62. Chang HH, Tseng W, Cui J, Costenbader K, Ho IC. Altered expression of protein tyrosine phos¬phatase, non-receptor type 22 isoforms in sys¬temic lupus erythematosus. Arthritis Res Ther. 2014;16(1):R14. Published 2014 Jan 17. Doi:10.1186/ar4440
63. Owen KA, Grammer AC, Lipsky PE. Deconvolut¬ing the heterogeneity of SLE: The contribution of ancestry. J Allergy Clin Immunol. 2022;149(1):12-23. Doi:10.1016/j.jaci.2021.11.005
64. Hernández-Doño S, Jakez-Ocampo J, Már-quez-García JE, et al. Heterogeneity of Ge-netic Admixture Determines SLE Susceptibility in Mexican. Front Genet. 2021;12:701373. Pub¬lished 2021 Aug 3. Doi:10.3389/fgene.2021.701373
65. Martinez-Marignac VL, Valladares A, Cameron E, et al. Admixture in Mexico City: implications for admixture mapping of type 2 diabetes ge¬netic risk factors. Hum Genet. 2007;120(6):807-819. Doi:10.1007/s00439-006-0273-3
66. Rubi-Castellanos R, Martínez-Cortés G, Muñoz-Valle JF, et al. Pre-Hispanic Mesoamerican de¬mography approximates the present-day an¬cestry of Mestizos throughout the territory of Mexico. Am J Phys Anthropol. 2009;139(3): 284-294. Doi:10.1002/ajpa.20980
67. Conley AB, Rishishwar L, Norris ET, et al. A Com¬parative Analysis of Genetic Ancestry and Ad¬mixture in the Colombian Populations of Chocó and Medellín. G3 (Bethesda). 2017;7(10):3435-3447. Published 2017 Oct 5. Doi:10.1534/g3.117.1118
68. Plenge RM, Seielstad M, Padyukov L, et al. TRAF1-C5 as a risk locus for rheumatoid arthri-tis--a genomewide study. N Engl J Med. 2007;357(12):1199-1209. Doi:10.1056/NEJMoa073491
69. Mokry FB, Buzanskas ME, de Alvarenga Mudadu M, et al. Linkage disequilibrium and haplotype block structure in a composite beef cattle breed. BMC Genomics. 2014;15 Suppl 7(Suppl 7):S6. Doi:10.1186/1471-2164-15-S7-S6
2. Tsokos GC, Lo MS, Costa Reis P, Sullivan KE. New insights into the immunopathogenesis of systemic lupus erythematosus. Nat Rev Rheu-matol. 2016;12(12):716-730. Doi:10.1038/nrrheum.2016.186.
3. Pieterse E, van der Vlag J. Breaking immuno-logical tolerance in systemic lupus erythemato-sus. Front Immunol. 2014; 5:164. Doi:10.3389/fimmu.2014.00164
4. Reefman E, Horst G, Nijk MT, Limburg PC, Kal-lenberg CG, Bijl M. Opsonization of late apop¬totic cells by systemic lupus erythematosus au¬toantibodies inhibits their uptake via an Fc-gamma receptor-dependent mechanism. Arthri¬tis Rheum. 2007;56(10):3399-3411. Doi:10.1002/art.22947.
5. Rees F, Doherty M, Grainge MJ, Lanyon P, Zhang W. The worldwide incidence and preva¬lence of systemic lupus erythematosus: a system¬atic review of epidemiological studies. Rheuma¬tology (Oxford). 2017;56(11):1945-1961. Doi:10.1093/rheumatology/kex260.
6. Weckerle CE, Niewold TB. The unexplained fe¬male predominance of systemic lupus erythe¬matosus: clues from genetic and cytokine stud¬ies. Clin Rev Allergy Immunol. 2011;40(1):42-49. Doi:10.1007/s12016-009-8192-4
7. McCarty DJ, Manzi S, Medsger TA Jr, Ramsey-Goldman R, LaPorte RE, Kwoh CK. Incidence of systemic lupus erythematosus. Race and gender differences. Arthritis Rheum. 1995;38(9):1260-1270. Doi:10.1002/art.1780380914
8. Ameer MA, Chaudhry H, Mushtaq J, et al. An Overview of Systemic Lupus Erythematosus (SLE) Pathogenesis, Classification, and Man-agement. Cureus. 2022;14(10):e30330. Pub-lished 2022 Oct 15. Doi:10.7759/cu-reus.30330
9. Alvarez-Nemegyei J, Peláez-Ballestas I, Sanin LH, Cardiel MH, Ramírez-Angulo A, Goy-cochea-Robles MV. Prevalence of musculoskel-etal pain and rheumatic diseases in the south-eastern region of Mexico. A COPCORD-based community survey. J Rheumatol Suppl. 2011;86:21-25. Doi:10.3899/jrheum.100954
10. Peláez-Ballestas I, Sanin LH, Moreno-Montoya J, et al. Epidemiology of the rheumatic diseases in Mexico. A study of 5 regions based on the COPCORD methodology. J Rheumatol Suppl. 2011 Mar;38(3):585]. J Rheumatol Suppl. 2011;86:3-8. Doi:10.3899/jrheum.100951
11. Deng Y, Tsao BP. Genetics of human SLE. Du-bois' Lupus Erythematosus and Related Syn-dromes (Ninth Edition). Wallace DJ, Hahn BH (ed): Elsevier, London; 2019. 54-68. 10.1016/B978-0-323-47927-1.00005-0
12. Armstrong DL, Zidovetzki R, Alarcón-Riquelme ME, et al. GWAS identifies novel SLE suscepti-bility genes and explains the association of the HLA region. Genes Immun. 2014;15(6):347-354. Doi:10.1038/gene.2014.23
13. Deng Y, Tsao BP. Genetic susceptibility to sys-temic lupus erythematosus in the genomic era. Nat Rev Rheumatol. 2010;6(12):683-692. Doi:10.1038/nrrheum.2010.176
14. Burn GL, Svensson L, Sanchez-Blanco C, Saini M, Cope AP. Why is PTPN22 a good candidate susceptibility gene for autoimmune disease?. FEBS Lett. 2011;585(23):3689-3698. Doi:10.1016/j.febslet.2011.04.032
15. Román-Fernández IV, Machado-Contreras JR, Muñoz-Valle JF, Cruz A, Salazar-Camarena DC, Palafox-Sánchez CA. Altered PTPN22 and IL10 mRNA Expression Is Associated with Dis¬ease Activity and Renal Involvement in Systemic Lupus Erythematosus. Diagnostics (Basel). 2022;12(11):2859. Published 2022 Nov 18. Doi:10.3390/diagnostics12112859
16. Stanford SM, Bottini N. PTPN22: the archetypal non-HLA autoimmunity gene. Nat Rev Rheu¬matol. 2014;10(10):602-611. Doi:10.1038/nrrheum.2014.109
17. Siminovitch KA. PTPN22 and autoimmune dis-ease. Nat Genet. 2004;36(12):1248-1249. Doi:10.1038/ng1204-1248.
18. Wu H, Cantor RM, Graham DS, et al. Associa-tion analysis of the R620W polymorphism of protein tyrosine phosphatase PTPN22 in sys-temic lupus erythematosus families: increased T allele frequency in systemic lupus erythemato-sus patients with autoimmune thyroid disease. Arthritis Rheum. 2005;52(8):2396-2402. Doi:10.1002/art.21223
19. Bottini N, Musumeci L, Alonso A, et al. A func-tional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet. 2004;36(4):337-338. Doi:10.1038/ng1323
20. Tizaoui K, Shin JI, Jeong GH, et al. Genetic Pol¬ymorphism of PTPN22 in Autoimmune Diseases: A Comprehensive Review. Medicina (Kaunas). 2022;58(8):1034. Published 2022 Aug 2. Doi:10.3390/medicina58081034
21. Kawasaki E, Awata T, Ikegami H, et al. System¬atic search for single nucleotide polymorphisms in a lymphoid tyrosine phosphatase gene (PTPN22): association between a promoter pol¬ymorphism and type 1 diabetes in Asian popu¬lations [published correction appears in Am J Med Genet A. 2007 Aug 1;143(15):18212-3. Uga, Mho [corrected to Uga, Miho]]. Am J Med Genet A. 2006;140(6):586-593. Doi:10.1002/ajmg.a.31124
22. Feng X, Li YZ, Zhang Y, et al. Association of the PTPN22 gene (-1123G > C) polymorphism with rheumatoid arthritis in Chinese patients. Tissue Antigens. 2010;76(4):297-300. Doi:10.1111/j.1399-0039.2010.01521.x
23. Fan ZD, Wang FF, Huang H, et al. STAT4 rs7574865 G/T and PTPN22 rs2488457 G/C polymorphisms influence the risk of developing juvenile idiopathic arthritis in Han Chinese pa-tients. PLoS One. 2015;10(3):e0117389. Pub-lished 2015 Mar 17. Doi:10.1371/jour-nal.pone.0117389
24. Liu F, Liu J, Zheng TS, et al. The -1123G>C var¬iant of PTPN22 gene promoter is associated with latent autoimmune diabetes in adult Chi¬nese Hans. Cell Biochem Biophys. 2012;62(2):273-279. Doi:10.1007/s12013-011-9291-4
25. Machado-Contreras JR, Muñoz-Valle JF, Cruz A, Salazar-Camarena DC, Marín-Rosales M, Palafox-Sánchez CA. Distribution of PTPN22 polymorphisms in SLE from western Mexico: cor¬relation with mRNA expression and disease ac¬tivity. Clin Exp Med. 2016;16(3):399-406. Doi:10.1007/s10238-015-0359-0
26. Kurreeman FA, Goulielmos GN, Alizadeh BZ, et al. The TRAF1-C5 region on chromosome 9q33 is associated with multiple autoimmune dis¬eases. Ann Rheum Dis. 2010;69(4):696-699. Doi:10.1136/ard.2008.106567
27. Albers HM, Kurreeman FA, Houwing-Duister-maat JJ, et al. The TRAF1/C5 region is a risk factor for polyarthritis in juvenile idiopathic ar¬thritis. Ann Rheum Dis. 2008;67(11):1578-1580. Doi:10.1136/ard.2008.089060
28. Behrens EM, Finkel TH, Bradfield JP, et al. Asso¬ciation of the TRAF1-C5 locus on chromosome 9 with juvenile idiopathic arthritis. Arthritis Rheum. 2008;58(7):2206-2207. Doi:10.1002/art.23603
29. Zervou MI, Vazgiourakis VM, Yilmaz N, et al. TRAF1/C5, eNOS, C1q, but not STAT4 and PTPN22 gene polymorphisms are associated with genetic susceptibility to systemic lupus ery¬thematosus in Turkey. Hum Immunol. 2011;72(12):1210-1213. Doi:10.1016/j.humimm.2011.09.003
30. Bradley JR, Pober JS. Tumor necrosis factor re-ceptor-associated factors (TRAFs). Oncogene. 2001;20(44):6482-6491. Doi:10.1038/sj.onc.1204788
31. Wajant H, Henkler F, Scheurich P. The TNF-re-ceptor-associated factor family: scaffold mole-cules for cytokine receptors, kinases and their regulators. Cell Signal. 2001;13(6):389-400. Doi:10.1016/s0898-6568(01)00160-7
32. So T, Nagashima H, Ishii N. TNF Receptor-Asso¬ciated Factor (TRAF) Signaling Network in CD4(+) T-Lymphocytes. Tohoku J Exp Med. 2015;236(2):139-154. Doi:10.1620/tjem.236.139
33. Lalani AI, Zhu S, Gokhale S, Jin J, Xie P. TRAF molecules in inflammation and inflammatory diseases. Curr Pharmacol Rep. 2018;4(1):64-90. Doi:10.1007/s40495-017-0117-y
34. Schmidt RE, Gessner JE. Fc receptors and their interaction with complement in autoimmunity. Immunol Lett. 2005;100(1):56-67. Doi:10.1016/j.imlet.2005.06.022
35. Weinstein A, Alexander RV, Zack DJ. A Review of Complement Activation in SLE. Curr Rheu-matol Rep. 2021;23(3):16. Published 2021 Feb 10. Doi:10.1007/s11926-021-00984-1
36. Plenge RM, Seielstad M, Padyukov L, et al. TRAF1-C5 as a risk locus for rheumatoid arthri-tis--a genomewide study. N Engl J Med. 2007;357(12):1199-1209. Doi:10.1056/NEJMoa073491
37. Abdul-Sater AA, Edilova MI, Clouthier DL, Mbanwi A, Kremmer E, Watts TH. The signaling adaptor TRAF1 negatively regulates Toll-like receptor signaling and this underlies its role in rheumatic disease. Nat Immunol. 2017;18(1):26-35. Doi:10.1038/ni.3618
38. González-Herrera L, Sosa-Escalante JE, López-González PN, et al. Ancestral proportions based on 22 autosomal STRs of an admixed population (Mestizos) from the Península of Yu¬catán, México. Forensic Science International: Genetics Supplement Series 7, 2019; 429-31. https://doi.org/10.1016/j.fsigss.2019.10.063
39. Welsh K, Bunce M. Molecular typing for the MHC with PCR-SSP. Rev Immunogenet. 1999;1(2):157-76
40. Tan EM, Cohen AS, Fries JF, et al. The 1982 re¬vised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25(11):1271-1277. Doi:10.1002/art.1780251101
41. Solé X, Guinó E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of associ¬ation studies. Bioinformatics. 2006;22(15): 1928-1929.
Doi:10.1093/bioin¬formatics/btl268
42. Tzeng J, Lu HH, Li WH. Multidimensional scaling for large genomic data sets. BMC Bioinformat¬ics. 2008;9:179. Published 2008 Apr 4. Doi:10.1186/1471-2105-9-179
43. Xu K, Peng H, Zhou M, et al. Association study of TRAF1/C5 polymorphism (rs10818488) with susceptibility to rheumatoid arthritis and sys¬temic lupus erythematosus: a meta-analysis. Gene. 2013;517(1):46-54. Doi:10.1016/j.gene.2012.12.092
44. Nishimoto K, Kochi Y, Ikari K, et al. Association study of TRAF1-C5 polymorphisms with suscep-tibility to rheumatoid arthritis and systemic lupus erythematosus in Japanese. Ann Rheum Dis. 2010;69(2):368-373. Doi:10.1136/ard.2008.104315
45. Sarantopoulos A, Theodorou I and Boura P. TRAF1-C5 rs3761847 SNP is associated with severe pattern of rheumatoid arthritis in Greek Patients. Open Journal of Rheumatology and Autoimmune Diseases. 2016 Feb; 6: 10-2. Doi: http://dx.doi.org/10.4236/ojra.2016.61002.
46. Palomino-Morales RJ, Rojas-Villarraga A, Gon¬zález CI, Ramírez G, Anaya JM, Martín J. STAT4 but not TRAF1/C5 variants influence the risk of developing rheumatoid arthritis and sys¬temic lupus erythematosus in Colombians. Genes Immun. 2008;9(4):379-382. Doi:10.1038/gene.2008.30
47. Moez P, Soliman E. Association of PTPN22 gene polymorphism and systemic lupus erythemato¬sus in a cohort of Egyptian patients: impact on clinical and laboratory results. Rheumatol Int. 2012;32(9):2753-2758. Doi:10.1007/s00296-011-2063-z.
48. Kyogoku C, Langefeld CD, Ortmann WA, et al. Genetic association of the R620W polymor¬phism of protein tyrosine phosphatase PTPN22 with human SLE. Am J Hum Genet. 2004;75(3):504-507. Doi:10.1086/423790
49. Kaufman KM, Kelly JA, Herring BJ, et al. Evalu¬ation of the genetic association of the PTPN22 R620W polymorphism in familial and sporadic systemic lupus erythematosus. Arthritis Rheum. 2006;54(8):2533-2540. Doi:10.1002/art.21963
50. Salmond RJ, Brownlie RJ, Zamoyska R. Multi-functional roles of the autoimmune disease-as-sociated tyrosine phosphatase PTPN22 in reg-ulating T cell homeostasis. Cell Cycle. 2015;14(5):705-711. Doi:10.1080/15384101.2015.1007018
51. Menard L, Saadoun D, Isnardi I, et al. The PTPN22 allele encoding an R620W variant in¬terferes with the removal of developing auto¬reactive B cells in humans. J Clin Invest. 2011;121(9):3635-3644. Doi:10.1172/JCI45790
52. Schrezenmeier E, Weißenberg SY, Stefanski AL, et al. Postactivated B cells in systemic lupus er¬ythematosus: update on translational aspects and therapeutic considerations. Curr Opin Rheu¬matol. 2019;31(2):175-184. Doi:10.1097/BOR.0000000000000576
53. Chang HH, Dwivedi N, Nicholas AP, Ho IC. The W620 Polymorphism in PTPN22 Disrupts Its In-teraction With Peptidylarginine Deiminase Type 4 and Enhances Citrullination and NETosis. Arthritis Rheumatol. 2015;67(9):2323-2334. Doi:10.1002/art.39215
54. Wang Y, Shaked I, Stanford SM, et al. The au¬toimmunity-associated gene PTPN22 potenti¬ates toll-like receptor-driven, type 1 interferon-dependent immunity. Immunity. 2013;39(1):111-122. Doi:10.1016/j.im-muni.2013.06.013
55. López-Cano DJ, Cadena-Sandoval D, Beltrán-Ramírez O, et al. The PTPN22 R263Q polymor¬phism confers protection against systemic lupus erythematosus and rheumatoid arthritis, while PTPN22 R620W confers susceptibility to Graves' disease in a Mexican population. In¬flamm Res. 2017;66(9):775-781. Doi:10.1007/s00011-017-1056-0
56. Begovich AB, Carlton VE, Honigberg LA, et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthri¬tis. Am J Hum Genet. 2004;75(2):330-337. Doi:10.1086/422827
57. Velaga MR, Wilson V, Jennings CE, et al. The codon 620 tryptophan allele of the lymphoid tyrosine phosphatase (LYP) gene is a major de¬terminant of Graves' disease. J Clin Endocrinol Metab. 2004;89(11):5862-5865. Doi:10.1210/jc.2004-1108
58. Kariuki SN, Crow MK, Niewold TB. The PTPN22 C1858T polymorphism is associated with skew¬ing of cytokine profiles toward high interferon-alpha activity and low tumor necrosis factor al¬pha levels in patients with lupus. Arthritis Rheum. 2008;58(9):2818-2823. Doi:10.1002/art.23728
59. Begovich AB, Carlton VE, Honigberg LA, et al. A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthri¬tis. Am J Hum Genet. 2004;75(2):330-337. Doi:10.1086/422827
60. Heneberg P, Malá M, Yorifuji T, et al. Low Fre¬quencies of Autoimmunity-Associated PTPN22 Polymorphisms in MODY Patients, Including Those Transiently Expressing Islet Cell Autoanti¬bodies. Int Arch Allergy Immunol. 2015;166(3):189-198. Doi:10.1159/000380853
61. Huraib GB, Harthi FA, Arfin M, et al. The Protein Tyrosine Phosphatase Non-Receptor Type 22 (PTPN22) Gene Polymorphism and Susceptibil¬ity to Autoimmune Diseases. In The Recent Topics in Genetic Polymorphisms; Mahmut Çalı¸skan, O.E., Gül, Ö., Eds.; IntechOpen: London, UK, 2020.
62. Chang HH, Tseng W, Cui J, Costenbader K, Ho IC. Altered expression of protein tyrosine phos¬phatase, non-receptor type 22 isoforms in sys¬temic lupus erythematosus. Arthritis Res Ther. 2014;16(1):R14. Published 2014 Jan 17. Doi:10.1186/ar4440
63. Owen KA, Grammer AC, Lipsky PE. Deconvolut¬ing the heterogeneity of SLE: The contribution of ancestry. J Allergy Clin Immunol. 2022;149(1):12-23. Doi:10.1016/j.jaci.2021.11.005
64. Hernández-Doño S, Jakez-Ocampo J, Már-quez-García JE, et al. Heterogeneity of Ge-netic Admixture Determines SLE Susceptibility in Mexican. Front Genet. 2021;12:701373. Pub¬lished 2021 Aug 3. Doi:10.3389/fgene.2021.701373
65. Martinez-Marignac VL, Valladares A, Cameron E, et al. Admixture in Mexico City: implications for admixture mapping of type 2 diabetes ge¬netic risk factors. Hum Genet. 2007;120(6):807-819. Doi:10.1007/s00439-006-0273-3
66. Rubi-Castellanos R, Martínez-Cortés G, Muñoz-Valle JF, et al. Pre-Hispanic Mesoamerican de¬mography approximates the present-day an¬cestry of Mestizos throughout the territory of Mexico. Am J Phys Anthropol. 2009;139(3): 284-294. Doi:10.1002/ajpa.20980
67. Conley AB, Rishishwar L, Norris ET, et al. A Com¬parative Analysis of Genetic Ancestry and Ad¬mixture in the Colombian Populations of Chocó and Medellín. G3 (Bethesda). 2017;7(10):3435-3447. Published 2017 Oct 5. Doi:10.1534/g3.117.1118
68. Plenge RM, Seielstad M, Padyukov L, et al. TRAF1-C5 as a risk locus for rheumatoid arthri-tis--a genomewide study. N Engl J Med. 2007;357(12):1199-1209. Doi:10.1056/NEJMoa073491
69. Mokry FB, Buzanskas ME, de Alvarenga Mudadu M, et al. Linkage disequilibrium and haplotype block structure in a composite beef cattle breed. BMC Genomics. 2014;15 Suppl 7(Suppl 7):S6. Doi:10.1186/1471-2164-15-S7-S6