Epidemiological Trends of Rheumatoid Arthritis and PADI4, PTPN22, and HLA-DRB9 Genes Distribution in the Kazakhstan Population

Argul Issilbayeva; Almagul  Kushugulova; Assel  Meiramova; Samat  Kozhakhmetov; Zhanar  Akhmetova; Madiyar   Nurgaziyev; Laura  Chulenbayeva; Dmitriy  Babenko; Jeannette  Kunz; Bayan  Ainabekova

doi:10.3889/oamjms.2021.6472

Authors

Argul Issilbayeva Laboratory of Human Microbiome and Longevity, Center for Life Sciences, National Laboratory Astana, Nazarbayev University, Nur-Sultan, Kazakhstan; Department of Internal Medicine with the Course of Gastroenterology, Endocrinology and Pulmonology, NJSC Astana Medical University, Nur-Sultan, Kazakhstan https://orcid.org/0000-0002-7350-6083
Almagul Kushugulova Laboratory of Human Microbiome and Longevity, Center for Life Sciences, National Laboratory Astana, Nazarbayev University, Nur-Sultan, Kazakhstan https://orcid.org/0000-0001-9479-0899
Assel Meiramova Laboratory of Human Microbiome and Longevity, Center for Life Sciences, National Laboratory Astana, Nazarbayev University, Nur-Sultan, Kazakhstan; Department of Internal Medicine with the Course of Gastroenterology, Endocrinology and Pulmonology, NJSC Astana Medical University, Nur-Sultan, Kazakhstan https://orcid.org/0000-0002-5427-3931
Samat Kozhakhmetov Laboratory of Human Microbiome and Longevity, Center for Life Sciences, National Laboratory Astana, Nazarbayev University, Nur-Sultan, Kazakhstan https://orcid.org/0000-0001-9668-0327
Zhanar Akhmetova Laboratory of Human Microbiome and Longevity, Center for Life Sciences, National Laboratory Astana, Nazarbayev University, Nur-Sultan, Kazakhstan; Department of Internal Medicine with Geriatrics course, NJSC Astana Medical University, Nur-Sultan, Kazakhstan https://orcid.org/0000-0001-9220-5596
Madiyar Nurgaziyev Laboratory of Human Microbiome and Longevity, Center for Life Sciences, National Laboratory Astana, Nazarbayev University, Nur-Sultan, Kazakhstan https://orcid.org/0000-0003-2397-4978
Laura Chulenbayeva Laboratory of Human Microbiome and Longevity, Center for Life Sciences, National Laboratory Astana, Nazarbayev University, Nur-Sultan, Kazakhstan https://orcid.org/0000-0002-8691-9485
Dmitriy Babenko Research Center, Karaganda Medical University, Karagandy, Kazakhstan https://orcid.org/0000-0003-2280-2146
Jeannette Kunz Department of Medicine, School of Medicine, Nazarbayev University, Nur-Sultan, Kazakhstan https://orcid.org/0000-0002-0776-3233
Professor Bayan Alkenovna Astana Medical University https://orcid.org/0000-0002-5427-3931

DOI:

https://doi.org/10.3889/oamjms.2021.6472

Keywords:

Rheumatoid arthritis, Epidemiology, Single-nucleotide polymorphisms, Peptidylarginine deiminase 4, Protein tyrosine phosphatase 22, Human leukocyte antigens-DRB9

Abstract

BACKGROUND: The prevalence of rheumatoid arthritis (RA) is 1% in the global population. The lack of epidemiological studies in developing countries makes it difficult to obtain a complete global epidemiological picture of RA. RA develops due to the interaction of multiple genetic and environmental factors, though the contribution of these factors to the various disease occurrence seen in different populations is unclear.

AIM: The aim of our study was to analyze the dynamics of the general prevalence and incidence of RA among the population of Kazakhstan in 2017–2019 as well as to investigate the three most common single-nucleotide polymorphisms (SNP) of RA in the Kazakhstan population.

METHODS: The analysis of statistical data on Form 12 “On the health of the people and the health care system” was carried out. Prevalence and incidence rates were calculated according to generally accepted rules. Demographic data for the Republic of Kazakhstan were obtained from the official website stat.gov.kz. Our study included 70 RA patients and 113 control subjects. Blood samples were collected and genotyped for peptidylarginine deiminase 4 (PADI4), protein tyrosine phosphatase 22, and human leukocyte antigen (HLA)-DRB9 SNPs by reverse transcription polymerase chain reaction.

RESULTS: The prevalence of RA in Kazakhstan in 2017–2019 was 0.36–0.38%, with an incidence rate of 0.085–0.087%, which can be comparable to data of other countries in Central Asia. The allele and genotypes frequency analyses were carried out between patients and controls. The HLA-DRB9 showed significant association of the G allele odds ratio (OR) 1.96 (95% confidence interval [CI]: 1.252–3.081), p= 0.0025 and G/G genotype OR = 3.67 (95% CI: 1.58–8.54), p = 0.00162 with RA in our sample. Strong association between anti-citrullinated protein antibody (ACPA) profile and PADI4 (OR 12.19 [95% CI: 2.19–67.94], p = 0.00115) was found.

CONCLUSION: There was an increase in RA prevalence with age among females and a higher crude prevalence and incidence of RA in the southern regions of Kazakhstan. HLA-DRB9 prevailed in Kazakhstani patients with RA, PADI4 showed association with ACPA-positive RA. Further studies on larger samples are required to confirm our obtained results.

Downloads

Download data is not yet available.

Metrics

Metrics Loading ...

Plum Analytics Artifact Widget Block

Author Biography

Professor Bayan Alkenovna, Astana Medical University

Professor. MD. The Head of the Department of Internal Medicine with the course of gastroenterology, endocrinology and pulmonology, NJSC Medical University Astana, Nur-Sultan.

References

Wang L, Wang FS, Gershwin ME. Human autoimmune diseases: A comprehensive update. J Intern Med. 2015;278(4):369-95. PMid:26212387

Nogaeva MG, Tuleutayeva AS. Prevalence of rheumatoid arthritis in the Republic of Kazakhstan in 2013-2017. Medicine. 2019;3:201.

Cross M, Smith E, Hoy D, Carmona L, Wolfe F, Vos T, et al. The global burden of rheumatoid arthritis: Estimates from the Global Burden of Disease 2010 study. Ann Rheum Dis. 2014;73(7):1316-22. https://doi.org/10.1136/annrheumdis-2013-20462 PMid:24550173

Safiri S, Kolahi AA, Hoy D, Smith E, Bettampadi D, Mansournia MA, et al. Global, regional and national burden of rheumatoid arthritis 1990-2017: A systematic analysis of the global burden of disease study 2017. Ann Rheum Dis. 2019;78(11):1463-71. https://doi.org/10.1136/annrheumdis-2019-215920 PMid:31511227

Almoallim H, Al Saleh J, Badsha H, Ahmed HM, Habjoka S, Menassa JA, et al. A review of the prevalence and unmet needs in the management of rheumatoid arthritis in Africa and the Middle East. Rheumatol Ther. 2021;8:1-16. https://doi.org/10.1007/s40744-020-00252-1

Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. Lancet. 2016;388(10055):2023-38. https://doi.org/10.1016/s0140-6736(16)30173-8 PMid:27156434

Alamanos Y, Voulgari PV, Drosos AA. Incidence and prevalence of rheumatoid arthritis, based on the 1987 American college of rheumatology criteria: A systematic review. Semin Arthritis Rheum. 2006;36(3):182-8. https://doi.org/10.1016/j.semarthrit.2006.08.006 PMid:17045630

Tobón GJ, Youinou P, Saraux A. The environment, geo-epidemiology, and autoimmune disease: Rheumatoid arthritis. J Autoimmun. 2010;35(1):10-4. https://doi.org/10.1016/j.autrev.2009.11.019 PMid:20080387

Myasoedova E, Davis JM, Crowson CS, Gabriel SE. Epidemiology of rheumatoid arthritis: Rheumatoid arthritis and mortality. Curr Rheumatol Rep. 2010;12(5):379-85. https://doi.org/10.1007/s11926-010-0117-y PMid:20645137

Crowson CS, Matteson EL, Myasoedova E, Michet CJ, Ernste FC, Warrington KJ, et al. The lifetime risk of adult-onset rheumatoid arthritis and other inflammatory autoimmune rheumatic diseases. Arthritis Rheum. 2011;63(3):633-9. https://doi.org/10.1002/art.30155. PMid:21360492

Deane KD. Best practice and research clinical rheumatology can rheumatoid arthritis be prevented? Best Pract Res Clin Rheumatol. 2013;27(4):467-85. https://doi.org/10.1016/j.berh.2013.09.002

van der Woude D, van der Helm-van Mil AH. Update on the epidemiology, risk factors, and disease outcomes of rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2018;32(2):174-87. https://doi.org/10.1016/j.berh.2018.10.005 PMid:30527425

Oton T, Carmona L. The epidemiology of established rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2020;33(5):101477. https://doi.org/10.1016/j.berh.2019.101477 PMid:31987685

Kvien TK, Uhlig T, Ødegård S, Heiberg MS. Epidemiological aspects of rheumatoid arthritis: The sex ratio. Ann N Y Acad Sci. 2006;1069:212-22. PMid:16855148

Demoruelle MK, Deane KD, Holers VM. When and where does inflammation begin in rheumatoid arthritis? Curr Opin Rheumatol. 2014;26(1):64-71. https://doi.org/10.1097/bor.0000000000000017 PMid:24247116

Lora V, Cerroni L, Cota C. Skin manifestations of rheumatoid arthritis. G Ital Dermatol Venereol. 2018;153(2):243-55. https://doi.org/10.23736/s0392-0488.18.05872-8 PMid:29368864

Ismaili H, Ismaili L, Rexhepi M. Values and correlations between C-reactive protein and apolipoprotein B after treatment with methotrexate at patients with rheumatoid arthritis. Open Access Maced J Med Sci. 2019;7(8):1293-8. https://doi.org/10.3889/ oamjms.2019.278 PMid:31110572

An JJ, Nyarko E, Hamad MA. Prevalence of comorbidities and their associations with health-related quality of life and healthcare expenditures in patients with rheumatoid arthritis. Clin Rheumatol. 2019;38(10):2717-26. https://doi.org/10.1007/s10067-019-04613-2 PMid:31134504

Myasoedova E, Crowson CS, Kremers HM, Therneau TM, Gabriel SE. Is the incidence of rheumatoid arthritis rising? Results from Olmsted County, Minnesota, 1955-2007. Arthritis Rheum. 2010;62(6):1576-82. https://doi.org/10.1002/art.27425 PMid:20191579

Minichiello E, Semerano L, Boissier MC. Time trends in the incidence, prevalence, and severity of rheumatoid arthritis: A systematic literature review. Joint Bone Spine. 2016;83(6):625-30. https://doi.org/10.1016/j.jbspin.2016.07.007 PMid:27616690

Silman AJ, Ollier W, Holligan S, Birrell F, Adebajo A, Asuzu MC, et al. Absence of rheumatoid arthritis in a rural Nigerian population. J Rheumatol. 1993;20(4):618-22. PMid:8496853

Batko B, Stajszczyk M, Świerkot J, Urbański K, Raciborski F, Jędrzejewski M, et al. Prevalence and clinical characteristics of rheumatoid arthritis in Poland: A nationwide study. Arch Med Sci. 2019;15(1):134-40. https://doi.org/10.5114/aoms.2017.71371 PMid:30697263

Rudan I, Sidhu S, Papana A, Meng SJ, Xin-Wei Y, Wang W, et al. Prevalence of rheumatoid arthritis in low- and middle-income countries: A systematic review and analysis. J Glob Health. 2015;5(1):010409. PMid:25969732

Bax M, Van Heemst J, Huizinga TW, Toes RE. Genetics of rheumatoid arthritis: What have we learned? Immunogenetics. 2011;63(8):459-66. https://doi.org/10.1007/s00251-011-0528-6 PMid:21556860

Stahl EA, Raychaudhuri S, Remmers EF, Xie G, Eyre S, Thomson BP, et al. Genome-wide association study meta-analysis identifies seven new rheumatoid arthritis risk loci. Nat Genet. 2010;42(6):508-14. PMid:20453842

Allam I, Gharnaout M, Louahchi S, Raaf N, Kheldoun N, Ladjouze A, Djidjik R. Association study of PTPN22 (rs2476601) and PADI4 (rs2240340) polymorphisms with rheumatoid arthritis in Algerian population. J Clin Cell Immunol. 2020;1(1):586.

Plant D, Flynn E, Mbarek H, Dieudé P, Cornelis F, Ärlestig L, et al. Investigation of potential non-HLA rheumatoid arthritis susceptibility loci in a European cohort increases the evidence for nine markers. Ann Rheum Dis. 2010;69(8):1548-53. https://doi.org/10.1136/ard.2009.121020 PMid:20498205

Report on the Number of Diseases Registered in the Area of Service of the Medical Organization and the Contingents of Patients under Dispensary Supervision 2017-2019. Kazakhstan: Med-Inform. Available from: http://www.medinfo.kz.

Agency of Strategic Planning and Reforms of the Republic of Kazakhstan Bereau of National Statistics. Available from: https://www.stat.gov.kz.

Prevoo ML, van’t Hof, MA, Kuper HH, van Rijswijk MA, van Leeuwen MH, van de Putte LB, et al. Modified disease activity scores that include twenty-eight-joint counts. development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995;38(1):44-8. https://doi.org/10.1002/art.1780380107 PMid:7818570

Fries JM, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. Arthritis Rheum. 1980;23(2):137-45. https://doi.org/10.1002/art.1780230202 PMid:7362664

Roux CH, Saraux A, Le Bihan E, Fardellone P, Guggenbuhl P, Fautrel B, et al. Rheumatoid arthritis and spondyloarthropathies: Geographical variations in prevalence in FranceTitle. J Rheumatol. 2007;34(1):117-122. PMid:17117490

Zlatković-Švenda MI, Stojanović RM, Šipetić-Grujičić SB, Guillemin F. Prevalence of rheumatoid arthritis in Serbia. Rheumatol Int. 2014;34(5):649-58. https://doi.org/10.1007/s00296-013-2897-7 PMid:24292809

Rossini M, Rossi E, Bernardi D, Viapiana O, Gatti D, Idolazzi L, et al. Prevalence and incidence of rheumatoid arthritis in Italy. Rheumatol Int. 2014;34(5):659-64. https://doi.org/10.1007/s00296-014-2974-6 PMid:24610538

Seoane-Mato D, Sánchez-Piedra C, Silva-Fernández L, Sivera F, Blanco FJ, Pérez Ruiz F, et al. Prevalence of rheumatic diseases in adult population in Spain (EPISER 2016 study): Aims and methodology. Reumatol Clin. 2019;15(2):90-6. https://doi.org/10.1136/annrheumdis-2018-eular.6463 PMid:28774657

Tunser T, Gilgil E, Kacar C, Kurtais I, Kutlay S, Bütün B, et al. Prevalence of rheumatoid arthritis and spondyloarthritis in Turkey: A nationwide study. Arch Rheumatol. 2018;33(2):128-36. https://doi.org/10.5606/archrheumatol.2018.6480

Galushko EA, Nasonov EL. Prevalence of rheumatic diseases in Russia. Alm Clin Med. 2018;46(1):32-9.

Humphreys JH, Verstappen SM, Hyrich KL, Chipping JR, Marshall T, Symmons DP. The incidence of rheumatoid arthritis in the UK: Comparisons using the 2010 ACR/EULAR classification criteria and the 1987 ACR classification criteria. Results from the Norfolk Arthritis Register. Ann Rheum Dis. 2013;72(8):1315-20. https://doi.org/10.1136/annrheumdis-2012-201960 PMid:22945499

Widdifield J, Paterson JM, Bernatsky S, Tu K, Tomlinson G, Kuriya B, et al. The epidemiology of rheumatoid arthritis in Ontario, Canada. Arthritis Rheumatol. 2014;66(4):786-93. https://doi.org/10.1002/art.38306 PMid:24757131

Hunter TM, Boytsov NN, Zhang X, Schroeder K, Michaud K, Araujo AB. Prevalence of rheumatoid arthritis in the United States adult population in healthcare claims databases, 2004-2014. Rheumatol Int. 2017;37(9):1551-7. https://doi.org/10.1007/s00296-017-3726-1 PMid:28455559

Slimani S, Ladjouze-Rezig A. Prevalence of rheumatoid arthritis in an urban population of Algeria: A prospective study. Rheumatol (United Kingdom). 2014;53(3):571-3. https://doi.org/10.1093/rheumatology/ket446 PMid:24425779

Essouma M, Nkeck JR, Endomba FT, Bigna JJ, Ralandison S. Epidemiology of rheumatoid arthritis in sub-Saharan Africa: A systematic review and meta-analysis protocol. Syst Rev. 2020;9(1):81. https://doi.org/10.1186/s13643-020-01342-5 PMid:32303250

Naqvi AA, Hassali MA, Aftab MT. Epidemiology of rheumatoid arthritis, clinical aspects and socio-economic determinants in Pakistani patients: A systematic review and meta-analysis. J Pak Med Assoc. 2019;69(3):389-98. PMid:30890833

Aslam MM, John P, Fan K, Bhatti A, Aziz W, Ahmed B, et al. Investigating the GWAS-implicated loci for rheumatoid arthritis in the pakistani population. Dis Markers. 2020;2020:1910215. https://doi.org/10.1155/2020/1910215

Sung YK, Cho SK, Choi CB, Bae SC. Prevalence and incidence of rheumatoid arthritis in South Korea. Rheumatol Int. 2013;33(6):1525-32. https://doi.org/10.1007/s00296-012-2590-2 PMid:23255140

Silman AJ, Pearson JE, Silman AJ, Pearson JE. Epidemiology and genetics of rheumatoid arthritis. Arthritis Res Ther. 2002;4(S3):265-72. PMid:12110146

Kojima M, Nakayama T, Tsutani K, Igarashi A, Kojima T, Suzuki S, et al. Epidemiological characteristics of rheumatoid arthritis in Japan: Prevalence estimates using a nationwide population-based questionnaire survey. Mod Rheumatol. 2020;30(6):941-7. https://doi.org/10.1080/14397595.2019.1682776 PMid:31625435

Pedersen JK, Svendsen AJ, Hørslev-Petersen k. Incidence of rheumatoid arthri- tis in the southern part of Denmark from 1995 to 2001. Open Rheumatol J. 2007;1:18-23. https://doi.org/10.2174/1874312900701010018 PMid:19088896

Eriksson JK, Neovius M, Ernestam S, Lindblad S, Simard JF, Askling J. Incidence of rheumatoid arthritis in Sweden: A Nationwide population-based assessment of incidence, its determinants, and treatment penetration. Arthritis Care Res. 2013;65(6):870-8. https://doi.org/10.1002/acr.21900 PMid:23281173

Karami J, Aslani S, Jamshidi A, Garshasbi M, Mahmoudi M. Genetic implications in the pathogenesis of rheumatoid arthritis: An updated review. Gene. 2019;702:8-16. https://doi.org/10.1016/j.gene.2019.03.033 PMid:30904715

Traylor M, Curtis C, Patel H, Breen G, Hyuck S, Xu X, et al. Original article Genetic and environmental risk factors for rheumatoid arthritis in a UK African ancestry population: The GENRA case control study. 2017;56(8):1282-92. https://doi.org/10.1093/rheumatology/kex048 PMid:28407095

Korczowska I. Rheumatoid arthritis susceptibility genes: An overview. World J Orthop. 2014:5(4):544-9. https://doi.org/10.5312/wjo.v5.i4.544 PMid:25232530

Okada Y, Kim K, Han B, Pillai NE, Ong RT, Saw WY, et al. Risk for ACPA-positive rheumatoid arthritis is driven by shared HLA amino acid polymorphisms in Asian and European populations. Hum Mol Genet. 2014;23(25):6916-26. http://doi.org/10.1093/hmg/ddu387. PMid:25070946

Okada Y, Wu D, Trynka G, Raj T, Terao C, Ikari K, et al. Genetics of rheumatoid arthritis contributes to biology and drug discovery. Nature. 2014:506(7488):376-81. PMid:24390342

Yamamoto K, Okada Y, Suzuki A, Kochi Y. Genetics of rheumatoid arthritis in Asia present and future. Nat Publ Gr. 2015;11(6):375-9. https://doi.org/10.1038/nrrheum.2015.7 PMid:25668139

Newton JL, Harney SM, Wordsworth BP, Brown MA. A review of the MHC genetics of rheumatoid arthritis., Genes Immunity. 200;5(3):151-7. https://doi.org/10.1038/sj.gene.6364045 PMid:14749714

Kampstra A, Toes R. HLA class II and rheumatoid arthritis: The bumpy road of revelation. Immunogenetics. 2017;69(8-9):597-603. https://doi.org/10.1007/s00251-017-0987-5 PMid:28695293

Nabi G, Akhter N, Wahid M, Bhatia K, Mandal RK, Dar SA, et al. Meta-analysis reveals PTPN22 1858C/T polymorphism confers susceptibility to rheumatoid arthritis in Caucasian but not in Asian population. Autoimmunity. 2016;49(3):197-210. https://doi.org/10.3109/08916934.2015.1134514 PMid:26763276

Schulz S, Zimmer P, Pütz N, Jurianz E, Schaller HG, Reichert S. rs2476601 in PTPN22 gene in rheumatoid arthritis and periodontitis a possible interface ? J Transl Med. 2020;18(1):389. https://doi.org/10.1186/s12967-020-02548-w PMid:33059697

Kurkó J, Besenyei T, Laki J, Glant TT, Mikecz K, Szekanecz Z. Genetics of rheumatoid arthritis a comprehensive review. Clin Rev Allergy Immunol. 2013;45(2):170-9. https://doi.org/10.1007/ s12016-012-8346-7 PMid:23288628

Mustelin T, Bottini N, Stanford SM. The contribution of PTPN22 to rheumatic disease. Arthritis Rheumatol. 2019;71(4):486-95. https://doi.org/10.1002/art.40790 PMid:30507064

Sahin N, Gunduz F, Inanc N, Direskeneli H, Saruhan- Direskeneli G. No association of PTPN22 gene polymorphism with rheumatoid arthritis in Turkey. Rheumatol Int. 2009;30:81-3. https://doi.org/10.1007/s00296-009-0919-2

Baños-Hernández CJ, Navarro-Zarza JE, Parra-Rojas I, Vázquez-Villamar M, Padilla-Gutiérrez JR, Valle Y, et al. PADI4 polymorphisms and the functional haplotype are associated with increased rheumatoid arthritis susceptibility : A replication study in a Southern Mexican population. Hum Imunol. 2017;78(9): 553-8. https://doi.org/10.1016/j.humimm.2017.05.005 PMid:28551357

Lu C, Xu K, Guo H, Peng K, Yang Z, Hao YQ, et al. The relationship of PADI4_94 polymorphisms with the morbidity of rheumatoid arthritis in Caucasian and Asian populations: A meta-analysis and system review. 2018;37(2): 289-96. https://doi.org/10.1007/s10067-017-3964-3 PMid:29302826

Too CL, Murad S, Dhaliwal JS, Larsson P, Jiang X, Ding B, et al. Polymorphisms in peptidylarginine deiminase associate with rheumatoid arthritis in diverse Asian populations: Evidence from MyEIRA study and meta-analysis. Arthritis Res Ther. 2012;14:R250. https://doi.org/10.1186/ar4093

Suzuki T, Ikari K, Yano K, Inoue E, Toyama Y, Taniguchi A. PADI4 and HLA-DRB1 are genetic risks for radiographic progression in RA patients, independent of ACPA status: Results from the IORRA cohort study. PLoS One. 2013;8(4):e61045. https://doi.org/10.1371/journal.pone.0061045 PMid:23577190

Martinez A, Valdivia A, Pascual-Salcedo D, Lamas JR, Fernández-Arquero M, Balsa A, et al. PADI4 polymorphisms are not associated with rheumatoid arthritis in the Spanish population. Rheumatology. 2005;44(10):1263-6. https://doi.org/10.1093/rheumatology/kei008 PMid:15998632

Ben Hassine H, Zemni R, Bouagina E, Zaglaoui H, Ben Fradj H, Slama F, et al. Lack of association between PADI4 polymorphisms and rheumatoid arthritis in the Tunisian population. Joint Bone Spine. 2012;79(3):329-30. https://doi.org/10.1016/j.jbspin.2011.11.005 PMid:22459419

Panati K, Pal S, Rao K V, Reddy VD. Association of single nucleotide polymorphisms (SNPs) of PADI4 gene with rheumatoid arthritis (RA) in Indian population. 2012;87(3):191-6. https://doi.org/10.1266/ggs.87.191 PMid:22976394

Cantaert T, Coucke P, De Rycke L, Veys EM, De Keyser F, Baeten D. Functional haplotypes of PADI4: Relevance for rheumatoid arthritis specific synovial intracellular citrullinated proteins and anticitrullinated protein antibodies. Ann Rheum Dis. 2005;64(9):1316-20. https://doi.org/10.1136/ard.2004.033548 PMid:15760928.