Protective role of HLA-DRB1*11 against juvenile idiopathic arthritis living in North Eastern Iran

Document Type: Original Article


1 Rheumatic Disease Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

2 Social Determination of Health Research Center, Mashhad University of Medical Sciences, Mashhad, Iran

3 Department of Pediatrics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran

4 Immunology Research Center, Inflammation and Inflammatory Diseases Division, Mashhad University of Medical Sciences, Mashhad, Iran


Objective(s): Juvenile idiopathic arthritis (JIA) is one of the most common chronic rheumatic diseases in children. The complex nature of this immune-mediated disease owes itself to several predisposing genes and environmental factors affecting its pathogenesis. Conducted in Iran, this study was originally intended to investigate every possible association between HLA DRB1 alleles and a susceptibility to JIA.
Materials and Methods: In this case-control study, 45 patients with a definite diagnosis of JIA based on International League against Rheumatism (ILAR) criteria were compared against 46 healthy controls. DNA samples taken from both groups were analyzed using PCR-sequence specific primers (PCR-SSP) method. Data analysis including parametric and nonparametric test and multivariate analysis was undertaken using the SPSS 11.5 software. A P-value< 0.05 was regarded as statistically significant.
Results: Mean ages in case  group and healthy controls were 14.64±6.21 and 13.73±6.39, respectively with no significant difference between the two groups (P=0.515). Sex difference between JIA group and healthy controls was also not significant (P=0.068) .The frequency of HLA-DRB1*01 was found the most frequent HLA-RB1 in our patients (33.3%). No significant statistical correlation between various HLA-DRB1 alleles and clinical subtypes of the disease could be established from the data. HLA-DRB1*11 was shown to raise protection to JIA (P=0.035, OR=2.755, 95% CI=0.963-8.055) in northeastern Iran. In addition, we found that HLA-RB1*09 is nominally associated with an increased risk of JIA (P=0.56, OR=2, 05, 95% CI=0.18-23.63).
Conclusion: HLA-DRB1*11 was shown to raise protection to JIA in northeastern Iran. The disparity of findings in other ethnicities prompts further investigations with larger sample sizes.


Main Subjects

1.  Prahalad S, Glass DN. A comprehensive review of the genetics of juvenile idiopathic arthritis. Pediatr Rheumatol Online J 2008; 6: 11.
2. Espinosa M, Gottlieb BS. Juvenile idiopathic arthritis. Pediatr Rev 2012; 33: 303-313.
3. Prahalad S, Thompson SD, Conneely KN, et al. Hierarchy of risk of childhood-onset rheumatoid arthritis conferred by HLA-DRB1 alleles encoding the shared epitope. Arthritis Rheum 2012; 64: 925-930.
4. Schork NJ. Genetics of complex disease: approaches, problems, and solutions. Am J Respir Crit Care Med 1997; 156: S103-109.
5. Lander ES, Schork NJ. Genetic dissection of complex traits. Science 1994; 265: 2037-2048.
6. Zeft A, Shear ES, Thompson SD, Glass DN, Prahalad S. Familial autoimmunity: maternal parent-of-origin effect in juvenile idiopathic arthritis. Clin Rheumatol 2008; 27: 241-244.
7. Woo P, Colbert RA. An overview of genetics of paediatric rheumatic diseases. Best Pract Res Clin Rheumatol 2009; 23: 589-597.
8. Ayala FJ, Escalante A, O’Huigin C, Klein J. Molecular genetics of speciation and human origins. Proc Natl Acad Sci U S A 1994; 91: 6787-6794.
9. Thomson W, Barrett JH, Donn R, et al. Juvenile idiopathic arthritis classified by the ILAR criteria: HLA associations in UK patients. Rheumatology (Oxford) 2002; 41: 1183-1189.
10. Ploski R, Vinje O, Ronningen KS, et al. HLA class II alleles and heterogeneity of juvenile rheumatoid arthritis. DRB1*0101 may define a novel subset of the disease. Arthritis Rheum 1993; 36: 465-472.
11. Yanagimachi M, Miyamae T, Naruto T, et al. Association of HLA-A*02:06 and HLA-DRB1*04:05 with clinical subtypes of juvenile idiopathic arthritis. J Hum Genet 2011; 56: 196-199.
12. Cleary AG, Sills JA, Davidson JE. Revision of the proposed classification criteria for juvenile idiopathic arthritis: Durban, 1997. J Rheumatol 2000; 27: 1568.
13. Farivar S, Shiari R, Hadi E. Genetic susceptibility to juvenile idiopathic arthritis in Iranian children. Arch Med Res 2011; 42: 301-4. S0188-4409.
14. Nepom BS, Glass DN. Juvenile rheumatoid arthritis and HLA: report of the Park City III workshop. J Rheumatol Suppl 1992; 33: 70-74.
15. Hisa K, Yanagimachi MD, Naruto T, Miyamae T, Kikuchi M, Hara R, et al. PADI4 and the HLA-DRB1 shared epitope in juvenile idiopathic arthritis. PLoS One 2017;12:e0171961.
16. Ombrello MJ, Remmers EF, Tachmazidou I, Grom A, Foell D, Haas JP, et al. HLA-DRB1* 11 and variants of the MHC class II locus are strong risk factors for systemic juvenile idiopathic arthritis. Proc Natl Acad Sci 2015;112:15970-15975.
17. Haas JP, Nevinny-Stickel C, Schoenwald U, Truckenbrodt H, Suschke J, Albert ED. Susceptible and protective major histocompatibility complex class II alleles in early-onset pauciarticular juvenile chronic arthritis. Hum Immunol 1994; 41: 225-233.
18. Silva-Ramirez B, Cerda-Flores RM, Rubio-Perez N, et al. Association of HLA DRB1 alleles with juvenile idiopathic arthritis in Mexicans. Clin Exp Rheumatol 2010;28:124-127
19. Sandoughi M, Fazaeli A, Bardestani G, Hashemi M. Frequency of HLA-DRB1 alleles in rheumatoid arthritis patients in Zahedan, southeast Iran. Ann Saudi Med 2011; 31: 171-173.
20. Saghafi M, Nohesara N, Rafatpanah H, Shariati J, Shakeri MT. HLA-DRB1 frequency in patients with familial and sporadic rheumatoid arthritis in north east of Iran. Clin Rheumatol 2014; 33:1397-1402.
21. Garavito G, Malagon C, Ramirez LA, et al. Polymorphism of human HLA-DRB1 leukocyte antigen alleles and its association to juvenile rheumatoid arthritis in a sample of Colombian mestizo children. Biomedica 2003; 23: 254-262.
22. Wu J, Zeng HS. HLA-DRB1 allelic polymorphism in children with juvenile idiopathic arthritis. Zhongguo Dang Dai Er Ke Za Zhi 2010; 12: 333-337.
23. Spârchez M, Constantinescu I, Samaşca G, Iancu M, Miu N, Sparchez Z. New HLA associations identified in Romanian juvenile idiopathic arthritis patients. Clinical laboratory 2013; 60: 449-454.
24. Esmaeil I, Rabe S, Mahmoudi M,  RastinM. Frequencies of HLA-A, B and DRB1 alleles in a large normal population living in the city of Mashhad, Northeastern Iran. Iran J Basic Med Sci 2017;20:940-943
25. Mohammadi M, Rastin M, Rafatpanah H, Sereshki HA, Zahedi MJ, Nikpoor AR, et al. Association of HLA-DRB1 Alleles with Ulcerative Colitis in the City of Kerman, South Eastern Iran. Iran J Allergy Asthma Immunol 2015 Jun 1; 14:306.
26. Abolfazli R, Samadzadeh S, Sabokbar T, Siroos B, Armaki SA, Aslanbeiki B, et al. Relationship between HLA-DRB1* 11/15 genotype and susceptibility to multiple sclerosis in Iran. J Neurol Sci 2014; 345:92-96.
27. Khosravi F, Amirzargar A, Sarafnejad A, Nicknam MH, Alimoghadam K, Dianat S, et al. HLA class II allele and haplotype frequencies in Iranian patients with leukemia. Iran J Allergy Asthma Immunol 2007; 6:137-142.
28. Sayad A, Akbari MT, Mehdizadeh M, Movafagh A, Hajifathali A. The Association of HLA-Class I and Class II with Hodgkin’s Lymphoma in Iranian Patients. BioMed Res Int 2014; 2014.