Objectives Dendritic cell immunoreceptor (DCIR) has been implicated in development of autoimmune disorders in rodent and DCIR polymorphisms were associated with anti-citrullinated proteins antibodies (ACPA)-negative rheumatoid arthritis (RA) in Swedish Caucasians. This study was undertaken to further investigate whether DCIR polymorphisms are also risk factors for the development of RA in four Asian populations originated from China and Malaysia. Methods We genotyped two DCIR SNPs rs2377422 and rs10840759 in Han Chinese population (1,193 cases, 1,278 controls), to assess their association with RA. Subsequently, rs2377422 was further genotyped in three independent cohorts of Malaysian-Chinese subjects (MY_Chinese, 254 cases, 206 controls), Malay subjects (MY_ Malay, 515 cases, 986 controls), and Malaysian-Indian subjects (MY_Indian, 378 cases, 285 controls), to seek confirmation of association in various ethnic groups. Meta-analysis was preformed to evaluate the contribution of rs2377422 polymorphisms to the development of ACPA-negative RA in distinct ethnic groups. Finally, we carried out association analysis of rs2377422 polymorphisms with DCIR mRNA expression levels. Results DCIR rs2377422 was found to be significantly associated with ACPA -negative RA in Han Chinese (OR 1.92, 95% CI 1.27–2.90, P = 0.0020). Meta-analysis confirms DCIR rs2377422 as a risk factor for ACPA-negative RA across distinct ethnic groups (ORoverall = 1.17, 95% CI 1.06–1.30, P = 0.003). The SNP rs2377422 polymorphism showed significant association with DCIR mRNA expression level, i.e. RA-risk CC genotype exhibit a significant increase in the expression of DCIR (P = 0.0023, Kruskal–Wallis). Conclusions Our data provide evidence for association between DCIR rs2377422 and RA in non-Caucasian populations and confirm the influence of DCIR polymorphisms on RA susceptibility, especially on ACPA-negative RA.
References
[1]
Bax M, van Heemst J, Huizinga TW, Toes RE (2011) Genetics of rheumatoid arthritis: what have we learned? Immunogenetics 63: 459–466.
[2]
Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, et al. (2006) A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 54: 38–46.
[3]
Huizinga TW, Amos CI, van der Helm-van MA, Chen W, van Gaalen FA, et al. (2005) Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. Arthritis Rheum 52: 3433–3438.
[4]
Kallberg H, Padyukov L, Plenge RM, Ronnelid J, Gregersen PK, et al. (2007) Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am J Hum Genet 80: 867–875.
[5]
Kokkonen H, Johansson M, Innala L, Jidell E, Rantapaa-Dahlqvist S (2007) The PTPN22 1858C/T polymorphism is associated with anti-cyclic citrullinated peptide antibody-positive early rheumatoid arthritis in northern Sweden. Arthritis Res Ther 9: R56.
[6]
Linn-Rasker SP, van der Helm-van MA, van Gaalen FA, Kloppenburg M, de Vries RR, et al. (2006) Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles. Ann Rheum Dis 65: 366–371.
[7]
Padyukov L, Seielstad M, Ong RT, Ding B, Ronnelid J, et al. (2011) A genome-wide association study suggests contrasting associations in ACPA-positive versus ACPA-negative rheumatoid arthritis. Ann Rheum Dis 70: 259–265.
[8]
Lee HS, Korman BD, Le JM, Kastner DL, Remmers EF, et al. (2009) Genetic risk factors for rheumatoid arthritis differ in Caucasian and Korean populations. Arthritis Rheum 60: 364–371.
[9]
Kochi Y, Suzuki A, Yamada R, Yamamoto K (2009) Genetics of rheumatoid arthritis: underlying evidence of ethnic differences. J Autoimmun 32: 158–162.
[10]
Kanazawa N (2007) Dendritic cell immunoreceptors: C-type lectin receptors for pattern-recognition and signaling on antigen-presenting cells. J Dermatol Sci 45: 77–86.
[11]
Guo JP, Backdahl L, Marta M, Mathsson L, Ronnelid J, et al. (2008) Profound and paradoxical impact on arthritis and autoimmunity of the rat antigen-presenting lectin-like receptor complex. Arthritis Rheum 58: 1343–1353.
[12]
Guo JP, Verdrengh M, Tarkowski A, Lange S, Jennische E, et al. (2009) The rat antigen-presenting lectin-like receptor complex influences innate immunity and development of infectious diseases. Genes Immun 10: 227–236.
[13]
Fujikado N, Saijo S, Yonezawa T, Shimamori K, Ishii A, et al. (2008) Dcir deficiency causes development of autoimmune diseases in mice due to excess expansion of dendritic cells. Nat Med 14: 176–180.
[14]
Lorentzen JC, Flornes L, Eklow C, Backdahl L, Ribbhammar U, et al. (2007) Association of arthritis with a gene complex encoding C-type lectin-like receptors. Arthritis Rheum 56: 2620–2632.
[15]
Greene CS, Penrod NM, Williams SM, Moore JH (2009) Failure to replicate a genetic association may provide important clues about genetic architecture. PLoS One 4: e5639.
[16]
Xu S, Yin X, Li S, Jin W, Lou H, et al. (2009) Genomic dissection of population substructure of Han Chinese and its implication in association studies. Am J Hum Genet 85: 762–774.
[17]
Eklow C, Makrygiannakis D, Backdahl L, Padyukov L, Ulfgren AK, et al. (2008) Cellular distribution of the C-type II lectin dendritic cell immunoreceptor (DCIR) and its expression in the rheumatic joint: identification of a subpopulation of DCIR+ T cells. Ann Rheum Dis 67: 1742–1749.
[18]
Ronninger M, Eklow C, Lorentzen JC, Klareskog L, Padyukov L (2008) Differential expression of transcripts for the autoimmunity-related human dendritic cell immunoreceptor. Genes Immun 9: 412–418.
[19]
Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, et al. (1988) The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 31: 315–324.
[20]
Chun-Lai T, Padyukov L, Dhaliwal JS, Lundstrom E, Yahya A, et al. (2011) Shared epitope alleles remain a risk factor for anti-citrullinated proteins antibody (ACPA)–positive rheumatoid arthritis in three Asian ethnic groups. PLoS One 6: e21069.
