Association of Interleukin-6 and Interleukin-10 Genotypes With Radiographic Damage in Rheumatoid Arthritis Is Dependent on Autoantibody Status

Objective Recent evidence has highlighted a major genetic contribution to radiographic damage in rheumatoid arthritis (RA). The objective of this study was to determine whether genetic variants in the loci for interleukin-1 (IL-1), IL-6, IL-10, protein tyrosine phosphatase N22 (PTPN22), and selenoprotein S are associated with radiographic damage. Methods Modified Larsen scores of radiographic damage were determined in a cross-sectional population of patients with RA (n = 964). Rheumatoid factor (RF) and anti–cyclic citrullinated peptide (anti-CCP) were also assayed. The Kruskal-Wallis nonparametric test was used to compare median radiographic damage scores across genotype groups, followed by the Cuzick nonparametric test for trend to assess gene-dose effects. Results An allele-dose association of IL-6 −174G with increasing radiographic damage was present (P = 0.005), but only in patients who were RF positive (P = 0.004) or anti-CCP positive (P = 0.01). Patients with the IL-10 −592CC genotype had more extensive radiographic damage than did those with the AC or AA genotype (P = 0.006), but this was observed only among patients who were RF negative (P = 0.002) or anti-CCP negative (P = 0.002). However, RF status and anti-CCP status were not associated with the IL-6 or IL-10 genotype. No other genetic associations were detected, apart from a marginal association of PTPN22 +1858T with increased radiographic damage. Conclusion The reported associations of IL-6 −174G with high IL-6 production and IL-10 −592 with low IL-10 production and our own results support a role of genetically determined dysregulated cytokine production in disease severity. The lack of association of these genotypes with RF and anti-CCP antibody status suggests that they act downstream of autoantibody production. We conclude that IL-6 and IL-10 genotypes may be useful in predicting disease severity in autoantibody-positive and autoantibody-negative patients, respectively.

[1]  I. Marinou,et al.  Independent associations of anti-cyclic citrullinated peptide antibodies and rheumatoid factor with radiographic severity of rheumatoid arthritis , 2006, Arthritis research & therapy.

[2]  P. Gregersen,et al.  Variation in radiologic joint destruction in rheumatoid arthritis differs between monozygotic and dizygotic twins and pairs of unrelated patients. , 2006, Arthritis and rheumatism.

[3]  E. Lechman,et al.  Human, viral or mutant human IL-10 expressed after local adenovirus-mediated gene transfer are equally effective in ameliorating disease pathology in a rabbit knee model of antigen-induced arthritis , 2006, Arthritis research & therapy.

[4]  A. Hinks,et al.  The association of PTPN22 with rheumatoid arthritis and juvenile idiopathic arthritis. , 2006, Rheumatology.

[5]  Elizabeth W Karlson,et al.  Replication of putative candidate-gene associations with rheumatoid arthritis in >4,000 samples from North America and Sweden: association of susceptibility with PTPN22, CTLA4, and PADI4. , 2005, American journal of human genetics.

[6]  Wei Chen,et al.  Refining the complex rheumatoid arthritis phenotype based on specificity of the HLA-DRB1 shared epitope for antibodies to citrullinated proteins. , 2005, Arthritis and rheumatism.

[7]  K. Elliott,et al.  Genetic variation in selenoprotein S influences inflammatory response , 2005, Nature Genetics.

[8]  A. Pawlik,et al.  IL‐6 promoter polymorphism in patients with rheumatoid arthritis , 2005, Scandinavian journal of rheumatology.

[9]  D. Heinegård,et al.  Prognostic laboratory markers of joint damage in rheumatoid arthritis , 2004, Annals of the rheumatic diseases.

[10]  T. Huizinga,et al.  Transcription of the IL10 gene reveals allele-specific regulation at the mRNA level. , 2004, Human molecular genetics.

[11]  Steven J. Schrodi,et al.  A missense single-nucleotide polymorphism in a gene encoding a protein tyrosine phosphatase (PTPN22) is associated with rheumatoid arthritis. , 2004, American journal of human genetics.

[12]  S. Fisher,et al.  The -174G allele of the interleukin-6 gene confers susceptibility to systemic arthritis in children: a multicenter study using simplex and multiplex juvenile idiopathic arthritis families. , 2003, Arthritis and rheumatism.

[13]  V. Holers,et al.  Can we accurately predict the development of rheumatoid arthritis in the preclinical phase? , 2003, Arthritis and rheumatism.

[14]  F. Breedveld,et al.  Are differences in interleukin 10 production associated with joint damage? , 2000, Rheumatology.

[15]  E C Coles,et al.  Relationship between time-integrated C-reactive protein levels and radiologic progression in patients with rheumatoid arthritis. , 2000, Arthritis and rheumatism.

[16]  A. Balsa,et al.  IL-6 promoter polymorphisms in rheumatoid arthritis , 2000, Genes and Immunity.

[17]  B. Mazières,et al.  Interleukin‐1β, interleukin‐1 receptor antagonist, interleukin‐4, and interleukin‐10 gene polymorphisms: Relationship to occurrence and severity of rheumatoid arthritis , 1999 .

[18]  Paul Wordsworth,et al.  Interleukin-10 microsatellite polymorphisms and IL-10 locus alleles in rheumatoid arthritis susceptibility , 1998, The Lancet.

[19]  J S Yudkin,et al.  The effect of novel polymorphisms in the interleukin-6 (IL-6) gene on IL-6 transcription and plasma IL-6 levels, and an association with systemic-onset juvenile chronic arthritis. , 1998, The Journal of clinical investigation.

[20]  R. Westendorp,et al.  Interleukin 10 secretion in relation to human IL-10 locus haplotypes. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[21]  D. Boomsma,et al.  Genetic influence on cytokine production and fatal meningococcal disease , 1997, The Lancet.

[22]  J. Todd,et al.  Genetic analysis of autoimmune disease: a review , 1996 .

[23]  John A Todd,et al.  Genetic Analysis of Autoimmune Disease , 1996, Cell.

[24]  M. Feldmann,et al.  Interleukin-10 inhibition of the progression of established collagen-induced arthritis. , 1996, Arthritis and rheumatism.

[25]  C. Weyand,et al.  Correlation between disease phenotype and genetic heterogeneity in rheumatoid arthritis. , 1995, The Journal of clinical investigation.

[26]  M. Feldmann,et al.  Immunoregulatory role of interleukin 10 in rheumatoid arthritis , 1994, The Journal of experimental medicine.

[27]  P. Bateson,et al.  Measuring behaviour: Analysis and interpretation of data , 1993 .

[28]  J. Symons,et al.  In situ hybridization of IL‐6 in rheumatoid arthritis , 1992, Clinical and experimental immunology.

[29]  F. Arnett.  Revised criteria for the classification of rheumatoid arthritis. , 1990, Orthopedic nursing.

[30]  M. Liang,et al.  The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. , 1988, Arthritis and rheumatism.

[31]  P. Gregersen,et al.  The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. , 1987, Arthritis and rheumatism.

[32]  J. Moreland,et al.  Methods of scoring the progression of radiologic changes in rheumatoid arthritis. Correlation of radiologic, clinical and laboratory abnormalities. , 1971, Arthritis and rheumatism.

[33]  The association of PTPN 22 with rheumatoid arthritis and juvenile idiopathic arthritis , 2006 .

[34]  Javier Martín,et al.  Association of a functional single-nucleotide polymorphism of PTPN22, encoding lymphoid protein phosphatase, with rheumatoid arthritis and systemic lupus erythematosus. , 2005, Arthritis and rheumatism.

[35]  T. Kishimoto.  Interleukin-6: from basic science to medicine--40 years in immunology. , 2005, Annual review of immunology.

[36]  A. Barton,et al.  Approaches to Identifying Genetic Predictors of Clinical Outcome in Rheumatoid Arthritis , 2003, American journal of pharmacogenomics : genomics-related research in drug development and clinical practice.

[37]  R. Coffman,et al.  Interleukin-10 and the interleukin-10 receptor. , 2001, Annual review of immunology.

[38]  M. Prevoo,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. , 1995, Arthritis and rheumatism.

[39]  B. Kirkham,et al.  Serial estimation of interleukin 6 as a measure of systemic disease in rheumatoid arthritis. , 1992, The Journal of rheumatology.

[40]  C. Werning.  [Rheumatoid arthritis]. , 1983, Medizinische Monatsschrift fur Pharmazeuten.

[41]  A. Larsen.  Radiological grading of rheumatoid arthritis. An interobserver study. , 1973, Scandinavian journal of rheumatology.

[42]  C. A. Fleming,et al.  The Acquisition of Data , 1969 .

[43]  D. Chaffee.  Statistical Analysis of , 1954 .