Quantitative heritability of anti-citrullinated protein antibody-positive and anti-citrullinated protein antibody-negative rheumatoid arthritis.

OBJECTIVE The majority of genetic risk factors for rheumatoid arthritis (RA) are associated with anti-citrullinated protein antibody (ACPA)-positive RA, while far fewer genetic risk factors have been identified for ACPA-negative RA. This study was undertaken to quantify the contribution of genetic risk factors in general, and of the predisposing HLA-DRB1 shared epitope (SE) alleles in particular, to the ACPA-positive and ACPA-negative subsets of RA, by computing their heritability and assessing the contribution of the HLA SE alleles. METHODS One hundred forty-eight RA twin pairs, in which at least 1 twin of each pair had RA, were tested for ACPAs and typed for HLA-DRB1 genotypes. Heritability was assessed in a logistic regression model including a bivariate, normally distributed random effect, representing the contribution of unobserved genetic factors to RA susceptibility, with the correlation of the random effects fixed according to twin zygosity. The contribution of the HLA SE alleles to genetic variance was assessed using a similar model, except that estimates were based on genotype-specific population prevalences. RESULTS The heritability of RA among the twin pairs was 66% (95% confidence interval [95% CI] 44-75%). For ACPA-positive RA, the heritability was 68% (95% CI 55-79%), and for ACPA-negative RA it was 66% (95% CI 21-82%). Presence of the HLA SE alleles explained 18% (95% CI 16-19%) of the genetic variance of ACPA-positive RA but only 2.4% (95% CI 1.6-10%) of the genetic variance of ACPA-negative RA. CONCLUSION The heritability of ACPA-positive RA is comparable with that of ACPA-negative RA. These data indicate that genetic predisposition plays an important role in the pathogenesis of ACPA-negative RA, for which most individual genetic risk factors remain to be identified.

[1]  A S Rigby,et al.  Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. , 2000, Arthritis and rheumatism.

[2]  H C van Houwelingen,et al.  Estimation of Individual Genetic Effects from Binary Observations on Relatives Applied to a Family History of Respiratory Illnesses and Chronic Lung Disease of Newborns , 2000, Biometrics.

[3]  G. Pruijn,et al.  Autoantibodies to citrullinated antigens in (early) rheumatoid arthritis. , 2006, Autoimmunity reviews.

[4]  Wentian Li,et al.  STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. , 2007, The New England journal of medicine.

[5]  F. Breedveld,et al.  An independent role of protective HLA class II alleles in rheumatoid arthritis severity and susceptibility. , 2005, Arthritis and rheumatism.

[6]  A. Begovich,et al.  Association of the PTPN22 C1858T single-nucleotide polymorphism with rheumatoid arthritis phenotypes in an inception cohort. , 2005, Arthritis and rheumatism.

[7]  A. Silman,et al.  Twin concordance rates for rheumatoid arthritis: results from a nationwide study. , 1993, British journal of rheumatology.

[8]  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.

[9]  A. A. Drosos,et al.  Epidemiology of rheumatoid arthritis. , 2004, Autoimmunity reviews.

[10]  F. Breedveld,et al.  Autoantibodies to cyclic citrullinated peptides predict progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study. , 2004, Arthritis and rheumatism.

[11]  A. Silman,et al.  Quantifying the exact role of HLA-DRB1 alleles in susceptibility to inflammatory polyarthritis: results from a large, population-based study. , 1999, Arthritis and rheumatism.

[12]  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.

[13]  S. Cessie,et al.  Smoking is a risk factor for anti-CCP antibodies only in rheumatoid arthritis patients who carry HLA-DRB1 shared epitope alleles , 2005, Annals of the rheumatic diseases.

[14]  D. Kimpel.  Meta-analysis: Diagnostic Accuracy of Anti–Cyclic Citrullinated Peptide Antibody and Rheumatoid Factor for Rheumatoid Arthritis , 2008 .

[15]  Göran Hallmans,et al.  Antibodies against cyclic citrullinated peptide and IgA rheumatoid factor predict the development of rheumatoid arthritis. , 2003, Arthritis and rheumatism.

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

[17]  A. Jeffreys,et al.  Individual-specific ‘fingerprints’ of human DNA , 1985, Nature.

[18]  C. Clark,et al.  Anti-keratin antibodies in rheumatoid arthritis. , 1979, British medical journal.

[19]  Carolyn Pillers Dobler,et al.  Mathematical Statistics , 2002 .

[20]  Saskia le Cessie,et al.  A prediction rule for disease outcome in patients with recent-onset undifferentiated arthritis: how to guide individual treatment decisions. , 2007, Arthritis and rheumatism.

[21]  A. Begovich,et al.  Risk of progression from undifferentiated arthritis to rheumatoid arthritis: the effect of the PTPN22 1858T-allele in anti-citrullinated peptide antibody positive patients. , 2007, Rheumatology.

[22]  L. Alfredsson,et al.  A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. , 2006, Arthritis and rheumatism.

[23]  Lars Alfredsson,et al.  A Candidate Gene Approach Identifies the TRAF1/C5 Region as a Risk Factor for Rheumatoid Arthritis , 2007, PLoS Medicine.

[24]  R. Nienhuis,et al.  New Serum Factor in Patients with Rheumatoid Arthritis: The Antiperinuclear Factor * , 1964, Annals of the rheumatic diseases.

[25]  Andrew W. Roddam,et al.  Measurement Error in Nonlinear Models: a Modern Perspective , 2008 .

[26]  G. Salama,et al.  The cytokeratin filament-aggregating protein filaggrin is the target of the so-called "antikeratin antibodies," autoantibodies specific for rheumatoid arthritis. , 1993, The Journal of clinical investigation.

[27]  A. Syvänen,et al.  Association of a haplotype in the promoter region of the interferon regulatory factor 5 gene with rheumatoid arthritis. , 2007, Arthritis and rheumatism.

[28]  F. V. D. van den Hoogen,et al.  Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies. , 1998, The Journal of clinical investigation.

[29]  F. Breedveld,et al.  The HLA-DRB1 shared epitope alleles are primarily a risk factor for anti-cyclic citrullinated peptide antibodies and are not an independent risk factor for development of rheumatoid arthritis. , 2006, Arthritis and rheumatism.

[30]  D. Hall.  Measurement Error in Nonlinear Models: A Modern Perspective , 2008 .

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

[32]  C. Deighton,et al.  The contribution of H LA to rheumatoid arthritis , 1989 .

[33]  F. Breedveld,et al.  Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis , 2005, Arthritis research & therapy.

[34]  A. Hofman,et al.  Heritabilities of radiologic osteoarthritis in peripheral joints and of disc degeneration of the spine. , 1999, Arthritis and rheumatism.

[35]  D. F. Roberts,et al.  The contribution of HLA to rheumatoid arthritis. , 1989, Clinical genetics.

[36]  L. Alfredsson,et al.  Immunity to citrullinated proteins in rheumatoid arthritis. , 2008, Annual review of immunology.

[37]  P. Gregersen,et al.  Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. , 2007, American journal of human genetics.

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

[39]  F. Breedveld,et al.  Association of HLA-DR3 with anti-cyclic citrullinated peptide antibody-negative rheumatoid arthritis. , 2005, Arthritis and rheumatism.

[40]  C. Wijmenga,et al.  Association of STAT4 with rheumatoid arthritis: a replication study in three European populations. , 2008, Arthritis and rheumatism.

[41]  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.