title: Non-HLA genes PTPN22, CDK6 and PADI4 are associated with specific autoantibodies in HLA-defined subgroups of rheumatoid arthritis.
abstract: BACKGROUND
  Genetic susceptibility to complex diseases has been intensively studied during the last decade, yet only signals with small effect have been found leaving open the possibility that subgroups within complex traits show stronger association signals. In rheumatoid arthritis (RA), autoantibody production serves as a helpful discriminator in genetic studies and today anti-citrullinated cyclic peptide (anti-CCP) antibody positivity is employed for diagnosis of disease. The HLA-DRB1 locus is known as the most important genetic contributor for the risk of RA, but is not sufficient to drive autoimmunity and additional genetic and environmental factors are involved. Hence, we addressed the association of previously discovered RA loci with disease-specific autoantibody responses in RA patients stratified by HLA-DRB1*04.
  
  
  METHODS
  We investigated 2178 patients from three RA cohorts from Sweden and Spain for 41 genetic variants and four autoantibodies, including the generic anti-CCP as well as specific responses towards citrullinated peptides from vimentin, alpha-enolase and type II collagen.
  
  
  RESULTS
  Our data demonstrated different genetic associations of autoantibody-positive disease subgroups in relation to the presence of DRB1*04. Two specific subgroups of autoantibody-positive RA were identified. The SNP in PTPN22 was associated with presence of anti-citrullinated enolase peptide antibodies in carriers of HLA-DRB1*04 (Cochran-Mantel-Haenszel test P = 0.0001, P corrected <0.05), whereas SNPs in CDK6 and PADI4 were associated with anti-CCP status in DRB1*04 negative patients (Cochran-Mantel-Haenszel test P = 0.0004, P corrected <0.05 for both markers). Additionally we see allelic correlation with autoantibody titers for PTPN22 SNP rs2476601 and anti-citrullinated enolase peptide antibodies in carriers of HLA-DRB1*04 (Mann Whitney test P = 0.02) and between CDK6 SNP rs42041 and anti-CCP in non-carriers of HLA-DRB1*04 (Mann Whitney test P = 0.02).
  
  
  CONCLUSIONS
  These data point to alternative pathways for disease development in clinically similar RA subgroups and suggest an approach for study of genetic complexity of disease with strong contribution of HLA.
authors.forename: Omri
authors.initials: O
authors.lastname: Snir
authors.forename: David
authors.initials: D
authors.lastname: Gomez-Cabrero
authors.forename: Ariana
authors.initials: A
authors.lastname: Montes
authors.forename: Eva
authors.initials: E
authors.lastname: Perez-Pampin
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Gómez-Reino
authors.forename: Maria
authors.initials: M
authors.lastname: Seddighzadeh
authors.forename: Katharina U
authors.initials: KU
authors.lastname: Klich
authors.forename: Lena
authors.initials: L
authors.lastname: Israelsson
authors.forename: Bo
authors.initials: B
authors.lastname: Ding
authors.forename: Anca I
authors.initials: AI
authors.lastname: Catrina
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Jesper
authors.initials: J
authors.lastname: Tegnér
authors.forename: Antonio
authors.initials: A
authors.lastname: Gonzalez
authors.forename: Vivianne
authors.initials: V
authors.lastname: Malmström
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
mesh_terms: D001172:Arthritis, Rheumatoid / Q000097:blood / Q000235:genetics* / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D020022:Genetic Predisposition to Disease; D005838:Genotype; D059811:HLA-DRB1 Chains / Q000235:genetics / Q000276:immunology; D006801:Humans; D006867:Hydrolases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D059811:HLA-DRB1 Chains; C527195:HLA-DRB1*04 antigen; C495911:CDK6 protein, human; D051361:Cyclin-Dependent Kinase 6; D006867:Hydrolases; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases