Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis

Abstract

Individuals with rheumatoid arthritis frequently have autoantibodies to citrullinated peptides, suggesting the involvement of the peptidylarginine deiminases citrullinating enzymes (encoded by PADI genes) in rheumatoid arthritis. Previous linkage studies have shown that a susceptibility locus for rheumatoid arthritis includes four PADI genes but did not establish which PADI gene confers susceptibility to rheumatoid arthritis. We used a case-control linkage disequilibrium study to show that PADI type 4 is a susceptibility locus for rheumatoid arthritis (P = 0.000008). PADI4 was expressed in hematological and rheumatoid arthritis synovial tissues. We also identified a haplotype of PADI4 associated with susceptibility to rheumatoid arthritis that affected stability of transcripts and was associated with levels of antibody to citrullinated peptide in sera from individuals with rheumatoid arthritis. Our results imply that the PADI4 haplotype associated with susceptibility to rheumatoid arthritis increases production of citrullinated peptides acting as autoantigens, resulting in heightened risk of developing the disease.

Haplotypes of PADI4 susceptible to rheumatoid arthritis are also associated with ulcerative colitis in the Japanese population

“…However, the rare frequent haplotypes, Hap 5, Hap 6, and Hap 7, were excluded in Tables 2 and 3. The frequencies and distributions of haplotypes in our study population corresponded to that in previous studies on association with RA in other Japanese populations (10,20). These results imply that the population studied had a homogeneous genetic background.…”

“…Recently, peptidylarginine deiminase type 4 (PADI4) located at 1p36 is identified as Czin 6 the rheumatoid arthritis (RA)-susceptible gene (10). RA is involved in autoimmune diseases, of which pathoetiology is probably similar to UC in a number of respects with not only mechanisms of immune defense abnormalities, such as the elevated production of autoantibody (1,2), but also arthritic manifestations, e.g.…”

“…Although RA complicated by UC is uncommon, recent report has described the development of UC in patients with RA (12). More importantly, PADI4 also lies within the IBD-susceptibility locus (IBD7) (8)(9)(10).…”

A genome‐wide scan for juvenile rheumatoid arthritis in affected sibpair families provides evidence of linkage

“…Multiple investigations have suggested linkage for chromosome region 1p36 in lupus (24)(25)(26), celiac disease (27), inflammatory bowel disease (28), and RA (29,30). This region was delineated further in adult RA using a case-control association design of single-nucleotide polymorphisms, resulting in a functional haplotype associated with RA that includes the gene PADI4 (31). This gene encodes a citrullinating enzyme that has been functionally associated with the production of RAspecific antibodies (32) and is also present in JRA, including some of the patients in our study cohort.…”

Inhibitors and Inactivators of Protein Arginine Deiminase 4: Functional and Structural Characterization,

“…IC 50 values were determined by fitting the concentration-response data to eq 1 fractional activity of PAD4 = 1 / (1 + [I] / IC 50 ) (1) using Grafit version 5.0.11 (28). The concentration of an inhibitor that corresponds to the midpoint (fractional activity = 0.5) is termed the IC 50 ; [I] is the concentration of inhibitor or inactivator.…”