Further research on PADI4, its citrullination of native peptides, subsequent breakdown of tolerance, and the role of these peptides in the development of RA, is expected to bring a better understanding of autoimmunity and arthritis, and advancements in the medical care of RA.
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.
Recent advances in the analysis of genetic polymorphisms associated with disease have identified several genes linked to RA susceptibility that encode proteins involved in the immune response to Mycobacterium tuberculosis infection, including TNF-alpha, NRAMP1, PARP-1, HLA-DRB1, and PADI4.
Association with four exonic SNPs (padi4_89*G/A, padi4_90*T/C, padi4_92*G/C, and padi4_104*T/C), mapping to the PADI4 gene and defining a haplotype previously reported to be associated with rheumatoid arthritis, was investigated.
Several multiple, large-scale, genetic studies on autoimmune-disease-associated SNPs have been reported recently: peptidylarginine deiminase type 4 (PADI4) in rheumatoid arthritis (RA); solute carrier family 22 members 4 and 5 (SLC22A4 and 5) in RA and Crohn's disease (CD); programmed cell death 1 (PDCD1) in systemic lupus erythematosus (SLE), type 1 diabetes mellitus (T1D), and RA; and protein tyrosine phosphatase nonreceptor type 22 (PTPN22) in T1D, RA, and SLE.
To test the hypothesis that the PADI4 gene may confer susceptibility to rheumatoid arthritis in a white French population, using powerful and highly reliable family based association tests.
The present study was undertaken to further investigate the association of PADI4 with RA, using a series of population-based samples from subjects with the same ethnic background as the subjects in the original study.
Here, we investigate whether human PADI4 can inhibit antithrombin by catalysing antithrombin citrullination and how the enzyme is involved in RA pathogenesis.
Functional haplotypes of PADI4: relevance for rheumatoid arthritis specific synovial intracellular citrullinated proteins and anticitrullinated protein antibodies.
The results of our group and from the British and French studies strongly suggest that polymorphisms of the PADI4 gene do not play a role in susceptibility to RA in European populations.
Recent reports on the high specificity of autoantibodies against citrullinated proteins to RA and the results of our study suggest that citrullination by PADI4 is a fundamental phenomenon of RA.
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.
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.