The PADI4 SNPs and haplotypes were associated with RA susceptibility, although no relation was observed between the PADI4 haplotypes and anti-MCV levels.
<b>Conclusion</b>: Serum capacity to activate PAD4 was associated with ACPA and RF positivity and earlier disease onset in early RA patients, and decreased after initiation of DMARD treatment, indicating that anti-PAD treatment could potentially be beneficial in RA.
Human peptidylarginine deiminase type IV (PAD4), a Ca(2+)-dependent enzyme known to convert arginine residues to citrulline residues in histones, has been shown to be associated with the development of rheumatoid arthritis.
The prevalence of anti-PAD4 antibodies in RA is similar to the prevalence described in other populations and these autoantibodies are associated with disease duration and anti-CCP in RA.
We review herein recent advances in the genetics of RA and discuss the underlying differences among populations of European and Asian ancestries, taking as examples our previous findings for RA-susceptibility genes in the Japanese population: PADI4; FCRL3; and CD244.
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.
Further, granulocytes treated with Gal-9 upregulated expression of peptidyl arginine deiminase 4 (PAD-4), a key enzyme required for RA-associated citrullination of proteins.
Unlike several other risk genes for RA such as PTPN22, PADI4, and FCRL3, a haplotype of the STAT4 gene shows consistent association with RA susceptibility across Whites and Asians, suggesting that this risk haplotype predates the divergence of the major racial groups.
Meta-analysis of published studies and our new data confirmed a highly significant association between PADI4 gene SNPs and increased risk of RA in East Asian populations (allele fixed-effects summary OR 1.31, 95% CI 1.22-1.41, P<0.0001).
A strong linkage between PADI4 polymorphism and rheumatoid arthritis has been found in Japanese and Korean patients, but there is no association study about PADI4 in AS.
Gene-gene interactions between the homozygous RA-risk PADI4 haplotype and SE alleles were significant in both anti-CCP-positive (AP 0.45, 95% CI 0.20 to 0.71) and -negative RA (AP 0.61, 95% CI 0.29 to 0.92).
PADI4 polymorphism highly predisposes male smokers to RA, and the genetic heterogeneity observed between Asian and European populations may be partly explained by differences in smoking prevalence among men.
Herein, we further investigate whether RA risk PADI4 haplotype (SNP PADI4; S55G, A82V and A112G) and the increase of its enzymatic activity induce apoptosis.
Increased RA susceptibility was significantly associated with the minor alleles of padi4_89 (P = 2.3 x 10(-5)), padi4_90 (P = 2.3 x 10(-5)), padi4_92 (P = 2.1 x 10(-5)), and padi4_104 (P = 1.1 x 10(-3)) and the haplotype carrying the 4 minor alleles (P = 1.0 x 10(-4)).
This work demonstrates the existence of PAD4-specific T cells in patients with RA and supports a mechanistic role for GrB in enhancing the presentation of autoantigenic CD4+ T cell epitopes.