Detailed analysis of the variability of peptidylarginine deiminase type 4 in German patients with rheumatoid arthritis: a case control study

Peptidylarginine deiminase type 4 (PADI4) genotypes were shown to
influence susceptibility to rheumatoid arthritis ( RA) in the
Japanese population. Such an association could not previously be
confirmed in different European populations. In the present study,
we analysed exons 2 - 4 of PADI4 in 102 German RA patients and 102
healthy individuals to study the influence of PADI4 variability on
RA susceptibility by means of haplotype-specific DNA sequencing.
Analyses of the influence of PADI4 and HLA-DRB1 genotypes on
disease activity and on levels of anti-cyclic citrullinated peptide
antibodies were performed. Comparing the frequencies of PADI4
haplotype 4 (padi4\_89* G, padi4\_90* T, padi4\_92* G, padi4\_94*
T, padi4\_104* C, padi4\_95* G, padi4\_96* T) ( patients, 14.7%;
controls, 7.8%; odds ratio = 2.0, 95% confidence interval = 1.1 -
3.8) and carriers of this haplotype ( patients, 27.5%; controls,
13.7%; odds ratio = 2.4, 95% confidence interval = 1.2 - 4.8), a
significant positive association of PADI4 haplotype 4 with RA could
be demonstrated. Other PADI4 haplotypes did not differ
significantly between patients and controls. Regarding the
individual PADI4 variants, padi4\_89 ( A. G), padi4\_90 (C -->
T), and padi4\_94 (C --> T) were significantly associated with
RA ( patients, 49.5%; controls, 38.7%; odds ratio = 1.6, 95%
confidence interval = 1.1 - 2.3). Considering novel PADI4 variants
located in or near to exons 2, 3, and 4, no quantitative or
qualitative differences between RA patients (8.8%) and healthy
controls (10.8%) could be demonstrated. While the PADI4 genotype
did not influence disease activity and the anticyclic citrullinated
peptide antibody level, the presence of the HLA-DRB1 shared epitope
was significantly associated with higher anti-cyclic citrullinated
peptide antibody levels ( P = 0.033). The results of this small
case - control study support the hypothesis that variability of the
PADI4 gene may influence susceptibility to RA in the German
population. Quantitative or qualitative differences in previously
undefined PADI4 variants between patients and controls could not be
demonstrated.