Evaluation of three different polymorphisms of PTPN22 in rheumatoid arthritis
(English)Manuscript (preprint) (Other academic)
Objectives To compare the associations of three SNPs (rs3811021, rs2476601 (1858C/T) and rs2488457 (-1123G/C)) of the PTPN22 gene: in patients with RA and to analyse functional properties of the 1858T allele.
Methods A total of 769 consecutively included patients with early RA and 1054 population-based matched controls were genotyped for the rs3811021, rs2476601, and rs2488457 polymorphisms using a TaqMan instrument. T-lymphocytes from RA patients, SLE patients and controls, heterozygous for the +1858T allele were compared with cells homozygous for +1858C. The T-cells were cultivated in the presence or absence of either PMA/Ionomycine or antibodies to CD3ε and CD28. Cell activation was quantified by measuring levels of interleukin-2 produced using an ELISA.
Results The -1123C and 1858T alleles were associated with RA (OR=1.35(1.14-1.60), p=0.0004 and OR=1.65(1.35-2.01), p=3x10-6, respectively). These associations, together with a haplotype containing both risk alleles, retained statistical significance after conducting a permutation test. The SNPs -1123G/C and 1858C/T were in strong linkage disequilibrium (LD), however, the 1858T allele was mainly associated with HLA-SE, IgM-RF or ACPA positive RA whereas the -1123C allele was associated regardless of any stratification of the patient group. Patients having both -1123C and 1858T had significantly higher frequency of HLA-SE (OR=2.03(1.29-3.19)) and ACPA (OR=2.21(1.38-3.53)) compared with patients having -1123C but not 1858T. In the functional study, the 1858T allele was not shown to increase the negative regulation of T-lymphocyte activation compared with 1858C in either patients or controls.
Conclusions The true association with RA was seen with the 1858T allele. The -1123C allele was only associated with RA through being in LD with the 1858T allele. The 1858T allele was associated with HLA-SE positive and ACPA positive RA whereas the -1123C allele was associated regardless of stratification. The proposed function of the 1858T allele could not be shown using this experimental protocol.
Rheumatoid arthritis, PTPN22, SNP, 1858T, -1123C. haplotype, functional study, T-lymphocyte
Rheumatology and Autoimmunity
Research subject Medicine
IdentifiersURN: urn:nbn:se:umu:diva-30387OAI: oai:DiVA.org:umu-30387DiVA: diva2:282537