The PTPN22 1858C/T polymorphism is associated with anti-cyclic citrullinated peptide antibody-positive early rheumatoid arthritis in northern Sweden

Abstract

The PTPN22 1858C/T polymorphism has been associated with several autoimmune diseases including rheumatoid arthritis (RA). We have shown that carriage of the T variant (CT or TT) of PTPN22 in combination with anti-cyclic citrullinated peptide (anti-CCP) antibodies highly increases the odds ratio for developing RA. In the present study we analysed the association between the PTPN22 1858C/T polymorphism and early RA in patients from northern Sweden, related the polymorphism to autoantibodies and the HLA-DR shared epitope, and analysed their association with markers for disease activity and progression. The inception cohort includes individuals who also donated samples before disease onset. A case-control study was performed in patients (n = 505; 342 females and 163 males) with early RA (mean duration of symptoms = 6.3 months) and in population-based matched controls (n = 970) from northern Sweden. Genotyping of the PTPN22 1858C/T polymorphism was performed using a TaqMan instrument. HLAshared epitope alleles were identified using PCR sequencespecific primers. Anti-CCP2 antibodies were determined using enzyme-linked immunoassays. Disease activity (that is, the number of swollen and tender joints, the global visual analogue scale, and the erythrocyte sedimentation rate) was followed on a regular basis (that is, at baseline and after 6, 12, 18 and 24 months). Both the 1858T allele and the carriage of T were associated with RA (χ 2 = 23.84, P = 0.000001, odds ratio = 1.69, 95% confidence interval = 1.36-2.11; and χ 2 = 22.68, P = 0.000002, odds ratio = 1.79, 95% confidence interval = 1.40-2.29, respectively). Association of the 1858T variant with RA was confined to seropositive disease. Carriage of 1858T and the presence of anti-CCP antibodies was independently associated with disease onset at an earlier age (P < 0.05 and P < 0.01, respectively), while the combination of both resulted in an even earlier age at onset. Smoking was identified as a risk factor independent of the 1858T variant and anti-CCP antibodies.

Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue

“…Five RA case-control studies based on anti-CCP antibody status were recruited for the meta-analysis. 18,22,28,40,101 The results showed a strong association between the T allele and anti-CCP þ RA (OR ¼ 1.78; 95% CI ¼ 1.59-2.01, Po1.00 Â 10 Figure 1b).…”

“…The highest T allele frequency (17.5%) was reported in northeast Russia, 14 followed by Finland (15.4%), 15 Ukraine (14.1%) 16 and Estonia (13.9%). 17 The frequency decreased toward the west, showing 11-13% in Poland, [18][19][20] 10-12% in Sweden, [21][22][23] Norway [24][25][26] and Germany, 24,[27][28][29] 11.7% in Croatia, 10-11% in the Czech Republic, 30,31 10.7% in Slovakia, 32 9.2% in Denmark, 33 and 8-10% in the UK [34][35][36][37][38][39] and the Netherlands. 24,[40][41][42] The decrease in the frequency toward the south was dramatic, with 7.75% in Hungary, 43 7.23% in Belgium, 7-8% in France, 44,45 5-7% in Spain 46-48 and 4.1% in Romania.…”

“…In total, 36 case-control studies were recruited for the present study with ORs ranging from 0.99 to 2.56. 3,14,15,18,22,24,26,28,32,35,[39][40][41][42]54,60,67,[92][93][94][95][96][97][98][99][100][101][102][103] Thirty-one out of thirty-six showed a significant association between PTPN22 and RA. Meta-analysis showed a strong association between the T allele and RA (OR ¼ 1.65; 95% CI ¼ 1.58-1.71, Po1.00 Â 10 À 16 ) (Figure 2b).…”

Anti-Cyclic Citrullinated Peptide Antibodies in Rheumatoid Arthritis and Behcet's Disease

“…Genetic differences may be the reason for this relatively lower prevalence. The protein tyrosine phosphatase (PTPN22) 1858C/T polymorphism has been reported to be associated with anti-CCP antibody positivity in early RA in a study from Northern Sweden (Kokkonen et al 2007). However, preliminary data from a recent study from Turkey has shown that PTPN22 polymorphism is not related with RA (the data presented in the 2007 Annual Turkish National Rheumatology Congress).…”

“…However, as genetic differences and environmental factors may alter the anti-CCP antibody positivity (van Gaalen et al 2004;Furuya et al 2007;Kokkonen et al 2007;Verpoort et al 2007), the aims of the present study were directed to evaluate the frequency of anti-CCP antibody positivity in Turkish patients Stored sera were tested for anti-CCP antibodies by ELISA using a second-generation commercial assay kit (Euroimmun, Lubeck, Germany). The ELISA was carried out according to the manufacturer's instructions with a cut-off value of 5.01 units.…”