Mutation screening of PTPN22: association of the 1858T-allele with Addison's disease

Abstract

The tyrosine-protein phosphatase non-receptor type 22 (PTPN22) gene was recently identified as an important genetic susceptibility factor in several autoimmune diseases. The increased risk has been broadly explained by the 1858T-allele (rs2476601). As two smaller studies on Addison's disease (AD) have shown diverging results, we aimed to elucidate the predisposing effect of the single-nucleotide polymorphism (SNP) 1858CT in a larger population of AD patients, especially focusing on the AD patients with known autoimmune etiology. We also screened for unknown rare or common variants in the PTPN22 gene that could predispose for AD. The case-control study of Norwegian AD patients (n ¼ 332) and controls (n ¼ 990) showed a significant association between autoimmune AD (n ¼ 302) and the PTPN22 1858T risk allele (P ¼ 0.016). The association of AD with 1858T was supported by a meta-analysis combining our genotype data with that of others published previously (P ¼ 0.003). The mutation screening of PTPN22 in AD patients (n ¼ 332) and controls (n ¼ 112) revealed eight missense variants, five of which have not been reported previously. In conclusion, the 1858T-allele is a PTPN22 genetic susceptibility factor for autoimmune AD. Other rare variants in PTPN22 do occur, and may also be involved in the pathogenesis.

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

“…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.…”

“…Three showed a significant association, whereas the other three studies showed a tendency toward a positive association but failed to reach the significance threshold. 25,87,109,110 Meta-analysis showed a significant association between the T allele and Addison's disease (OR ¼ 1.43; 95% CI ¼ 1.21-1.68, P ¼ 2.36 Â 10 À 5 ) (Figure 2e). Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis includes Wegener's granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome.…”

Autoimmunity to Steroid-Producing Cells

“…The CTLA-4 gene polymorphism and the PTPN22 gene polymorphism have been found to modulate genetic risk for AAD (Falorni et al, 2008;Skinningsrud et al, 2008a). A recent metanalysis of European studies has confirmed that the CTLA-4 Ala 17 polymorphism is strongly associated with genetic risk for AAD, independentenly from the well known association with the polymorphism of HLA class II genes (Brozzetti et al, 2010b).…”

PTPN22 polymorphisms associated with type 1 diabetes mellitus in ethnic populations of Russian Federation

“…1, G788A, rs33996649, MAF≈2% (minor allele frequencies) внутри каталитиче-ского домена PTPN22 приводит к уменьшению фосфа-тазной активности и ассоциирована с уменьшенным риском возникновения системной красной волчанки (СКВ) [15]. Протективные свойства аллеля Q 263 рас-пространяются и на болезнь Адиссона [16], но не диа-бет первого типа [17]. Первые сообщения об ассоциации с СД1 полиморфизма R620W (C1858T, rs2476601) были опубликованы в 2004 г.…”