Heneberg Petr, Malá Milena, Yorifuji Tohru, Gat-Yablonski Galia, Lebenthal Yael, Tajima Toshihiro, Nogaroto Viviane, Rypáčková Blanka, Kocková Lucie, Urbanová Jana, Anděl Michal
Third Faculty of Medicine, Charles University in Prague, Prague, Czech Republic.
Int Arch Allergy Immunol. 2015;166(3):189-98. doi: 10.1159/000380853. Epub 2015 Apr 18.
The protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene encodes lymphoid tyrosine phosphatase (LYP), which is expressed primarily in lymphoid tissues. The functional but geographically highly variable PTPN22 single-nucleotide polymorphisms (SNPs), particularly c.1858C>T, contribute to the onset and progression of autoimmunity-associated diseases and facilitate the expression of disease-associated autoantibodies. In Central Europe, 17-25% of patients with monogenic diabetes (maturity-onset diabetes of the young, MODY) transiently express islet cell autoantibodies.
We addressed the links between the functional and geographically variable PTPN22 SNPs with MODY manifestation and the expression of islet cell autoantibodies in 276 MODY patients who originated from four regions (the Czech Republic, Israel, Japan and Brazil).
The frequency of PTPN22 polymorphisms in the MODY patients was similar to those in geographically matched healthy populations, with the exception of c.788G>A, the minor allele frequency of which was significantly elevated in the Czech hepatocyte nuclear factor 1-α (HNF1A) MODY patients [odds ratio (OR) 4.8, 95% confidence interval (CI) 2.2-10.7] and the Brazilian MODY patients (OR 8.4, 95% CI 1.8-39.1). A barely significant increase in the c.788G>A minor allele was also detected in the islet cell autoantibody-positive Czech MODY patients. However, c.788A behaves as a loss-of-function mutant in T cells, and thus protects against autoimmunity.
MODY patients (including islet cell autoantibody-positive cases) do not display any increase in autoimmunity-associated PTPN22 alleles. The absence of autoimmunity-associated PTPN22 alleles was also demonstrated in latent autoimmune diabetes in adults, which suggests that the slow kinetics of the onset of autoantibodies is subject to a regulation that is different from that experienced in type 1 diabetes and other autoimmune disorders.
蛋白酪氨酸磷酸酶非受体22型（PTPN22）基因编码淋巴细胞酪氨酸磷酸酶（LYP），其主要在淋巴组织中表达。功能性但在地理分布上高度可变的PTPN22单核苷酸多态性（SNP），尤其是c.1858C>T，与自身免疫相关疾病的发生和发展有关，并促进疾病相关自身抗体的表达。在中欧，17%至25%的单基因糖尿病患者（青年发病的成年型糖尿病，MODY）会短暂表达胰岛细胞自身抗体。
我们研究了功能性且地理分布可变的PTPN22 SNP与MODY表现以及276例来自四个地区（捷克共和国、以色列、日本和巴西）的MODY患者胰岛细胞自身抗体表达之间的联系。
MODY患者中PTPN22多态性的频率与地理匹配的健康人群相似，但c.788G>A除外，其次要等位基因频率在捷克的肝细胞核因子1-α（HNF1A）MODY患者中显著升高[比值比（OR）4.8，95%置信区间（CI）2.2 - 10.7]，在巴西的MODY患者中也显著升高（OR 8.4，95% CI 1.8 - 39.1）。在胰岛细胞自身抗体阳性的捷克MODY患者中也检测到c.788G>A次要等位基因略有显著增加。然而，c.788A在T细胞中表现为功能丧失突变体，因此可预防自身免疫。
MODY患者（包括胰岛细胞自身抗体阳性病例）在与自身免疫相关的PTPN22等位基因方面没有任何增加。在成人隐匿性自身免疫性糖尿病中也证实不存在与自身免疫相关的PTPN22等位基因，这表明自身抗体产生的缓慢动力学受到一种与1型糖尿病和其他自身免疫性疾病不同的调节。
