Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes
Lymphoid tyrosine phosphatase (LYP/PTPN22) Arg620Trp variant regulates insulin autoimmunity and progression to type 1 diabetes
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DOI：
10.1007/s00125-006-0225-4
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发表时间：
2006-06-01
期刊：
影响因子：
8.2
通讯作者：
Ilonen, J
中科院分区：
文献类型：
--
作者：
Hermann, R;Lipponen, K;Ilonen, J
目的/假设：我们分析了淋巴样蛋白酪氨酸磷酸酶（LYP） Arg620Trp变异（对应于PTPN22 C1858T多态性）在人类β细胞特异性体液自身免疫的出现和发展为1型糖尿病中的作用。我们还探讨了这种多态性在已知疾病位点、性别和发病年龄之间的疾病易感效应的异质性。研究对象和方法：对HLA-DQB1导致疾病易感性增加的芬兰人群出生队列进行胰岛细胞自身抗体的监测，并对发现阳性的个体进行胰岛素（IAA）、谷氨酸脱羧酶和胰岛抗原-2自身抗体的检测（n=574，平均随访时间4.9年）。在病例对照和家族系列（546例患者，538例对照组，245个核心家庭）中分析基因相互作用对疾病易感性的影响。所有受试者均进行HLA DR-DQ、胰岛素基因（INS）、CTLA4和PTPN22 C1858T多态性分型。结果：PTPN22 1858TT基因型与IAA的出现相关（校正风险比=4.6,95% CI 2.4 ~ 9.0; p=0.000013）。PTPN22、INS和HLA-DRB1对IAA的发生有加性作用。1858TT和CT基因型增加了发生额外自身抗体或临床疾病的风险（风险比分别为4.1,95% CI 1.5-11.6; 1.6, 95% CI 1.1-2.4; p=0.003）。PTPN22对疾病易感性的强烈影响（p=2.1x10(-8)）在男性（p=0.021）和非dr4 - dq8 /低危HLA基因型的受试者中更为明显（p=0.0004）。结论/解释：在1型糖尿病的发病机制中，PTPN22 C1858T多态性的潜在机制似乎与胰岛素特异性自身免疫的调节有关。重要的是，它强烈影响从糖尿病前期到临床疾病的进展。
Aims/hypothesis: We analysed the contribution of the lymphoid protein tyrosine phosphatase (LYP) Arg620Trp variant (which corresponds to the PTPN22 C1858T polymorphism) to the emergence of beta-cell-specific humoral autoimmunity and progression to type 1 diabetes in man. We also explored the heterogeneity in the disease-predisposing effect of this polymorphism in relation to known disease loci, sex and age at disease onset. Subjects and methods: A population-derived Finnish birth cohort with increased disease susceptibility conferred by HLA-DQB1 was monitored for the appearance of islet cell autoantibodies, and individuals found to be positive were tested for autoantibodies against insulin (IAA), glutamic acid decarboxylase and islet antigen-2 (n=574; mean follow-up time 4.9 years). Gene interaction effects on disease susceptibility were analysed in case-control and family series (546 patients, 538 controls, 245 nuclear families). All subjects were typed for HLA DR-DQ, insulin gene (INS), CTLA4 and PTPN22 C1858T polymorphisms. Results: The PTPN22 1858TT genotype was associated with the appearance of IAA (adjusted hazard ratio=4.6, 95% CI 2.4-9.0; p=0.000013). PTPN22, INS and HLA-DRB1 had an additive effect on the emergence of IAA. The 1858TT and CT genotypes conferred an increased risk of developing additional autoantibodies or clinical disease (hazard ratio=4.1, 95% CI 1.5-11.6; and 1.6, 95% CI 1.1-2.4, respectively; p=0.003). The strong effect of PTPN22 on disease susceptibility (p=2.1x10(-8)) was more pronounced in males (p=0.021) and in subjects with non-DR4-DQ8/low-risk HLA genotypes (p=0.0004). Conclusions/interpretation: In the pathogenesis of type 1 diabetes the underlying mechanism of the PTPN22 C1858T polymorphism appears to involve regulation of insulin-specific autoimmunity. Importantly, it strongly affects progression from prediabetes to clinical disease.