The association between rs1893217, rs478582 in PTPN2 and T1D risk with different diagnosed age, and related clinical characteristics in Chinese Han population

Abstract

Objective: To investigate the association between polymorphisms in PTPN2 (rs1893217 and rs478582) and type 1 diabetes (T1D) risk with different diagnosed age, as well as related clinical characteristics in Chinese Han population.

Methods: A total of 2270 Chinese Han individuals (1023 T1D patients and 1247 healthy controls) were genotyped for rs1893217 and rs478582. And 306 newly diagnosed T1D patients were measured for C-peptide levels based on a standard mixed-meal tolerance test. In addition, 40 healthy controls were analyzed for different T cell subsets by multi-color flow cytometry.

Results: Neither rs1893217 nor rs478582 showed any association with T1D risk under an additive model. Stratified analysis for T1D diagnosed age revealed that rs1893217, but not rs478582, was significantly associated with T1D patients diagnosed age ≤18 (OR =0.80, 95% CI: 0.67–0.97, p = 0.02). For those diagnosed age >18, neither of them showed any association. We also found that rs1893217 had a higher positive rate of ZnT8A (CC vs. TT carrier, OR = 2.07, 95% CI: 1.07–4.03, p = 0.026) and IA-2A (CT vs. TT carrier, OR = 1.36, 95% CI: 1.02–1.80, p = 0.038). Furthermore, for rs478582, compared with TT, healthy individuals carrying CC/CT carriers had significantly lower frequency and Helios expression of naive Treg subsets (p = 0.049 and 0.048 respectively), but not secreting or activating Treg subsets. In addition, we did not find any association between these two polymorphisms and residual β-cell function in newly diagnosed T1D patients.

Conclusions: Our results suggest that rs1893217 may increase the risk of early-onset T1D and affect humoral immunity, while rs478582 may affect Treg subsets.

Keywords:

• type 1 diabetes
• PTPN2
• polymorphism

Acknowledgements

We thank Dr S Alice Long at Benaroya Research Institute at Virginia Mason, Seattle, WA, US for Treg subsets panel development. We also thank Dr Meng Zhu at Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University for data analysis.

Author contributions

Kuanfeng Xu directed the study design, performed statistical analysis and interpretation of data, drafted the initial manuscript and revised the manuscript. Shu Chen performed statistical analyses and drafted the initial manuscript. Yinjie Feng and Yuyue Zhang were responsible for data analysis and various versions of the paper. Hongqi Fan, Yang Chen, Yong Gu, Yun Shi, Hao Dai, and Mei Zhang contributed to collection and selection of samples. Xinyu Xu and Heng Chen commented on various versions of the paper, and suggested revisions. Tao Yang directed the study design, and critical revision of the manuscript. All the coauthors gave final approval of the version.

Disclosure statement

The authors declare that there is no duality of interest associated with this manuscript.

Additional information

Funding

The study was supported by grants from the National Natural Science Foundation of China (81670715 and 81270897), Key Program of National Natural Science Foundation of China (81530026), the National Key Project of Research and Development Plan (2016YFC1305000), Jiangsu Province Youth Medical talents Project (QNRC2016584), the Jiangsu Province Key Science and Technology Development Project (BE2017753), Jiangsu Provincial Special Program of Medical Science (BL2012026), the Natural Science Foundation of Jiangsu province (BK2012486), Jiangsu Government Scholarship for Overseas Studies (JS-2013-260), and the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).