CTLA-4 +49\u2009G/A, a functional T1D risk SNP, affects CTLA-4 level in Treg subsets and IA-2A positivity, but not beta-cell function

Yang Chen,Mei Zhang,Yingjie Feng,Heng Chen,Zhixiao Wang,Xinyu Xu,Qi Fu,Shuai Zheng,Yun Cai,Yong Gu,Yun Shi,Tao Yang,Kuanfeng Xu,Hao Dai,Shu Chen,Min Sun

doi:10.1038/s41598-018-28423-9

Yang Chen, Mei Zhang + Show 14 more

Open Access

https://doi.org/10.1038/s41598-018-28423-9

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Abstract

To investigate whether CTLA-4 +49 G/A (rs231775), a tagSNP in Asian, is a functional T1D SNP, we genotyped this SNP with 1035 T1D patients and 2575 controls in Chinese Han population. And 1280 controls measured insulin release and sensitivity based on an oral glucose tolerance test; 283 newly diagnosed T1D patients assayed C-peptide level based on a mixed-meal tolerance test. 31 controls were analyzed for different T cell subsets by multi-color flow cytometry. Under additive model, we found that CTLA-4 +49 G/A was significantly associated with T1D (P = 2.82E-04, OR = 1.25, 95% CI: 1.12–1.41), which was further confirmed by meta-analysis (P = 1.19E-08, OR = 1.65, 95% CI: 1.38–1.96) in Chinese Han population. Although we did not find any association between this SNP and beta-cell function in either healthy individuals or newly diagnosed T1D patients, healthy individuals carrying GG/GA genotypes had lower CTLA-4 expression in naïve or activated CD4 Treg subsets (P = 0.0046 and 0.0317 respectively). A higher positive rate of IA-2A was observed among T1D patients with GG genotype compared with AA (OR = 0.51, 95% CI: 0.30–0.84, p = 0.008). Collectively, CTLA-4 +49 G/A reached a GWAS significant association with T1D risk in Chinese Han population, affects CTLA-4 expression in Treg subsets and subsequently humoral immunity in T1D patients.

Highlights

Common single nucleotide polymorphisms (SNPs) in CTLA-4 have been found to have a role in susceptibility to autoimmune diseases in different populations, such as type 1 diabetes, celiac disease and rheumatoid arthritis[12,13,14,15]
As studies were not enough to perform a meta-analysis for CT60, we only assessed the association for CTLA-4 +49 G/A
Our results indicated that +49 G/A was associated with T1D risk at a GWAS significance (P = 1.19E-08, odds ratio (OR) = 1.65, 95% confidence interval (CI): 1.38–1.96) (Figure S2)

Summary

Introduction

Common single nucleotide polymorphisms (SNPs) in CTLA-4 have been found to have a role in susceptibility to autoimmune diseases in different populations, such as type 1 diabetes, celiac disease and rheumatoid arthritis[12,13,14,15]. The significance of CTLA-4 +49 G/A and CT60 SNPs with T1D risk in Chinese Han population remains elusive, as previous studies were mostly conducted on smaller size, and were less powerful with conflicting findings. We investigated the possible association between CTLA-4 +49 G/A, CT60 and T1D risk in a Chinese Han population. We assessed their impacts on glycemic traits based on an oral glucose tolerance test (OGTT) in healthy individuals and residual C-peptide levels in newly diagnosed T1D patients, and their www.nature.com/scientificreports/. Influences on quantitative changes of CTLA-4 expression in different T cell subsets and autoantibody positivity during T1D development

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