Association of Cytotoxic T-Lymphocyte-Associated Protein 4 (CTLA4) Gene Polymorphisms with Autoimmune Thyroid Disease in Children and Adults: Case-Control Study.

Wei‐Hsin Ting ,Bi-Wen Cheng,Chon-In Chan,Chia-Ching Chen,Chen-Mei Hung,Hsin-Jung Li,Yann-Jinn Lee,Ya-Ping Lien,Ming-Nan Chien,Chiung‐Ling Lin ,Yi-Hsin Wu ,Wenshan Lin ,Chao‐Hsu Lin ,Chao Hung Wang ,Weifang Chen ,Fu‐Sung Lo ,Chi‐Yu Huang ,Tzu‐Yang Chang ,Horng‐Woei Yang

doi:10.1371/journal.pone.0154394

Abstract

Autoimmune thyroid disease (AITD), including Graves disease (GD) and Hashimoto disease (HD), is an organ-specific autoimmune disease with a strong genetic component. Although the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) polymorphism has been reported to be associated with AITD in adults, few studies have focused on children. The aim of our study was to investigate whether the CTLA4 polymorphisms, including -318C/T (rs5742909), +49A/G (rs231775), and CT60 (rs3087243), were associated with GD and HD in Han Chinese adults and children. We studied 289 adult GD, 265 pediatric GD, 229 pediatric HD patients, and 1058 healthy controls and then compared genotype, allele, carrier, and haplotype frequencies between patients and controls. We found that CTLA4 SNPs +49A/G and CT60 were associated with GD in adults and children. Allele G of +49A/G was significantly associated with GD in adults (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.21–1.84; corrected P value [Pc] < 0.001) and children (OR, 1.42; 95% CI, 1.15–1.77; Pc = 0.002). Allele G of CT60 also significantly increased risk of GD in adults (OR, 1.63; 95% CI, 1.27–2.09; Pc < 0.001) and GD in children (OR, 1.58; 95% CI, 1.22–2.04; Pc < 0.001). Significant linkage disequilibrium was found between +49A/G and CT60 in GD and control subjects (D’ = 0.92). Our results showed that CTLA4 was associated with both GD and HD and played an equivalent role in both adult and pediatric GD in Han Chinese population.

Highlights

Autoimmune thyroid disease (AITD), including Graves disease (GD) and Hashimoto disease (HD), is an organ-specific autoimmune disease characterized by the presence of autoantibodies and T cell-mediated autoimmunity against self-antigens [1]
We found that cytotoxic T-lymphocyte-associated protein 4 (CTLA4) single nucleotide polymorphisms (SNPs) +49A/G and CT60 were associated with GD in adults and children
Our results showed that CTLA4 was associated with both GD and HD and played an equivalent role in both adult and pediatric GD in Han Chinese population

Summary

Introduction

Autoimmune thyroid disease (AITD), including Graves disease (GD) and Hashimoto disease (HD), is an organ-specific autoimmune disease characterized by the presence of autoantibodies and T cell-mediated autoimmunity against self-antigens [1]. Both GD and HD involve similar genetic background and additional environmental and hormonal factors. Antibody-mediated thyroid stimulation prominently occurs in GD, whereas lymphocyte- and cytokine-mediated thyroid apoptosis predominates in HD, but overlap may occur [1] They are the most prevalent autoimmune endocrinological diseases in children and adolescents [2], and are estimated to affect approximately 1% of the general population [3]. Twin studies reveal that genetic factors contribute to about 75% of the development of AITD [10]. These observations strongly suggest that genetic factors are important in the pathogenesis of AITD

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