Investigation of the Correlation between Graves' Ophthalmopathy and CTLA4 Gene Polymorphism.

Ding-Ping Chen,Ding-Ping Chen,Ai-Ling Hour,Ying-Hao Wen,Wei-Tzu Lin,Wei-Ting Wang,Yen-Chang Chu

doi:10.3390/jcm8111842

Abstract

Graves’ disease (GD) is an autoimmune inflammatory disease, and Graves’ ophthalmopathy (GO) occurs in 25–50% of patients with GD. Several susceptible genes were identified to be associated with GO in some genetic analysis studies, including the immune regulatory gene CTLA4. We aimed to find out the correlation of CTLA4 gene polymorphism and GO. A total of 42 participants were enrolled in this study, consisting of 22 patients with GO and 20 healthy controls. Chi-square or Fisher’s exact test were used to appraise the association between Graves’ ophthalmopathy and CTLA4 single nucleotide polymorphisms (SNPs). All regions of CTLA4 including promoter, exon and 3’UTR were investigated. There was no nucleotide substitution in exon 2 and exon 3 of CTLA4 region, and the allele frequencies of CTLA4 polymorphisms had no significant difference between patients with GO and controls. However, the genotype frequency of “TT” genotype in rs733618 significantly differed between patients with GO and healthy controls (OR = 0.421, 95%CI: 0.290–0.611, p = 0.043), and the “CC” and “CT” genotype in rs16840252 were nearly significantly differed in genotype frequency (p = 0.052). Haplotype analysis showed that CTLA4 Crs733618Crs16840252 might increase the risk of GO (OR = 2.375, 95%CI: 1.636–3.448, p = 0.043). In conclusion, CTLA4 Crs733618Crs16840252 was found to be a potential marker for GO, and these haplotypes would be ethnicity-specific. Clinical application of CTLA4 Crs733618Crs16840252 in predicting GO in GD patients may be beneficial.

Highlights

Graves’ disease (GD) is an autoimmune inflammatory disease
Graves’ ophthalmopathy (GO) called thyroid eye disease occurs in 25–50% of patients suffered from GD [2]
Rs733618 were associated with GD and GO, and “TT” genotype of rs733618 which was found to increasing the risk of GO in our study may affect major transcription level of cytotoxic T-lymphocyte–associated antigen 4 (CTLA4)

Summary

Introduction

Graves’ disease (GD) is an autoimmune inflammatory disease. The annual incidence of Graves’ disease is 20 to 50 cases per 100,000 persons [1]. Graves’ ophthalmopathy (GO) called thyroid eye disease occurs in 25–50% of patients suffered from GD [2]. The reported prevalence rates of Graves’ ophthalmopathy among different ethnic populations are limited. Recent studies reported similar prevalence rate in Malaysians (Malay, Chinese, and Indian) [4] and Indians [5] with GD as compared with Caucasian GD patients. Patients may experience frequent diplopia, dry eye, chemosis, eyelid swelling and even vision loss in severe cases [7]. Patients with Graves’ disease tend to have concomitant hyperthyroidism

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