Clinical associations of the genetic variants of CTLA-4, Tg, TSHR, PTPN22, PTPN12 and FCRL3 in patients with Graves' disease.
OBJECTIVE
Graves' disease (GD) is an organ-specific autoimmune disorder. Both immune-modulating genes and thyroid-specific genes are involved in its genetic pathogenesis. It remains unclear, however, how the interactions of various susceptibility genes contribute to the pathogenesis and clinical severity of the disease. The purpose of this study was to investigate the relationships between GD and single nucleotide polymorphisms (SNPs) from CTLA-4, PTPN22, PTPN12, FCRL3 (general autoimmunity genes regulating T and B cells) and the TSHR and Tg genes (disease-specific genes). Furthermore, we evaluated the influences these SNPs have on the risk and severity of GD.


METHODS
This cross-sectional clinical study was performed in 436 GD patients and 316 healthy, gender-matched individuals. Twenty-eight SNPs from CTLA-4, PTPN22, PTPN12, FCRL3, TSHR and Tg genes were genotyped and their associations with the risk and severity of GD were analysed.


RESULTS
The CTLA-4 rs231779, Tg rs2069550 and PTPN22 rs3789604 SNPs were associated with GD, with additive risk effects present in rs231779 and rs2069550. The ACACC and ACGCT haplotypes, composed of five SNPs in the CTLA-4 gene (rs4553808, rs5472909, rs231775, rs231777 and rs231779), were protective and risk haplotypes respectively. The AA genotype of PTPN22 rs3789604 and AA genotype of FCRL3 rs7528684 were correlated with a reduced risk of GD, while the CC genotype of TSHR rs2239610 was associated with higher serum concentrations of FT4 and TRAb. Logistic analysis confirmed the contribution of CTLA-4 rs231779 to the development of GD.


CONCLUSIONS
These preliminary results demonstrate that the immune-regulatory gene CTLA-4 and the thyroid-specific gene Tg contribute to the risk of Graves' disease with additive effects, while PTPN22 rs3789604 and FCRL3 rs7528684 polymorphisms are protective against the disease. In addition, the TSHR rs2239610 SNP is related to the severity of Graves' disease.
Department of Endocrine and Metabolic Diseases, Rui-jin Hospital, Shanghai Jiao-tong University School of Medicine, Shanghai Clinical Center For Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Shanghai, China.
Li-qun
LQ
Gu
Wei
W
Zhu
Shuang-xia
SX
Zhao
Lin
L
Zhao
Min-jia
MJ
Zhang
Bin
B
Cui
Huai-dong
HD
Song
Guang
G
Ning
Yong-ju
YJ
Zhao
D000328:Adult; D015703:Antigens, CD / Q000235:genetics*; D060908:CTLA-4 Antigen; D003430:Cross-Sectional Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006111:Graves Disease / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D016014:Linear Models; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12 / Q000235:genetics*; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D011971:Receptors, Immunologic / Q000235:genetics*; D011989:Receptors, Thyrotropin / Q000235:genetics*
D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C457775:FCRL3 protein, human; D011971:Receptors, Immunologic; D011989:Receptors, Thyrotropin; C516765:PTPN22 protein, human; D054594:Protein Tyrosine Phosphatase, Non-Receptor Type 12; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22