HLA, CTLA-4 and TNF-beta Gene Polymorphisms and Disease Susceptibility in Korean Children with Graves' Disease.
- Author:
Moon Young SONG
1
;
Min Ho JUNG
;
Jun Seong LEE
;
Tai Gyu KIM
;
Sei Won YANG
;
Byung Churl LEE
Author Information
1. Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul, Korea. byungcl@catholic.ac.kr
- Publication Type:Original Article
- Keywords:
Graves' disease;
HLA;
CTLA-4;
TNF-beta
- MeSH:
Alleles;
Child*;
Disease Susceptibility*;
Exons;
Exophthalmos;
Female;
Genotype;
Graves Disease*;
HLA-A2 Antigen;
HLA-A24 Antigen;
Humans;
Leukocytes;
Lymphocytes;
Lymphotoxin-alpha*;
Necrosis;
Thyrotropin
- From:Journal of Korean Society of Endocrinology
2003;18(1):32-44
- CountryRepublic of Korea
- Language:Korean
-
Abstract:
BACKGROUND: Graves' disease(GD) is an organ-specific autoimmune disorder that is inherited as a complex trait. At present three loci, namely the human leukocyte antigen(HLA), the cytotoxic T lymphocyte antigen-4(CTLA-4) and a thyroid stimulating hormone receptor(TSHR) are the only well-known genetic determinants for GD. To understand the mechanisms underlying the development of GD, we investigated the relationship of HLA alleles, polymorphisms of CTLA-4 gene and the tumor necrosis factor(TNF)-beta gene, with the disease susceptibility. METHODS: Fifty-two Korean children with GD(45 girls and 7 boys), and 119 healthy children, were investigated in this study. The HLA alleles were determined by a standard lymphocyte microtoxicity technique, ARMS-PCR(Amplification Refractory Mutation System-Polymerase Chain Reaction), PCR-SSP(Sequence Specific Primer) and PCR-SSOP(Sequence Specific Oliogonucleotide Probe) method. The CTLA-4 gene polymorphism was analyzed by PCR-SSCP(Single Strand Conformation Polymorphism), and the TNF-beta gene polymorphism by PCR-RFLP(Restriction Fragment Length Polymorphism). RESULTS: (1) The frequencies of HLA-A2, B46, DRB1*08 and DPB1*0202 were significantly increased, and those of HLA-A24, DQA1*01 and DQB1*05 were significantly decreased, in the GD patients compared to the control subjects. (2) A significant difference in the distributions of the AA, AG, and GG genotypes of the CTLA-4 exon 1 were observed between the GD patients and the control subjects, and a significant increase in the frequency of the G (alanine) allele was seen in the GD patients compared with the control subjects(84.6% vs 63.4%; RR=3.2; p<0.0001). A significant difference in the distributions of the AA, AG, and GG genotypes of the CTLA-4 exon 1 was observed between the GD patients with and without exophthalmos. A significant increase in the frequency of the G allele was seen in the GD patients with exophthalmos compared to those without(94.0% vs 75.9%; RR=7.0; p<0.05). (3) No significant difference in the distributions of the 1/1, 1/2 and 2/2 genotypes, and the 1 and 2 alleles of TNF-beta was observed between the GD patients and the control subjects. No significant difference in the distributions of the 1/1, 1/2, and 2/2 genotypes and the 1 and 2 alleles of TNF-beta were observed between the GD patients with or without exophthalmos but a significant increase in the frequency of the 2/2 allele was seen in the GD patients having TSHRAb > or =45% compared with GD patients having TSHRAb <45%(37.5% vs 3.6%; RR=14.8; p<0.01). CONCLUSION: These data suggest that HLA-A2, B46, Cw*0102, DRB1*08 and DPB1*0202 are markers for disease susceptibility, and that HLA-A24, DQA1*01 and DQB1*05 are markers for disease protection, in Korean children with GD. This study showed that the CTLA-4 gene polymorphism was an additional marker of susceptibility in the GD patients, and was associated with exophthalmos, and that the TNF-beta gene polymorphism was associated with the TSHRAb activity.
