Association of HLA-DR, -DQ Genotype and CTLA-4 Gene Polymorphism with Graves’ Disease in Japanese Children

Abstract

Objective: Childhood onset Graves’ disease (GD) has been documented to be clinically distinct from adult onset GD, and an association with the genes encoding HLA and CTLA-4 (cytotoxic T lymphocyte antigen-4) has been reported in both Caucasian and Japanese adult GD patients. The aim of this study was to determine whether HLA-DR, -DQ and CTLA-4 are associated with childhood onset GD in Japanese individuals. Methods: We investigated the genotype of HLA class II (DRB1, DQB1) and the A/G transition polymorphism of CTLA-4 exon 1 position 49 in 43 GD patients and in healthy controls for comparison. The CTLA-4 alleles were identified by the polymerase chain reaction (PCR) of genomic DNA and restriction fragment-length polymorphism analysis (PCR-RFLP) with Ita1. Results: The frequency of both HLA-DRB1*0405 and DQB1*0401 was increased in the patient group (DRB1*0405: 26.7%, p < 0.001; DQB1*0401: 25.6%, p < 0.005) compared with the controls. Patients with GD had a significantly lower frequency of the AA genotype of CTLA-4 than the controls, but there was no difference in allele frequency between the G and A allele. Conclusions: the association of HLA-DRB1 and DQB1 genotype with susceptibility to childhood onset GD differs from that in adult onset GD, whereas the association between CTLA-4 gene polymorphism and childhood onset GD is similar to that in adult onset GD in Japanese individuals, but the association is weak.

Graves’ Disease in Brazilian Children and Adults: Lack of Genetic Association with CTLA-4 +49A>G Polymorphism

“…The CTLA-4 +49A>G polymorphism has already been investigated in several adult GD populations, but only two studies were performed in the pediatric population [31, 32]. Our study aimed a t determining the frequency of the +49A>G polymorphism and its association with GD in Brazilian children and adults.…”

New HLA DRB1 and DQB1 Haplotypes in a Pedigree of Familial Graves' Disease in Japan

“…In the present study the haplotypes of DRB1* 150101 and DQB1*0602 were highly frequent in the members of maternal pedigree including affected and unaffected Graves' disease, except for the cousin. These haplotypes were not found in the patients with sporadic Graves' disease in Japanese and other ethnic population [7,9,13,24,28]. Because the HLA haplotypes specifically conferred an increased risk for Graves' disease in sporadic form, it is of value to find the differences in HLA typing between familial and sporadic forms of Graves' disease.…”

“…Such an autoimmune mechanism could be associated with HLA on chromosome 6p [5][6][7][8][9][10][11][12][13][24][25][26][27][28][29][30][31][32][33] and CTLA-4 on chromosome 2q33 [14][15][16][17][18]. There are several different results regarding HLA haplotypes associated with Graves' disease in Japan [13,28,29,32,33]. Positive associations were obtained with the haplotypes of DRB1*0803, DQB1*1403, DQA1*0103 alleles [32], DRB1*0803, DQA1*0103, DQB1*0601 alleles [32], DRB1*1403, DQA1*0501, DQB1*0301 alleles [32], DRB1*0405, DQB1*0401 alleles [13], and DPB1*0501 alleles [28,33].…”

“…There are several different results regarding HLA haplotypes associated with Graves' disease in Japan [13,28,29,32,33]. Positive associations were obtained with the haplotypes of DRB1*0803, DQB1*1403, DQA1*0103 alleles [32], DRB1*0803, DQA1*0103, DQB1*0601 alleles [32], DRB1*1403, DQA1*0501, DQB1*0301 alleles [32], DRB1*0405, DQB1*0401 alleles [13], and DPB1*0501 alleles [28,33]. Also, the positive association of different haplotypes with Graves' disease was reported in other ethnic population; that is, DQB1* 0301, DR 11 and DR 3 in male Caucasian patients [30], DRB3*0202, DQA1*0501 in adult African Americans [31], DRB1*0301, DRB1*0201, DRB3*0101 in juvenile Danish patients [25,26], and DQB1*0303 in child Chinese patients [24].…”

“…The genetic factors include polymorphism of human leukocyte antigen (HLA), cytotoxic T cell antigen-4 (CTLA-4) and unknown genes in other chromosomes . In the literature HLA typing has a strong association with the development of Graves' disease with childhood onset, but CTLA-4 polymorphism does not [13]. In addition, HLA polymorphism associated with Graves' disease is different between childhood and adult onset [5][6][7][8][9][10][11][12][13][24][25][26][27][28][29][30][31][32][33].…”