Association of the HLA-DRB1*0301 and HLA-DQA1*0501 Alleles with Graves' Disease in a Population Representing the Gene Contribution from Several Ethnic Backgrounds

Abstract

Graves' disease (GD) is the most frequent cause of hyperthyroidism. Although the etiology is not completely elucidated, there are several lines of evidence suggesting multifactorial mechanisms. Genetic, constitutional, and environmental factors are involved in its pathogenesis. Major histocompatibility complex (MHC) class II alleles have been associated with GD in several populations of distinct ethnic backgrounds and there is increasing evidence supporting an association between GD and HLA-DR3 in Caucasian populations. The MHC class II alleles were evaluated in 75 Brazilian patients presenting with GD and in 166 control individuals from the same geographic area. HLA-DRB, DQB, and DQA alleles were identified using polymerase chain reaction (PCR)-amplified DNA hybridized with sequence-specific probes. The HLA-DRB1*0301 allele was significantly increased in patients (34/75, 45.3%) as compared with controls (37/166, 22.3%, p = 0.009), conferring a relative risk (RR) of 2.8 and an etiologic fraction (EF) of 0.287. The HLA-DQA1*0501 allele was also overrepresented in patients (48/71, 67.6%) in relation to controls (24/71, 33.8%; p = 0.004), conferring an RR of 3.74 and an EF of 0.351. The susceptibility conferred by HLA-DQA1*0501 was independent of the HLA-DRB1*0301 allele. On the other hand, the HLA-DQB1*0602 allele was significantly decreased in patients (6/75, 8.0%) in relation to controls (53/166, 31.9%, p = 0.0008), conferring an RR of 0.18 and a preventive fraction of 0.267. Although the Brazilian population comprises individuals of several ethnic backgrounds, these results corroborate the participation of the HLA-DRB1*0301 and HLA-DQA1*0501 alleles as susceptibility markers for GD, and emphasize the participation of the HLA-DQB1*0602 allele as conferring protection against the development of the disease.

Immune Profile and Signal Transduction of T-Cell Receptor in Autoimmune Thyroid Diseases

“…Besides genes of the MHC class II system such as HLA-DR3 and DQA1 * 0501 on chromosome 6p21 (Yanagawa, Mangklabruks et al, 1993;Zamani, Spaepen et al, 2000;Maciel, Rodrigues et al, 2001), on chromosome 2q33, we found the loci of genes involved in the regulation of T lymphocytes: CD28, CTLA4 and ICOS in which, specifically polymorphisms of the cytotoxic T lymphocyte antigen-4 (CTLA-4) are associated to various autoimmune diseases (Chistiakov and Turakulov 2003;Vaidya and Pearce 2004).…”

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.…”

“…Both genetic and environmental factors may affect the development 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].…”

“…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].…”

Genetics of autoimmune thyroid disease in the Lebanese population

“…Several studies have reported the association of GD with DQA1*05 where it was considered a susceptibility marker for GD. Indeed DQA1*05 has been associated with GD in Latvians and Brazilians (Marga et al 2001;Maciel et al 2001). However, it was not found to be associated with GD in the Greek population (Philippou et al 2001) or in African-American patients (Yanagawa and De Groot 1996;Ofosu et al 1996).…”