HLA-DRB3 gene alleles in Caucasian patients with Graves' disease

Abstract

Graves' disease (GD) is a human leukocyte antigen (HLA) linked organ-specific autoimmune disease. In German GD patients the disease is associated with HLA specificities of the HLA-DRw52 family (HLA-DR3, -DR5, and DR6; HLA-DRB3 positive HLA haplotypes). Recently, a strong association with a HLA-DRB3 restriction fragment length polymorphism gene has been described. To study HLA-DRB3 alleles and their association with the disease, a large cohort of controls (n = 3724) and GD patients (n = 304) was analyzed. HLA-DR allelic combinations revealed an increase in HLA-DR3/DR5 heterozygous patients (relative risk 2.9; P < 0.001). HLA-DRB3 alleles, as defined by DNA typing in HLA-DR matched groups revealed a significant increase in DRB3*0101 homozygosity (relative risk 17.5; P < 0.001) in HLA-DR3 homozygous patients. In GD patients with ophthalmopathy (grade II or higher, according to Werner) DRB3*0101/*0202 heterozygosity revealed an increased relative risk of 5.5 (P < 0.001). Non-HLA-DR3 homozygous, DRB3*0101/*0202 heterozygous patients were at the highest risk for endocrine ophthalmopathy (relative risk 10; P < 0.001). Our data, based on DNA typing methods of HLA-D genes, provide evidence that the susceptibility is strongly associated with HLA-DRB3 genes.

HLA-DRB1108, DRB1103/DRB310101, and DRB310202 Are Susceptibility Genes for Graves’ Disease in North American Caucasians, Whereas DRB1107 Is Protective1

“…DRB3 is known to be associated with Graves' disease, as in our study here and as previously reported by others in patients with a variety of ages of disease onset (5,22). However, DRB1*03 and DRB3 are in such tight linkage disequilibrium (23) that it has been difficult to identify which is the primary locus.…”

“…Human leukocyte antigens (HLA) DRB1*0301, DRB3*0101, DQA1*0501, and DQB1*0201 have been reported to be associated with Graves' disease in Caucasian patients (1,(5)(6)(7)(8). However, the primary locus (loci) has not been resolved, whereas HLA associations with Graves' disease have not been fully addressed in terms of age at onset.…”

“…Graves' disease occurs in patients with a wide range of age at onset, but it occurs less common in young children or adolescents (9), although some ethnic groups have a relative high prevalence at these ages (10). Recent studies of HLA associations with Graves' disease in Caucasians contained patients with a wide range of ages at onset (1,(5)(6)(7)(8). If HLA susceptibility differed in patients with different ages at onset of Graves' disease, this could bias the analysis when the subject groups were composed of different ratios of patients with early vs. later onsets.…”

A systematic approach to the assessment of known TNF-α polymorphisms in Graves' disease

“…As this extended haplotype has been consistently reported to be associated with GD in most, 7,9 but not all, 22,23 ethnic groups and because LD is strong across the HLA region it is important to exclude the HLA-DRB1*03 haplotype as the explanation for association with the TNF-a SNPs. Furthermore, the HLA-DRB1*03 haplotype is also associated with an increase in TNF-a production.…”

Graves' Disease Associated with Infectious Mononucleosis due to Primary Epstein-Barr Virus Infection: Report of 3 Cases

“…* 0501 in Graves' disease patients, as compared to controls (15)(16)(17). HLA haplotype DRB1 * 0304-DQB1 * 02-DQA1 * 0501 is associated with a maximal risk in autoimmune thyrotoxicosis (17).…”