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

Chen, Qiao-Yi; Huang, Wei; She, Jin‐Xiong; Baxter, Felicia; Volpé, Robert; Maclaren, Noel K.

doi:10.1210/jcem.84.9.5991

Cited by 55 publications

(45 citation statements)

References 25 publications

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“…Indeed, analysis of electronic sequence databases indicated that DRb-Gln74 is always present on DR7, an allele that was found to be protective for GD in our data set (DR7 was found in 10.1% of our GD patients and in 17.0% of the controls, w 2 ¼ 4.1, P ¼ 0.04), as well as in other Caucasian datasets. 19 This suggests that position 74 of the DRb1 chain is critical for GD development, with DRb-Arg74 conferring susceptibility and DRb-Gln74 conferring protection.…”

Section: Discussionmentioning

confidence: 99%

Arginine at position 74 of the HLA-DR β1 chain is associated with Graves' disease

et al. 2004

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Graves' disease (GD) is associated with HLA-DR3 (DRB1*03) in Caucasians, but the exact amino-acid sequence in the DR b1 chain conferring susceptibility to GD is unknown. Therefore, the aim of our study was to identify the critical sequence among the HLA-DRB1 amino-acid residues occupying the peptide-binding pocket, which conferred susceptibility to GD. We sequenced the HLA-DRB1 locus in 208 Caucasian GD patients and 149 Caucasian controls. Sequence analysis showed an increased frequency of DR b-Arg-74 in GD patients compared to controls (41.8 and 13.4%, respectively; P ¼ 2.3 Â 10 À8 , OR ¼ 4.6). Moreover, subset analyses showed that DR b-Arg-74 was also significantly more frequent in the HLA-DR3 negative GD patients than in controls (7.6 vs 0.8%, P ¼ 0.02, OR ¼ 10.5), suggesting that the association with DR b-Arg-74 is independent of the association with HLA-DR3. Structural modeling studies demonstrated that the change at position 74 from the neutral amino acids Ala or Gln to the positively charged amino-acid Arg significantly modifies the three-dimensional structure of the DR peptide-binding pocket. Our results suggested that structural heterogeneity of the DR b-chain peptidebinding pocket P4 at residue 74 predispose some at risk individuals to GD.

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Section: Discussionmentioning

confidence: 99%

Arginine at position 74 of the HLA-DR β1 chain is associated with Graves' disease

et al. 2004

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“…Although the DRB3 gene-encoded molecules have not been as well studied as those encoded by DRB1 genes, these MHCII molecules have been linked to several autoimmune diseases; for example, DR52a has been associated with Crohn's sarcoidosis (8), Graves' disease (9,10), and Löfgren's syndrome (11); DR52b has been associated with Graves' disease (12), multiple sclerosis (13), and essential hypertension caused by Chlamydia pneumoniae infection (14); and DR52c has been related to Crohn's disease (15) and cedar pollen allergies (16). Recently, we identified DR52c as the MHC-restriction element for a human nickel-reactive T cell isolated from a patient with contact sensitivity to nickel in jewelry (4).…”

mentioning

confidence: 99%

The structure of HLA-DR52c: Comparison to other HLA-DRB3 alleles

Dai

Crawford

Marrack

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Class II major histocompatibility complex (MHCII) molecules present antigens to CD4 ؉ T cells. In addition to the most commonly studied human MHCII isotype, HLA-DR, whose ␤ chain is encoded by the HLA-DRB1 locus, several other isotypes that use the same ␣ chain but have ␤ chains encoded by other genes. These other DR molecules also are expressed in antigen-presenting cells and are known to participate in peptide presentation to T cells and to be recognized as alloantigens by other T cells. Like some of the HLA-DRB1 alleles, several of these alternate DR molecules have been associated with specific autoimmune diseases and T cell hypersensitivity. Here we present the structure of an HLA-DR molecule (DR52c) containing one of these alternate ␤ chains (HLA-DRB3*0301) bound to a self-peptide derived from the Tu elongation factor. The molecule shares structurally conserved elements with other MHC class II molecules but has some unique features in the peptide-binding groove. Comparison of the three major HLA-DBR3 alleles (DR52a, b, and c) suggests that they were derived from one another by recombination events that scrambled the four major peptide-binding pockets at peptide positions 1, 4, 6, and 9 but left virtually no polymorphisms elsewhere in the molecules.antigen presentation ͉ MHC Class II ͉ peptide antigens ͉ peptide motif ͉ x-ray structure

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“…In the previous studies, the associations between age at onset and different HLA genotypes in Caucasians (18), and Japanese (19), and ICAM-1 gene alleles in Caucasians (20) and CD40 genotypes in Japanese (21), have been reported. Therefore, we evaluated the differences between the frequencies of the CD40 and TG genotypes in Taiwanese patients with GD onset aged below 40 years and those with a later onset of GD.…”

Section: Discussionmentioning

confidence: 98%

Association of CD40 and thyroglobulin genes with later-onset Graves' disease in Taiwanese patients

Hsiao¹,

Hsieh²,

Hsiao³

et al. 2008

European Journal of Endocrinology

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Objective: Graves' disease (GD) is known to be associated with thyroglobulin (TG) and CD40 genes. Therefore, we decided to investigate the relationship of age at onset of GD with CD40 and TG gene susceptibilities in a Taiwanese population. Design and method: We analyzed the association of TG and CD40 polymorphisms with age at onset of GD in Taiwanese patients. We stratified patients into those with early onset (!40 years; 30.3G4.8 years; nZ135) and later onset (R40 years; 52.3G6.3 years; nZ80) and compared the results with those of 141 normal controls. Results: We found a significant statistical difference in the T/T genotype frequency of E33 single nucleotide polymorphism (SNP) and G/G genotype frequency of E12 SNP when compared with the control group (P!0.001). In addition, the frequencies of the T allele and TT genotype of the CD40 SNP were found to be significantly increased in GD patients who developed GD aged over 40 years than those below 40 years (allele: c 2 Z5.299, PZ0.021, ORZ1.597; genotype: c 2 Z6.168, PZ0.046). By contrast, the frequencies of genotypes in the TG gene E10, E12, and E33 SNPs were not found to be significantly different in GD patients who developed GD when aged over 40 years when compared with those aged below 40 years. Conclusions: These data suggest that the T/T genotype and T allele in the CD40 gene are more likely to be associated with late-onset GD in Taiwanese patients.European Journal of Endocrinology 159 617-621

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

Abstract: Graves' disease is known to be HLA-D associated; however, the primary loci involved remain unclear. We examined HLA genotypes of DRB1 and DQB1 plus DRB3 subtypes using PCR-based sequence-

Cited by 55 publications

References 25 publications

Arginine at position 74 of the HLA-DR β1 chain is associated with Graves' disease

Arginine at position 74 of the HLA-DR β1 chain is associated with Graves' disease

The structure of HLA-DR52c: Comparison to other HLA-DRB3 alleles

Association of CD40 and thyroglobulin genes with later-onset Graves' disease in Taiwanese patients

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