Human histocompatibility leukocyte antigen-DQA1*0501 allele associated with genetic susceptibility to Graves' disease in a Caucasian population

Yanagawa, Tatsuo

doi:10.1210/jc.76.6.1569

Cited by 95 publications

(78 citation statements)

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“…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.…”

Section: Discussionmentioning

confidence: 99%

“…2 Many environmental agents have been postulated to influence the development of GD, including stressful life events, 3 iodine intake 4 and bacterial or viral infection, 5 but to date no conclusive evidence favouring any of these factors has been produced. Many genetic studies have been performed, but only the human leukocyte antigen (HLA) gene region of the major histocompatibility complex (MHC) on chromosome 6p21 6,7 and the cytotoxic T lymphocyte associated (CTLA-4) gene on chromosome 2q33 8,9 have been consistently shown to be associated with GD. Collectively, these loci are likely to contribute to less than 50% of the genetic susceptibility to GD in the UK, leaving at least 50% unaccounted for.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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Single-nucleotide polymorphisms (SNPs) within the tumour necrosis factor alpha (TNF-a) gene on chromosome 6p21.3 have been associated with many autoimmune diseases; however, results have been conflicting and accurate allele frequencies have never been established in a UK Caucasian population. The aim of this study was to assess the frequency of 22 known TNF-a SNPs in a UK Caucasian control population and investigate association of all polymorphisms with 45% minor allele frequency in a large case-control data set of patients with Graves' disease (GD). Eight of the 22 SNPs had minor allele frequencies 45% and were investigated further. The other 14 SNPs were present in the UK population at frequencies ranging from 0 to 4.7%. A significant increase of the A allele of the À238 SNP was seen in GD patients when compared with control subjects (9.6 vs 6.8%, respectively; P ¼ 0.003) and mirrored in the genotype distribution (P ¼ 0.009). Furthermore, association of the -238 SNP appears not to be due to linkage disequilibrium of the known HLA-DRB1*03 associations with GD. This study has established accurate allele frequencies of TNF-a SNPs in a UK population and provides preliminary evidence for association of the TNF-a gene with GD.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2004

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“…Several case-control studies have demonstrated association of alleles of the class II MHC (HLA) region on chromosome 6p with Graves' disease (Boehm et al 1992, Yanagawa et al 1993, Badenhoop et al 1995, Barlow et al 1996) and Hashimoto's thyroiditis (Tandon et al 1991). In the majority of these studies, results have been consistent, with allelic association reported between Graves' disease and the alleles DR3 and DQA1*0501 (Boehm et al 1992, Yanagawa et al 1993, Badenhoop et al 1995, Barlow et al 1996. Because of the sensitivity of the case-control method and results already reported, most adequately sized, well matched data sets would be expected to identify the HLA region as a susceptibility locus.…”

Section: Population-based Case-control Studiesmentioning

confidence: 99%

The different approaches to the genetic analysis of autoimmune thyroid disease

Allahabadia¹,

Gough²

1999

Journal of Endocrinology

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Graves' disease and Hashimoto's thyroiditis are organspecific autoimmune disorders of multifactorial aetiology with a polygenic mode of inheritance. Familial clustering and twin studies provide evidence for a genetic predisposition. Three main approaches have been used in the search for susceptibility loci: population-based case-control studies, classical linkage analysis, and intrafamilial linkage disequilibrium. Case-control studies are a sensitive method of gene detection and the collection of subjects is resource-efficient. However, they require prior knowledge of a candidate gene and are prone to inconsistent results due to false positives that may arise from population mismatch. Linkage analysis is a powerful tool for detecting 'major' genes that does not require a candidate gene and is, therefore, a means of genome screening. This method, however, has limited power to detect genes of 'modest' effect, and the collection of sibpairs and multiple family members may be difficult. Intrafamilial linkage disequilibrium analysis is more sensitive than classical linkage analysis, requires only one affected offspring, and eliminates population mismatch. This approach has confirmed linkage disequilibrium of the HLA region with Graves' disease, previously not detected by linkage analysis. Knowledge of a candidate locus is required, however, and this method cannot, therefore, at present be used for genome screening. It is likely that a combination of all three approaches will be required to identify susceptibility loci for autoimmune thyroid disease.

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“…Caucasian GD patients have been shown to have an increased frequency of HLA-DR3 (DRB1*03) [7][8][9] and HLA-DQA1*0501 haplotypes. 10 The odds ratio (OR) for people with DR3 is about 2-4. 7,9,11 Nevertheless, there are no sequencing data to implicate a specific HLA-DR3 sequence variant.…”

Section: Introductionmentioning

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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Human histocompatibility leukocyte antigen-DQA1*0501 allele associated with genetic susceptibility to Graves' disease in a Caucasian population

Cited by 95 publications

References 0 publications

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

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

The different approaches to the genetic analysis of autoimmune thyroid disease

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

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