The Genetics of Graves’ Disease: HLA and Disease Susceptibility*

Stenszky, V.; Kozma, L.; Balázs, C; Rochlitz, Sz.; Bear, J. C.; Farid, Nadir R.

doi:10.1210/jcem-61-4-735

Cited by 137 publications

(65 citation statements)

References 13 publications

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“…Since the HLA region is highly polymorphic and contains many immune response genes, it was the first candidate genetic region to be studied for association and linkage with GD (reviewed in Tomer and Davies 4 ). 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.…”

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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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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“…1 Its aetiology is unknown, but is thought to be caused by a complex interaction between genetic and environmental factors. 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.…”

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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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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“…5 Our patient presented with Graves' disease, goiter, left vocal cord immobility, and an enlarged thymus. After treatment with methimazole for 3 months, her voice recovered.…”

Section: Discussionmentioning

confidence: 83%

Reversible Left Recurrent Laryngeal Nerve Palsy in Pediatric Graves’ Disease

et al. 2013

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Vocal cord paralysis associated with goiter usually indicates the presence of a malignancy. Pediatric patients retain significant thymic tissue that regresses only later in life. This thymic tissue can develop significant hyperplasia during an acute autoimmune process. We describe a case of a 17-year-old girl who presented with a goiter secondary to severe Graves' disease and a 2-month history of hoarseness, choking on liquid intake, and small-volume vomiting especially after eating. She demonstrated a left vocal cord paralysis probably secondary to a unilateral left recurrent laryngeal nerve palsy. A marked enlargement of the thymus was discovered on thoracic imaging. Treatment was initiated with methimazole, with near complete remission of her vocal cord paralysis within 3 months. Given the immunomodulatory effects of methimazole, a potential mechanism of the left recurrent laryngeal nerve palsy was autoimmune hyperstimulation of the thymus and consequent hyperplasia, resulting in distension of the nerve. Attenuation of the hyperactive immune process with methimazole may have resulted in regression of the mass effect of the thymus and associated reduction of the nerve distension. This case illustrates the unique risk of left recurrent laryngeal nerve palsy in pediatric patients with an acute immune stimulation and hyperplasia of the thymus and the reversibility in the context of mitigation of the immune hyperactivity. Methimazole may be an optimal initial treatment choice in pediatric patients with Graves' disease and left recurrent laryngeal nerve palsy. Pediatrics 2013;132:e1704-e1708 Dr Chiu provided the endocrinology consultation for the patient, conceptualized the significance of the case report, and drafted the initial manuscript; Dr Ledbetter provided the general surgery consultation for the patient and reviewed and revised the manuscript; Dr Richter provided the initial medical evaluation for the patient and reviewed and revised the manuscript; Dr Iyer contributed a radiology assessment of the patient' s imaging and reviewed and revised the manuscript; Dr Merati provided the otolaryngology consultation for the patient and reviewed and revised the manuscript; and all authors approved the final manuscript as submitted.www.pediatrics.org/cgi

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The Genetics of Graves’ Disease: HLA and Disease Susceptibility*

Cited by 137 publications

References 13 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

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

Reversible Left Recurrent Laryngeal Nerve Palsy in Pediatric Graves’ Disease

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