Genetic Analysis of Families with Autoimmune Diabetes and Thyroiditis: Evidence for Common and Unique Genes

Golden, Brian K.; Levin, Lara; Ban, Yoshiyuki; Concepcion, Erlinda; Greenberg, David A.; Tomer, Yaron

doi:10.1210/jc.2004-2236

Cited by 98 publications

(92 citation statements)

References 63 publications

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“…Thyroid autoantibodies in type 1 diabetes Of 4,364 patient samples tested, 462 (10.6%) were TPOAbs-positive, which is similar to previous studies [4,5]. The ratio of women: men was significantly elevated in the TPOAbs-positive patients (1.94:1) compared with the TPOAbs-negative patients (0.86:1) or the type 1 diabetes patients overall (0.94:1) ( Fig.…”

Section: Resultssupporting

confidence: 86%

“…At the same time, we cannot ignore the role of the yet-to-bedefined environmental and developmental factors in determining the penetrance of susceptibility genes. Finally, the bias in the proportion of female type 1 diabetic patients with TPOAbs is comparable with previous, small studies of 35 [5], 28 [18] and 77 [17] APS (type 1 diabetes + AITD) patients, in which the ratios of women:men were 1.7:1, 2.5:1 and 2.3:1, respectively, suggesting that Xlinked factors are operating. One possibility is that the skewing of X inactivation, which has been described in AITD patients [35,36], alters expression of immune genes on chromosome X, thereby predisposing to autoimmunity in females.…”

Section: Discussionsupporting

confidence: 87%

“…In addition to associations with HLA class II alleles and haplotypes, notably DRB1*03-DQB1*02 [10][11][12], and the lymphoid-specific phosphatase T cell activation gene, protein tyrosine phosphatase non-receptor type 22 (lymphoid) (PTPN22) [13], AITD and type 1 diabetes have been associated with the cytotoxic T-lymphocyte-associated antigen-4 gene (CTLA4) [5], which encodes a vital negative immunoregulatory receptor in T cell activation and expansion. The association with AITD is strong (odds ratio [OR] ∼1.5) with single nucleotide polymorphisms (SNPs) in the 3′UTR of the gene being the strongest candidates for the causal variant(s) [14].…”

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confidence: 99%

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A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene

et al. 2007

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Aims/hypothesis HLA haplotypes DRB1*03_DQB1*02 and DRB1*04_DQB1*0302, and allelic variation of the T cell regulatory gene cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) and of the T cell activation gene protein tyrosine phosphatase, non-receptor type 22 (lymphoid) (PTPN22) have been associated with type 1 diabetes and autoimmune thyroid disease. Using thyroid peroxidase autoantibodies (TPOAbs) as an indicator of thyroid autoimmunity, we assessed whether the association of these loci is different in type 1 diabetes patients with TPOAbs than in those without. Materials and methods TPOAbs were measured in 4,364 type 1 diabetic patients from across Great Britain, 67% of whom were aged under 18 years. These patients and 6,866 geographically matched control subjects were genotyped at CTLA4, PTPN22, HLA-DRB1 and HLA-DQB1. Results TPOAbs were detected in 462 (10.6%) of the type 1 diabetic patients. These patients had a stronger association with CTLA4 (odds ratio [OR]=1.49 for the G allele of the single nucleotide polymorphism rs3087243; 95% CI=1.29-1.72) than did the TPOAbs-negative patients (p=0.0004; OR=1.16; 95% CI=1.10-1.24) or type 1 diabetes patients overall (OR=1.20; 95% CI=1.13-1.27). The ratio of women:men was higher (1.94:1) in this subgroup than in type 1 diabetes patients without TPOAbs (0.94:1; p=1.86× 10 −15

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Section: Resultssupporting

confidence: 86%

Section: Discussionsupporting

confidence: 87%

mentioning

confidence: 99%

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A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene

et al. 2007

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“…An association between AITD and HLA-DR3 [36], HLA-DR4 [24,37] and DRB1*04-DQB1*03:01 [38] has been reported. In addition, HLA-DR3 and DR3/DQB1*03:02 has also been reported to contribute to both type 1 diabetes and AITD in a study of families with both diseases, while DR4 was associated with type 1 diabetes but not with AITD [25,28,39]. Others have failed to find an association between HLA and TPOAb [1].…”

Section: Discussionmentioning

confidence: 99%

Thyroid autoimmunity in relation to islet autoantibodies and HLA-DQ genotype in newly diagnosed type 1 diabetes in children and adolescents

et al. 2013

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Aims/hypothesis The aim of this work was to investigate, in children newly diagnosed with type 1 diabetes: (1) the prevalence of autoantibodies against thyroid peroxidase (TPOAb) and thyroglobulin (TGAb); and (2) the association between TPOAb, TGAb or both, with either islet autoantibodies or HLA-DQ genes. Methods Blood samples from 2,433 children newly diagnosed with type 1 diabetes were analysed for TPOAb and TGAb in addition to autoantibodies against arginine zinc transporter 8 (ZnT8RA), tryptophan zinc transporter 8 (ZnT8WA), glutamine zinc transporter 8 (ZnT8QA), glutamic acid decarboxylase (GADA), insulin (IAA), insulinoma-associated protein-2 (IA-2A), HLA-DQA-B1 genotypes, thyroid-stimulating hormone (TSH) and free thyroxine (T4). Results At type 1 diabetes diagnosis, 12% of the children had thyroid autoantibodies (60% were girls; p<0.0001). GADA was positively associated with TPOAb (p<0.001) and with TGAb (p<0.001). In addition, ZnT8A was associated with both TPOAb (p=0.039) and TGAb (p=0.015). DQB1*05:01 in any genotype was negatively associated with TPOAb (OR 0.55, 95% CI 0.37, 0.83, p value corrected for multiple comparisons (p c )=0.012) and possibly with TGAb (OR 0.55, 95% CI 0.35, 0.87, p c =0.07). Thyroid autoimmunity in children newly diagnosed with type 1 diabetes was rarely (0.45%) associated with onset of clinical thyroid disease based on TSH and free T4. Conclusions/interpretation GADA and ZnT8A increased the risk for thyroid autoimmunity at the time of clinical diagnosis of type 1 diabetes, while HLA-DQB1*05:01 reduced the risk. However, the associations between thyroid autoimmunity and HLA-DQ genotype were weak and did not fully explain the co-occurrence of islet and thyroid autoimmunity.

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“…It was observed that the HLA class II locus is responsible for the significant shared risk for T1DM and AIT, and the major HLA haplotype contributing to this association was DR3-DQB1*0201. 9 In presence of T1DM, AD has been associated with the presence of HLA subtype of DR3-DQ2 and DR4-DQ8. 10,11 Individuals with 21-hydroxylase autoantibodies (21-OHAA) are more likely to have genotype DR3-DQ2, DR4-DR8 with DRB1*0404 when compared with normal subjects or diabetic controls.…”

Section: Genetic Factorsmentioning

confidence: 99%

Organ specific autoimmune disorders in type 1 diabetes mellitus

Ashok¹,

Sachan²

2017

jcsr

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Type 1 Diabetes Mellitus (T1DM) is an autoimmune disease that results in absolute insulin deficiency due to destruction of the pancreatic beta cells. It is frequently associated with other autoimmune diseases like autoimmune thyroid (AIT) disease, celiac disease (CD), Addison's disease (AD), and vitiligo. These diseases, including T1DM are associated with organ specific autoantibodies. These autoantibodies are important as diagnostic markers and detectable antibodies may precede the clinical onset of the disease. These diseases usually occur together in same patient and have shared genetic predisposition. These autoimmune diseases can severely affect clinical management of T1DM. It is possible to screen for these associated diseases by testing for relevant autoantibodies. Earlier detection of organ specific autoimmunity will enable physicians to treat these diseases at an initial stage and can prevent development of fullblown clinical condition.

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Genetic Analysis of Families with Autoimmune Diabetes and Thyroiditis: Evidence for Common and Unique Genes

Cited by 98 publications

References 63 publications

A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene

A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong association with the cytotoxic T-lymphocyte-associated antigen-4 gene

Thyroid autoimmunity in relation to islet autoantibodies and HLA-DQ genotype in newly diagnosed type 1 diabetes in children and adolescents

Organ specific autoimmune disorders in type 1 diabetes mellitus

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