Analysis of HLA genes in families with autoimmune diabetes and thyroiditis

Levin, Lara; Ban, Yoshiyuki; Concepcion, Erlinda; Davies, Terry F.; Greenberg, David A.; Tomer, Yaron

doi:10.1016/j.humimm.2004.02.026

Cited by 74 publications

(52 citation statements)

References 35 publications

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“…Our findings, that DQ5.1 was protective for TPOAb and TGAb, confirm the results of a previous study [13]. Additionally, our finding of a weak association between TGAb and DQ2 in part confirms previously reported associations between AITD and DQ2 [24,25]. However, our data were not consistent with an association between AITD and HLA-DQB1*03:02 (DQ8) [13,24,37].…”

Section: Discussionsupporting

confidence: 87%

“…Our study therefore indicates that primarily HLA-DQ5.1, but perhaps also DQ8, protects children with type 1 diabetes against developing AITD. These results and the association between AITD and DQ2, as earlier described [24,25], draw attention to the probable importance of HLA-DQ alleles for the risk of AITD in type 1 diabetes. However, the associations between thyroid autoimmunity and HLA-DQ were weak and did not fully explain the cooccurrence of islet and thyroid autoimmunity.…”

Section: Discussionsupporting

confidence: 75%

“…Individuals with thyroid autoantibodies at onset of type 1 diabetes diagnosis are often older and less frequently carry the high-risk DQ2/8 genotype. Our finding of an association between HLA-DQ2 and thyroid autoimmunity may explain some of the joint genetic susceptibility and family clustering of type 1 diabetes and AITD [25]. However, other non-HLA genes, as well as environmental factors, may contribute to the covariance of AITD and type 1 diabetes.…”

Section: Discussionmentioning

confidence: 62%

“…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%

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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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Section: Discussionsupporting

confidence: 87%

Section: Discussionsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 62%

Section: Discussionmentioning

confidence: 99%

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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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“…HFE C282Y occurs in linkage disequilibrium with class I alleles at human leukocyte antigen (HLA)-A and -B loci and with the hemochromatosis ancestral haplotype HLA-A*03,B*07 on chromosome 6p (1,36). In Western European whites, Hashimoto thyroiditis and Graves' disease have been associated with HLA class II loci (37)(38)(39), but there are few reports of these disorders in whites with hemochromatosis phenotypes or C282Y homozygosity (6,40,41). This suggests that linkage disequilibrium of HFE C282Y with HLA class II loci is not great, that the ancestral hemochromatosis haplotype does not include susceptibility alleles for common autoimmune thyroid disorders, or that there are other susceptibility factors for Hashimoto thyroiditis and Graves' disease.…”

Section: Thyroid Levels In C282y Homozygotesmentioning

confidence: 99%

Thyroid-Stimulating Hormone and Free Thyroxine Levels in Persons with HFE C282Y Homozygosity, a Common Hemochromatosis Genotype: The HEIRS Study

Barton¹,

Leiendecker–Foster

Reboussin

et al. 2008

Thyroid

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for the Hemochromatosis and Iron Overload Screening Study Research InvestigatorsBackground: Relationships of thyroid and iron measures in large cohorts are unreported. We evaluated thyroidstimulating hormone (TSH) and free thyroxine (T4) in white participants of the primary care-based Hemochromatosis and Iron Overload Screening (HEIRS) Study. Methods: We measured serum TSH and free T4 in 176 HFE C282Y homozygotes without previous hemochromatosis diagnoses and in 312 controls without HFE C282Y or H63D who had normal serum iron measures and were matched to C282Y homozygotes for Field Center, age group, and initial screening date. We defined hypothyroidism as having TSH >5.00 mIU=L and free T4 <0.70 ng=dL, and hyperthyroidism as having TSH <0.400 mIU=L and free T4 >1.85 ng=dL. Multivariate analyses were performed using age, sex, Field Center, log 10 serum ferritin (SF), HFE genotype, log 10 TSH, and log 10 free T4. Results: Prevalences of hypothyroidism in C282Y homozygotes and controls were 1.7% and 1.3%, respectively, and of hyperthyroidism 0% and 1.0%, respectively. Corresponding prevalences did not differ significantly. Correlations of log 10 SF with log 10 free T4 were positive ( p ¼ 0.2368, C282Y homozygotes; p ¼ 0.0492, controls). Independent predictors of log 10 free T4 were log 10 TSH (negative association) and age (positive association); positive predictors of log 10 SF were age, male sex, and C282Y homozygosity. Proportions of C282Y homozygotes and controls who took medications to supplement or suppress thyroid function did not differ significantly. Conclusions: Prevalences of hypothyroidism and hyperthyroidism are similar in C282Y homozygotes without previous hemochromatosis diagnoses and controls. In controls, there is a significant positive association of SF with free T4. We conclude that there is no rationale for routine measurement of TSH or free T4 levels in hemochromatosis or iron overload screening programs.

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Predictors of associated autoimmune diseases in families with type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium

Wägner

Santana

Herńndez

et al. 2011

Diabetes Metabolism Res

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Background Type 1 diabetes (T1D) is a clinically heterogeneous disease. The presence of associated autoimmune diseases (AAID) may represent a distinct form of autoimmune diabetes, with involvement of specific mechanisms. The aim of this study was to find predictors of AAID in the Type 1 Diabetes Genetics Consortium (T1DGC) data set. Methods 3263 families with at least 2 siblings with T1D were included. Clinical information was obtained using questionnaires, anti-GAD and anti-IA-2 were measured and HLA-genotyping was performed. Siblings with T1D with and without AAID were compared and a multivariate regression analysis was performed to find predictors of AAID. T1D-associated HLA haplotypes were defined as the 4 most susceptible and protective, respectively. Results AAID was present in 14.4% of the T1D affected siblings. Age of diabetes onset, current age and time since diagnosis were higher, and there was a female predominance and more family history of AAID in the group with AAID, as well as more frequent anti-GAD and less frequent anti-IA2 positivity. Risk and protective HLA haplotype distributions were similar, though DRB1*0301-DQA1*0501-DQB1*0201 was more frequent in the group with AAID. In the multivariate analysis, female gender, age of onset, family history of AAID, time since diagnosis and anti-GAD positivity were significantly associated with AAID. Conclusions In patients with T1D, the presence of AAID is associated with female predominance, more frequent family history of AAID, later onset of T1D and more anti-GAD antibodies, despite longer duration of the disease. The predominance of certain HLA haplotypes suggests that specific mechanisms of disease may be involved.

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Analysis of HLA genes in families with autoimmune diabetes and thyroiditis

Cited by 74 publications

References 35 publications

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

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

Thyroid-Stimulating Hormone and Free Thyroxine Levels in Persons with HFE C282Y Homozygosity, a Common Hemochromatosis Genotype: The HEIRS Study

Predictors of associated autoimmune diseases in families with type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium

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