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1.
Eur J Endocrinol ; 164(5): 781-8, 2011 May.
Article in English | MEDLINE | ID: mdl-21367965

ABSTRACT

OBJECTIVE: Minor variation in serum thyroid hormone (TH) levels can have important effects on various clinical endpoints. Although 45-65% of the inter-individual variation in serum TH levels is due to genetic factors, the causative genes are not well established. We therefore studied the effects of genetic variation in 68 TH pathway genes on serum TSH and free thyroxine (FT(4)) levels. DESIGN AND METHODS: Sixty-eight genes (1512 polymorphisms) were studied in relation to serum TSH and FT(4) levels in 1121 Caucasian subjects. Promising hits (P<0.01) were studied in three independent Caucasian populations (2656 subjects) for confirmation. A meta-analysis of all four studies was performed. RESULTS: For TSH, eight PDE8B polymorphisms (P=4×10(-17)) remained significant in the meta-analysis. For FT(4), two DIO1 (P=8×10(-12)) and one FOXE1 (P=0.0003) polymorphisms remained significant in the meta-analysis. Suggestive associations were detected for one FOXE1 (P=0.0028) and three THRB (P=0.0045) polymorphisms with TSH, and one SLC16A10 polymorphism (P=0.0110) with FT(4), but failed to reach the significant multiple-testing corrected P value (P<0.0022 and P<0.0033 respectively). CONCLUSIONS: Using a large-scale association analysis, we replicated previously reported associations with genetic variation in PDE8B, THRB, and DIO1. We demonstrate effects of genetic variation in FOXE1 on serum FT(4) levels, and borderline significant effects on serum TSH levels. A suggestive association of genetic variation in SLC16A10 with serum FT(4) levels was found. These data provide insight into the molecular basis of inter-individual variation in TH serum levels.


Subject(s)
Forkhead Transcription Factors/genetics , Genetic Association Studies/methods , Signal Transduction/physiology , Thyroxine/blood , Thyroxine/genetics , Adult , Aged , Cohort Studies , Female , Forkhead Transcription Factors/blood , Genetic Variation/genetics , Humans , Male , Middle Aged , Population Surveillance/methods , Prospective Studies , Thyroid Hormones/blood , Thyroid Hormones/genetics
2.
Clin Endocrinol (Oxf) ; 73(5): 666-70, 2010 Nov.
Article in English | MEDLINE | ID: mdl-20718768

ABSTRACT

OBJECTIVE: The pituitary-thyroid axis (PTA) set point is determined by a combination of genetic and environmental factors. However, despite considerable efforts to characterize the background, the causative genes as well as environmental factors are not well established. Theoretically, as shown for autoimmune thyroid disease, the pattern of X chromosome inactivation (XCI) could offer a novel explanation for the observed variability of the PTA set point in women. DESIGN AND PATIENTS: To examine the impact of XCI pattern on the PTA set point, we studied whether within-cohort (n = 318 subjects) and within-twin pair (n = 159 pairs) differences in XCI are correlated with serum concentrations of thyrotropin (TSH), free triiodothyronine (FT3) and free thyroxine (FT4). METHODS: X chromosome inactivation was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. Thyroid variables were measured using a solid-phase time-resolved fluoroimmunometric assay. Zygosity was established by DNA fingerprinting. RESULTS: In the overall study population (within cohort), no significant correlations were found between TSH [regression coefficient (ß) = -0·28 (95% confidence intervals, -0·66 to 0·11), P = 0·158], FT3 [ß = -0·25 (-0·85 to 0·34), P = 0·403], FT4 [ß = 0·08 (-0·91 to 1·07), P = 0·876] and XCI pattern. Essentially similar results were found in the within-pair analysis. Controlling for confounders such as age, body mass index, smoking and zygosity did not change the findings. CONCLUSIONS: In a sample of female twins, we found no evidence of a relationship between XCI pattern and PTA set point.


Subject(s)
Pituitary Gland/physiology , Thyroid Gland/physiology , X Chromosome Inactivation/genetics , Adult , Autoantibodies/blood , Cohort Studies , Female , Humans , Middle Aged , Thyrotropin/blood , Thyroxine/blood , Triiodothyronine/blood , Twins, Dizygotic/genetics , Twins, Monozygotic/genetics
3.
Clin Endocrinol (Oxf) ; 69(3): 491-6, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18284638

ABSTRACT

BACKGROUND: Yersinia enterocolitica (YE) infection has long been implicated in the pathogenesis of Graves' disease (GD). The association between YE and GD could, however, also be due to common genetic or environmental factors affecting the development of both YE infection and GD. This potential confounding can be minimized by investigation of twin pairs discordant for GD. AIM: To examine whether YE infection is associated with GD. DESIGN: We first conducted a classical case-control study of individuals with (61) and without (122) GD, and then a case-control study of twin pairs (36) discordant for GD. METHODS: Immunoglobulin (Ig)A and IgG antibodies to virulence-associated Yersinia outer membrane proteins (YOPs) were measured. MAIN OUTCOME MEASURES: The prevalence of YOP IgA and IgG antibodies. RESULTS: Subjects with GD had a higher prevalence of YOP IgA (49%vs. 34%, P = 0.054) and YPO IgG (51%vs. 35%, P = 0.043) than the external controls. The frequency of chronic YE infection, reflected by the presence of both IgA and IgG YOP antibodies, was also higher among cases than controls (49%vs. 33%, P = 0.042). Similar results were found in twin pairs discordant for GD. In the case-control analysis, individuals with GD had an increased odds ratio (OR) of YE infection: IgA 1.84 (95% CI 0.99-3.45) and IgG 1.90 (95% CI 1.02-3.55). In the co-twin analysis, the twin with GD also had an increased OR of YE infection: IgA 5.5 (95% CI 1.21-24.81) and IgG 5.0 (95% CI 1.10-22.81). CONCLUSION: The finding of an association between GD and YE in the case-control study and within twin pairs discordant for GD supports the notion that YE infection plays an aetiological role in the occurrence of GD, or vice versa. Future studies should examine the temporal relationship of this association in more depth.


Subject(s)
Graves Disease/etiology , Yersinia Infections/complications , Yersinia enterocolitica/physiology , Adult , Aged , Antibodies, Bacterial/blood , Case-Control Studies , Female , Graves Disease/blood , Graves Disease/epidemiology , Graves Disease/immunology , Humans , Male , Middle Aged , Odds Ratio , Prevalence , Seroepidemiologic Studies , Yersinia Infections/blood , Yersinia Infections/epidemiology , Yersinia Infections/immunology , Yersinia enterocolitica/immunology
4.
Eur J Endocrinol ; 154(1): 29-38, 2006 Jan.
Article in English | MEDLINE | ID: mdl-16381988

ABSTRACT

OBJECTIVE: In euthyroid individuals, autoantibodies to thyroid peroxidase (TPOab) and thyroglobulin (Tgab) are regarded as early markers of thyroid autoimmunity. Family and twin studies suggest that development of thyroid autoantibodies in first-degree relatives of patients with autoimmune thyroid disease is under genetic influence. We aimed to estimate the relative importance of genetic and environmental effects for the presence of thyroid autoantibodies in euthyroid subjects. METHODS: A representative sample of healthy twin pairs was identified through the Danish Twin Registry; 1372 individuals, divided into 283 monozygotic (MZ), 285 dizygotic same sex (DZ), and 118 opposite sex twin pairs were investigated. Serum TPOab and serum Tgab were measured. Proband-wise concordance and intraclass correlations were calculated, and quantitative genetic modelling was performed. RESULTS: Probandwise concordance and intraclass correlations were consistently higher for MZ than for DZ twin pairs indicating genetic influence. Genetic components (with 95% confidence intervals) accounted for 73% (46-89%) of the liability of being thyroid antibody positive. Adjusting for covariates (age, TSH and others), the estimate for genetic influence on serum TPOab concentrations was 61% (49-70%) in males and 72% (64-79%) in females. For serum Tgab concentrations, the estimates were 39% (24-51%) and 75% (66-81%) respectively. CONCLUSIONS: Early markers of thyroid autoimmunity appear to be under strong genetic influence. The analyses suggest that it is the same set of genes that operate in males and females. However, complex mechanisms such as dominance and/or epistasis may be involved.


Subject(s)
Autoimmune Diseases/genetics , Diseases in Twins/immunology , Thyroid Diseases/immunology , Adult , Autoantibodies/analysis , Autoimmune Diseases/immunology , Diseases in Twins/genetics , Environment , Female , Humans , Iodide Peroxidase/immunology , Male , Middle Aged , Models, Genetic , Thyroglobulin/immunology , Thyroid Diseases/genetics , Thyroid Gland/immunology , Twins, Dizygotic/immunology , Twins, Monozygotic/immunology
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