Preliminary evidence of a noncausal association between the X-chromosome inactivation pattern and thyroid autoimmunity: a twin study.

An increased frequency of skewed X-chromosome inactivation (XCI) is found in clinically overt autoimmune thyroid disease (AITD) compared with controls. Whether skewed XCI is involved in the pathogenesis of autoantibodies to thyroid peroxidase (TPOAb) in euthyroid subjects is unknown. To examine the impact of XCI on the serum concentration of TPOAb, we studied whether within-cohort and within-twin-pair differences in XCI are associated with differences in serum concentrations of TPOAb. A total of 318 euthyroid female twin individuals distributed in 159 pairs were investigated. XCI was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. TPOAb concentrations were measured using a solid-phase time-resolved fluoroimmunometric assay. Overall (within cohort), there was a significant association between XCI and serum concentrations of TPOAb; regression coefficient (beta)=1.45 (95% confidence interval, 0.52-2.38), P=0.003. The association remained significant in the within-pair analysis; beta=1.74 (0.79-2.69), P<0.001. The relationship was nonsignificant within the 82 monozygotic pairs (beta=0.57 (-0.78-1.92), P=0.405), whereas the association was significant in the 77 dizygotic pairs (beta=2.17 (0.81-3.53), P=0.002). This preliminary finding of a significant association between TPOAb concentrations and XCI within cohort and within dizygotic but not within monozygotic twin pairs may indicate that XCI per se does not have a major role in the pathogenesis of TPOAb. More likely, XCI and TPOAb are influenced by shared genetic determinants.

Aggregation of thyroid autoantibodies in twins from opposite-sex pairs suggests that microchimerism may play a role in the early stages of thyroid autoimmunity.

CONTEXT: Microchimerism is the presence of small populations of cells from one individual in another genetically distinct individual. This phenomenon can arise from pregnancy, blood transfusion, or bidirectional cell trafficking between twins in utero. Microchimerism has recently been proposed to play a role in the pathogenesis of thyroid autoimmunity. In that case, twins from opposite-sex pairs (OS) should have an increased risk of thyroid autoantibodies (TA). AIM: The aim of the study was to compare the frequency of TA in twin individuals from OS and monozygotic (MZ) twin pairs. DESIGN: This was a case-control study of 240 individuals (120 females and 120 males) from OS twin pairs (cases) and 568 control individuals from MZ pairs (284 females and 284 males). METHODS: Antibodies toward thyroid peroxidase (TPOAb), thyroglobulin (TgAb), and the TSH receptor (TSHRAb) were measured and considered positive if greater than 60 U/ml, greater than 60 U/ml, and greater than 1.0 U/liter, respectively. RESULTS: The frequency of TPOAb, TgAb, and TSHRAb among female cases was 15.0, 5.0, and 4.2%, respectively, which was higher than the corresponding prevalences in the female control population: 7.4% (P = 0.018), 1.1% (P = 0.023), and 0.7% (P = 0.026), respectively. However, when corrected for the number of phenotypes studied (TPOAb, TgAb, TSHRAb, and any thyroid antibody), the association remained significant only in the combined group, P(corrected) = 0.012. Essentially similar results were obtained in males. CONCLUSION: Both female and male twins from OS pairs, as opposed to MZ pairs, have an increased frequency of TA, indicating a potential role of microchimerism in developing TA.

X Chromosome inactivation pattern is not associated with interindividual variations in thyroid volume: a study of euthyroid Danish female twins.

Ahigher frequency of skewed X chromosome inactivation (XCI) is found in patients with autoimmune thyroid disease (AITD) than in controls. Although goitre is often present in AITD, a recent study failed to show an association between XCI and clinically overt nontoxic goitre. However, the etiology of overt goitre is complex, and the mechanisms influencing thyroid volume may involve fewer factors than the mechanisms underlying overt goitre. In order to examine the impact of XCI on thyroid volume in euthyroid females, we studied whether within cohort (n = 138) and within twin pair (n = 69) differences in XCI are correlated with differences in thyroid volume. XCI was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. Thyroid volume was determined by ultrasound. Neither in the within cohort nor in the within twin pair analysis could we demonstrate a statistically significant association between XCI and thyroid volume: Regression coefficient (beta) = 0.023 (95% confidence interval, -0.062-0.108), p = 0.592 and beta = 0.038 (-0.080-0.156), p = 0.521, respectively. Controlling for potential confounders such as zygosity, age, TSH, smoking habits and use of oral contraceptives did not change the findings. In conclusion, in a sample of euthyroid Danish female twins, we found no evidence of a relationship between XCI pattern and thyroid volume.

No link between X chromosome inactivation pattern and simple goiter in females: evidence from a twin study.

BACKGROUND: Simple goiter (SG) comprises diffuse (DG) and nodular (NG) benign nonautoimmune nontoxic goiter. In nonendemic goiter areas, the ratio of females to males may exceed 5:1, indicating that gender and/or sex hormones may play a role in the etiology of SG in these areas. Theoretically, as shown for autoimmune thyroid disease, X chromosome inactivation (XCI) and resultant tissue chimerism could offer a novel explanation for the female preponderance of SG. To examine whether skewed XCI is associated with SG, we first compared XCI in 71 twin individuals with SG with that in 142 unrelated healthy control twin individuals, and then performed a within-pair comparison of XCI in 48 twin pairs discordant for SG. METHODS: DNA was extracted from peripheral blood cells. XCI analysis was performed by predigestion of DNA using the methylation-sensitive enzyme Hpall, followed by polymerase chain reaction of the polymorphic CAG repeat of the androgen receptor gene. A polymerase chain reaction product is obtained from the inactive X chromosome only. The XCI pattern was classified as skewed when 80% or more of the cells preferentially inactivated the same X chromosome. Twin zygosity was established by DNA fingerprinting. RESULTS: The frequency of skewed XCI in female twins with SG, DG, and NG was 11% (8/71), 13% (6/46), and 8% (2/25), respectively, which was not significantly different from the prevalences in the corresponding control populations, 14% (20/142, p = 0.56), 14% (13/92, p = 1.00), and 14% (7/50, p = 0.71), respectively. Essentially, similar results were obtained when comparing the prevalence of skewed XCI in twin pairs discordant for SG (48 pairs), DG (30 pairs), and NG (18 pairs). CONCLUSION: In a sample of Danish female twins, we did not find evidence for involvement of skewed XCI in the etiology or the female preponderance of SG.

The effect of genetic variation in the type 1 deiodinase gene on the interindividual variation in serum thyroid hormone levels: an investigation in healthy Danish twins.

INTRODUCTION: Genetic factors have a considerable influence on serum thyroid hormone levels. The C785T and A1814G polymorphisms, located in the 3' untranslated region of the type 1 deiodinase (D1) gene have been associated with serum FT4 and rT3 levels. OBJECTIVE: In healthy Danish twins, we examined the association of these polymorphisms with serum thyroid hormone levels and determined the proportion of genetic influence explained by these variants. We analysed the underlying functional mechanism by performing mRNA stability measurements and analysed the effect of these variants on D1 activity. METHODS: Serum thyroid measurements and genotypes of the D1-C785T and D1-A1814G polymorphisms were determined in 1192 twins. Structural equation modelling was used to determine heritability estimates. Functional analyses were carried out in D1-transfected JEG3 cells. RESULTS: Carriers of the D1-785T allele had 3.8% higher FT4 and 14.3% higher rT3 levels, resulting in a lower T3/T4 and T3/rT3 ratio and a higher rT3/T4 ratio. This polymorphism explained 0.87% and 1.79%, respectively, of the variation in serum FT4 and rT3. The D1-A1814G polymorphism was not associated with serum thyroid hormone levels. No differences in D1 mRNA decay rate or D1 activity were observed between wild-type D1 and the two variants. CONCLUSION: The D1-C785T polymorphism is consistently and significantly associated with serum thyroid hormone levels. However, the proportion of genetic influence explained by this particular polymorphism is small. No effect of the polymorphism on D1 mRNA decay rate or D1 activity was observed. The underlying functional mechanism needs to be elucidated.

Identification and consequences of polymorphisms in the thyroid hormone receptor alpha and beta genes.

OBJECTIVE: Genetic factors exert considerable influence on thyroid function variables. Single nucleotide polymorphisms (SNPs) in thyroid hormone pathway genes have been associated with serum thyroid parameters implying small alterations in the hypothalamus-pituitary-thyroid axis. However, little is known about SNPs in the THRA (17q11.2) and THRB (3p24.2) genes. The aim of this study was to map THRA and THRB for the occurrence and frequencies of SNPs and relate these to thyroid parameters. DESIGN AND METHODS: SNPs were identified by sequencing all THRA and THRB exons and flanking regions in 52 randomly selected subjects. SNPs were genotyped in 1116 healthy Danish twins by TaqMan assays and related to thyroid parameters. One SNP in THRB was additionally genotyped in the elderly population of the Rotterdam Scan Study (n = 940). MAIN OUTCOME: 15 SNPs (7 novel) in THRA and THRB were identified. Two SNPs in the 3' untranslated region of THRA were genotyped: a novel SNP (2390A/G) and 1895C/A (rs12939700). In THRB, a synonymous (735C/T; rs3752874) and an intronic SNP (in9-G/A; rs13063628) were genotyped. No associations between SNPs and thyroid hormone levels (total and free 3,3',5-triiodo-L-thyronine [T3] and thyroxine, reverse T3) were found. THRB-in9-G/A was significantly associated with higher serum thyroid stimulating hormone (TSH) (p(lnTSH) = 0.01) in the Danish twins, but not in subjects of the Rotterdam Scan Study, although it showed a similar trend. CONCLUSIONS: Analysis of the T3 receptor genes revealed 15 SNPs, including 7 novel. Only THRB-in9-G/A was associated with higher serum TSH in a large population of Danish twins.

Thyroid hormone transport and metabolism by organic anion transporter 1C1 and consequences of genetic variation.

Organic anion transporting polypeptide (OATP) 1C1 has been characterized as a specific thyroid hormone transporter. Based on its expression in capillaries in different brain regions, OATP1C1 is thought to play a key role in transporting thyroid hormone across the blood-brain barrier. For this reason, we studied the specificity of iodothyronine transport by OATP1C1 in detail by analysis of thyroid hormone uptake in OATP1C1-transfected COS1 cells. Furthermore, we examined whether OATP1C1 is rate limiting in subsequent thyroid hormone metabolism in cells cotransfected with deiodinases. We also studied the effect of genetic variation in the OATP1C1 gene: polymorphisms were determined in 155 blood donors and 1192 Danish twins and related to serum thyroid hormone levels. In vitro effects of the polymorphisms were analyzed in cells transfected with the variants. Cells transfected with OATP1C1 showed increased transport of T4 and T4 sulfate (T4S), little transport of rT3, and no transport of T3 or T3 sulphate, compared with mock transfected cells. Metabolism of T4, T4S, and rT3 by cotransfected deiodinases was greatly augmented in the presence of OATP1C1. The OATP1C1-intron3C>T, Pro143Thr, and C3035T polymorphisms were not consistently associated with thyroid hormone levels, nor did they affect transport function in vitro. In conclusion, OATP1C1 mediates transport of T4, T4S, and rT3 and increases the access of these substrates to the intracellular active sites of the deiodinases. No effect of genetic variation on the function of OATP1C1 was observed.

The impact of a TSH receptor gene polymorphism on thyroid-related phenotypes in a healthy Danish twin population.

OBJECTIVES: The Asp727Glu polymorphism in the TSH receptor (TSHR) gene is associated with serum TSH levels. However, the proportion of genetic variation accounted for by this polymorphism is unknown. In this study, we (1) examined the association of the Asp727Glu polymorphism with thyroid size, serum levels of TSH, thyroid hormones, and thyroid antibodies in 1241 healthy Danish twin individuals and (2) assessed the contribution of the polymorphism to the trait variation and the genetic variance. MEASUREMENTS: The effect of the genotype on the traits (mean +/- SD) was established; associations between the TSHR-Asp727Glu polymorphism and measures of thyroid homeostasis were assessed and the effect of the polymorphism on the trait's phenotypic variability was quantified by incorporating the genotype information in structural equation modelling. RESULTS: The genotype distribution was Asp/Asp 84.9%; Asp/Glu 14.5% and Glu/Glu 0.6%. Carriers of the TSHR-Glu727 allele had lower TSH levels (noncarriers vs. carriers: 1.78 +/- 0.93 vs. 1.60 +/- 0.84 mU/l, P = 0.04). Regression analysis showed an association between the TSHR-Asp727Glu polymorphism and serum TSH (P = 0.007). The polymorphism accounted for 0.91% of the total phenotypic variance in serum TSH levels. Including the genotype in quantitative genetic modelling improved the model fit (P = 0.001); however, the genetic influence on serum TSH not attributable to this specific genetic variant was only reduced from 68.2% to 67.8%. The polymorphism was not significantly associated with thyroid size, thyroid hormones or thyroid antibody levels. CONCLUSIONS: The TSHR-727Glu allele was associated with decreasing TSH levels; however, the contribution to the genetic variance was very small. No association was found with other thyroid-related measures.

Genetic and environmental interrelations between measurements of thyroid function in a healthy Danish twin population.

Serum thyrotropin (TSH), free thyroxine (T4), and free triiodothyronine (T3) levels illustrate the thyroid function set point, but the interrelations between these have never been characterized in detail. The aim of this study was to examine the associations between TSH and thyroid hormone levels in healthy euthyroid twins and to determine the extent to which the same genes influence more than one of these biochemical traits; 1,380 healthy euthyroid Danish twins (284 monozygotic, 286 dizygotic, 120 opposite-sex twin pairs) were recruited. Genetic and environmental associations between thyroid function measurements were examined using quantitative genetic modeling. In bivariate genetic models, the phenotypic relation between two measurements was divided into genetic and environmental correlations. Free T4 and free T3 levels were positively correlated (r=0.32, P<0.0001). The genetic correlation between serum free T4 and free T3 levels was rg=0.25 (95% CI 0.14-0.35), suggesting that a set of common genes affect both phenotypes (pleiotropy). The correlation between the environmental effects was re=0.41 (0.32-0.50). From this we calculated that the proportion of the correlation between free T4 and free T3 levels mediated by common genetic factors was 48%. Only 7% of the genetic component of serum free T3 levels is shared with serum free T4. Serum TSH and thyroid hormone levels did not share any genetic influences. In conclusion, thyroid hormone levels are partly genetically correlated genes that affect free T4 levels and exert pleiotropic effects on free T3 levels, although most of the genetic variance for these measurements is trait specific.

Establishment of reference distributions and decision values for thyroid antibodies against thyroid peroxidase (TPOAb), thyroglobulin (TgAb) and the thyrotropin receptor (TRAb).

BACKGROUND: The National Academy of Clinical Biochemistry (NACB) stresses that the reference intervals for thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and thyroid stimulating hormone (TSH)-receptor antibodies (TRAb) should be based on young men who lack certain risk factors and have serum TSH between 0.5 and 2.0 mIU/L. However, some young men without any of the risk factors have autoantibodies, and cannot be identified by the present tools. A model for reference intervals and cut-off values should not be influenced by the prevalence of risk factors. METHODS: We developed a model of "composite logarithmic Gaussian distributions" and tested it in 1441 well-characterised subjects without clinically overt thyroid disease. RESULTS: TPOAb and TgAb could be measured in all individuals. The 97.5% upper limits 1) on a traditional non-parametric scale, 2) according to the NACB criteria, and 3) for our model were 284, 24 and 9.8 kIU/L for TPOAb, and 84, 22 and 19 kIU/L for TgAb, respectively. The decision value (defined as the concentration corresponding to 0.1% false positives) was 15 kIU/L for TPOAb and 31 kIU/L for TgAb. Concentrations above our reference intervals affected the corresponding distribution of TSH values. For TRAb the upper reference limits were 1) 0.75 and 2) 0.75 IU/L, while our model was not applicable to TRAb because only 2-3% of the results were above the functional assay sensitivity. CONCLUSIONS: In contrast to the NACB guidelines, our model for TPOAb and TgAb is more robust, as it is independent of the characteristics of the reference population.

Low birth weight is not associated with thyroid autoimmunity: a population-based twin study.

CONTEXT: Low birth weight has been proposed as a risk factor for the development of antibodies toward thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) in adult life. However, the association could also be due to genetic or environmental factors affecting both birth weight and the development of thyroid autoantibodies. The effect of these confounders can be minimized through investigation of twin pairs. OBJECTIVE AND DESIGN: To examine the impact of low birth weight on the development of thyroid autoimmunity, we studied whether within-twin-cohort and within-twin-pair differences in birth weight are associated with differences in the serum concentration of TPOAb and TgAb in adult life. PARTICIPANTS: We studied 1024 euthyroid twin individuals who were distributed in 512 same-sex twin pairs. METHODS: Original midwife protocols were traced manually through the Provincial Archives of Denmark. TPOAb and TgAb were measured using solid-phase time-resolved fluoroimmunometric assays. RESULTS: There were no statistically significant associations between birth weight and serum concentrations of TPOAb [regression coefficient (beta) = 0.003 (95% confidence interval, -0.010 to 0.015); P = 0.67] or TgAb [beta = 0.002 (-0.010 to 0.014); P = 0.77]. When restricting the analysis to twin pairs with a within-pair difference in birth weight of 500 g or greater or to twin pairs born 4 wk or more before term, the regression coefficients were almost unchanged. Controlling for potential confounders (sex, zygosity, gestational age, TSH, and smoking) did not change the findings of nonsignificant regression coefficients. CONCLUSION: Low birth weight per se has no evident role in the etiology of thyroid autoimmunity.

The relative importance of genetic and environmental factors in the aetiology of thyroid nodularity: a study of healthy Danish twins.

BACKGROUND: A large proportion of healthy, euthyroid, nongoitrous individuals have thyroid nodules. The aetiology of these ultrasonographically detected morphological abnormalities is largely unknown. Factors such as age, gender, iodine intake, smoking and parity are associated with nodularity of the thyroid. Whether there is a genetic susceptibility is unclear. AIM: To gain insight into the aetiology of thyroid nodularity by investigating a large cohort of healthy euthyroid monozygotic and dizygotic twins. DESIGN: A cross-sectional twin study. PARTICIPANTS: A representative sample of self-reported healthy twin pairs was identified through the Danish Twin Registry. A total of 520 individuals divided into 104 monozygotic (MZ), 107 dizygotic same sex (DZ) and 49 opposite sex (OS) twin pairs were investigated. MEASUREMENTS: Probandwise concordance and tetrachoric correlations. Quantitative genetic modelling was used to elucidate the relative importance of genetic and environmental effects for the variation in the liability of nodularity. RESULTS: A higher concordance rate for thyroid nodularity was found in MZ twins [0.57 (95% CI 0.36-0.76)] than in DZ twins [0.36 (95% CI 0.17-0.56, P = 0.074)]. The same was true for tetrachoric correlations: 0.67 (95% CI 0.34-0.87) in MZ twins and 0.17 (CI - 0.28-0.56, P = 0.053) in DZ twins. The difference, although not significant, was more pronounced for multiple nodules than for solitary nodules. Controlling for covariates (age, gender and smoking habits), it was calculated that genetic factors accounted for 67% (95% CI 35-87%) and environmental factors for 33% (95% CI 13-65%) of the individual differences in the liability to thyroid nodularity. CONCLUSIONS: This study suggests that genetic factors are of aetiological importance for thyroid nodularity in clinically healthy and euthyroid individuals, and indicates a difference in the aetiology of solitary and multiple thyroid nodules.

Establishment of a serum thyroid stimulating hormone (TSH) reference interval in healthy adults. The importance of environmental factors, including thyroid antibodies.

It has previously been shown that thyroid antibodies affect thyroid stimulating hormone (TSH) concentrations in men and women and that TSH levels are predictive of future thyroid disease. We investigated the validity of the National Academy of Clinical Biochemistry (NACB) guidelines regarding the TSH reference interval by studying 1512 individuals. Two hundred and fifty had at least one thyroid antibody, 121 were taking medications other than estrogens and occasional analgesics, and 105 reported a family history of thyroid disease. Serum TSH, thyroid peroxidase antibodies (TPOab) and thyroglobulin antibodies (Tgab) were determined on AutoDELFIA and TSHRab by a radioreceptor assay (RRA) from Brahms Diagnostica. For individuals without thyroid antibodies and other risk factors, no effect of age and gender was seen for serum TSH. Neither medication nor the presence of Tgab alone had any influence on serum TSH. TPOab alone or in combination with Tgab were associated with an increased serum TSH level. The 'cumulative percentage distributions' of subgroups, as well as the combined population, was In-Gaussian distributed. The central 95% of the population was within the 95% CI in rankit-plots. Consequently, a common reference interval for serum TSH of 0.58-4.07 mlU/l for all adults between 17 and 66 years of age was established. This reference interval is much higher than expected from the NACB-guidelines.

Genetic and environmental causes of individual differences in thyroid size: a study of healthy Danish twins.

Factors such as iodine intake, serum TSH concentration, gender, age, body mass index, parity, and cigarette smoking are thought to influence thyroid size. The purpose of our study was to determine the relative roles of these environmental and physiological factors compared with genetic factors in euthyroid subjects with a clinically normal thyroid gland. A representative sample of self-reported healthy twin pairs was identified through the Danish Twin Registry. A total of 520 individuals divided into 104 monozygotic (MZ), 107 dizygotic same sex (DZ), and 49 opposite sex twin pairs were investigated. After adjustment for age, gender, and other covariates, intraclass correlations were calculated. To elucidate the relative importance of genetic and environmental factors to the variation of ultrasonically determined thyroid volume, quantitative genetic modeling was used. Regression analysis suggested that serum TSH, serum free T(4), gender, age, smoking, and body mass index each played a small, but significant, role for variation in thyroid volume. The intraclass correlations for thyroid volume were consistently higher for MZ than for DZ twin pairs (r(MZ) = 0.71; r(DZ) = 0.18; P < 0.001). Using quantitative genetic modeling, it was calculated that genetic factors (with 95% confidence intervals) accounted for 71% (61-78%) of the individual differences in thyroid volume. Genetic influences are important in the regulation of normal thyroid size. This fits the observation that goiter may be seen also in the absence of evident environmental goitrogens such as iodine deficiency and that not all individuals develop goiter even in iodine-deficient areas.

Aggregation of thyroid autoantibodies in first-degree relatives of patients with autoimmune thyroid disease is mainly due to genes: a twin study.

BACKGROUND: Family studies have repeatedly shown aggregation of thyroid autoantibodies to thyroid peroxidase (TPOab) and thyroglobulin (Tgab) in first-degree relatives of patients with autoimmune thyroid disease (AITD). This phenomenon has generally been interpreted as evidence of a genetic component in the development of thyroid autoantibodies. However, family studies cannot determine whether the observed familial aggregation of these antibodies is due to shared genes or shared environment. AIM: To test the hypothesis that the familial aggregation of thyroid autoantibodies is mainly genetically determined. DESIGN: A cross-sectional study of healthy twin siblings to twins with AITD. PARTICIPANTS: Thirty-eight healthy twin siblings to twins with AITD and a control group of 76 healthy twins, matched for age, sex and zygosity, but without AITD among their first-degree relatives. MAIN OUTCOME MEASURES: Prevalence of TPOab, Tgab and TSH-receptor antibodies (TSHRab). METHODS: All antibodies were measured by routine commercial kits. TPOab, Tgab and TSHRab were regarded as positive if > 60 U/ml, > 60 U/ml and > 1.0 U/l, respectively. Zygosity was established by DNA fingerprinting. RESULTS: The prevalence of TPOab, Tgab and TSHRab in the 38 healthy twin siblings was 34% (13/38), 26% (10/38) and 13% (5/38), respectively, which was higher than the corresponding prevalences in the control population, 9% (7/76; P = 0.002), 7% (5/76; P = 0.006) and 1.3% (1/76; P = 0.015), respectively. Combination of two or more thyroid autoantibodies was also significantly more common among index subjects (10/38 or 26%) than in the control group (2/76 or 3%), P = 0.0001. Among the healthy monozygotic twin siblings, 53%, 47% and 20% had TPOab, Tgab and TSHRab, respectively, compared with 22% (P = 0.045), 13% (P = 0.02) and 9% (P = 0.36), respectively, in the dizygotic twin siblings. Significantly more monozygotic twin siblings were positive for two or more autoantibodies than dizygotic twin siblings (8/15 vs. 2/23; P = 0.006). CONCLUSION: Healthy first-degree relatives to patients with AITD show significant clustering of thyroid autoantibodies. Moreover, healthy monozygotic and dizygotic twin siblings to twins with AITD differ in prevalence of thyroid autoantibodies. These observations strongly support the hypothesis that the familial aggregation of thyroid autoantibodies is mainly genetically determined.

Major genetic influence on the regulation of the pituitary-thyroid axis: a study of healthy Danish twins.

Intraindividual variation is smaller than the interindividual variation in serum TSH, free T(4), and free T(3) concentrations. This suggests that each individual may have a genetically determined thyroid function set-point. A representative sample of self-reported healthy twin pairs was identified through the Danish Twin Registry. A total of 284 monozygotic (MZ), 286 dizygotic same-sex (DZ), and 120 opposite-sex (OS) twin pairs were investigated. A classical twin study was performed. After adjustment for age, sex, and other covariates, the intraclass correlations of serum TSH, free T(4), and free T(3) were calculated. To elucidate the relative importance of hereditary and environmental factors on the variation of these hormone levels, quantitative genetic modeling was used. The intraclass correlations were consistently higher for MZ twin pairs than for DZ twin pairs. Regression analysis suggested that iodine intake played a small but significant role for the concentration of serum TSH and free T(4), whereas cigarette smoking was without influence. In quantitative genetic modeling, the heritability (with 95% confidence intervals) accounted for 64% (57-70%) of the variation in serum TSH concentration and 65% (58-71%) and 64% (57-70%), for the concentrations of free T(4) and free T(3), respectively. Genetic factors play a substantial role in controlling the pituitary-thyroid axis, indicating that each individual has a genetically determined thyroid function set-point. Whether this is of importance when treating individuals in whom pituitary-thyroid function has been disrupted by, e.g. hypo- or hyperthyroidism, remains to be clarified.