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BRIX
The relative importance of genetic and environmental effects for the early stages of thyroid autoimmunity: a study of healthy Danish twins.Hansen
PS, Brix TH, Iachine I, Kyvik KO, Hegedus L. [abstract only]
"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."
A genome-wide screen in 1119 relative pairs with autoimmune thyroid disease.Taylor
JC, Gough SC, Hunt PJ, Brix TH, Chatterjee K, Connell JM, Franklyn JA, Hegedus
L, Robinson BG, Wiersinga WM, Wass JA, Zabaneh D, Mackay I, Weetman AP. [abstract only]
"CONTEXT: Autoimmune thyroid diseases (AITD), comprising Graves' disease and autoimmune hypothyroidism, are characterized by loss of immunological self-tolerance to thyroid antigens. These are complex diseases arising from a combination of genetic and environmental factors. An understanding of the genetic susceptibility factors for AITD could help to target treatments more effectively and identify people at risk for these conditions.
OBJECTIVE: The objective of this study was to identify regions of genetic linkage to AITD that could potentially harbor genetic susceptibility factors for these conditions.
DESIGN: The study design was a genome-wide screen performed on affected relative pairs with AITD. SETTING: Patients were recruited through hospital endocrinology clinics. PARTICIPANTS: Some 1119 Caucasian relative pairs affected with AITD (Graves' disease or autoimmune hypothyroidism) were recruited into the study. INTERVENTION: Blood samples were obtained from each participant for DNA analysis, and clinical questionnaires were completed. MAIN OUTCOME MEASURE: The study aimed to identify regions of genetic linkage to AITD.
RESULTS: Three regions of suggestive linkage were obtained on chromosomes 18p11 (maximum LOD score, 2.5), 2q36 (maximum LOD score, 2.2), and 11p15 (maximum LOD score, 2.0). No linkage to human leukocyte antigen was found.
CONCLUSIONS: The absence of significant evidence of linkage at any one locus in such a large dataset argues that genetic susceptibility to AITD reflects a number of loci, each with a modest effect. Linkage analysis may be limited in defining such loci, and large-scale association studies may prove to be more useful in identifying genetic susceptibility factors for AITD."
High frequency of skewed X-chromosome inactivation in females with autoimmune thyroid disease: a possible explanation for the female predisposition to thyroid autoimmunity.Brix
TH, Knudsen GP, Kristiansen M, Kyvik KO, Orstavik KH, Hegedus L.
"CONTEXT: Autoimmune thyroid diseases (AITD) comprise Graves' disease (GD) and Hashimoto's thyroiditis (HT). They are characterized by loss of immunological self-tolerance and female preponderance. Theoretically, X chromosome inactivation (XCI) and resultant tissue chimerism could offer an explanation for the female predisposition to AITD.
AIM: Our aim was to examine whether skewed XCI is associated with AITD.
DESIGNS: We first conducted a classical case-control study of twin individuals with and without AITD, and then a case-control study of twin pairs discordant for AITD. PARTICIPANTS: Participants included 32 female twins with AITD and a control group of 96 healthy female twin individuals. METHODS: XCI analysis was performed by enzymatic predigestion of DNA with a methylation-sensitive enzyme followed by PCR of the polymorphic CAG repeat of the androgen receptor gene. The XCI pattern was classified as skewed when 80% or more of the cells preferentially inactivated the same X chromosome. MAIN OUTCOME MEASURES: We assessed the prevalence of skewed XCI.
RESULTS: The frequency of skewed XCI in female twins with AITD, GD, and HT was 34, 37, and 31%, respectively, which was higher than the prevalence in the corresponding control populations, 11% (P = 0.003), 14% (P = 0.045), and 8% (P = 0.057), respectively. Similar results were found in twin pairs discordant for AITD. Overall, skewed XCI was associated with an increased risk of developing AITD, with an odds ratio of 9.0 (95% confidence interval, 1.64-49.4) (P = 0.022).
CONCLUSION: These observations suggest a possible role of XCI in the etiology of AITD and may in part explain the female preponderance of AITD."
Twin study of genetic and aging effects on X chromosome inactivation.Kristiansen
M, Knudsen GP, Bathum L, Naumova AK, Sorensen TI, Brix TH, Svendsen AJ,
Christensen K, Kyvik KO, Orstavik KH. [abstract only]
"To investigate the genetic influence on X chromosome inactivation and on age-related skewing of X inactivation, in particular, we analysed the X inactivation pattern (XIP) in peripheral blood cells from 118 young monozygotic (MZ) twin pairs (18-53 years), 82 elderly MZ twin pairs (55-94 years), 146 young dizygotic (DZ) twin pairs (20-54 years) and 112 elderly DZ twin pairs (64-95 years). Elderly twins had a higher frequency of skewed X inactivation (34%) than young twins (15%) (P<0.001). Our data suggest that the increase in skewing occurs after age 50-60 years. The intraclass correlation was 0.61 and 0.58 in young and elderly MZ twin pairs, and 0.08 and 0.09 in young and elderly DZ twin pairs. Biometric analysis showed that dominant genetic effects accounted for 63 and 58% of the variance of XIP in the young and elderly twin pairs, respectively. The dominant genetic effect and the shared environment for monochorionic MZ twins may explain the high intraclass correlation for the MZ twin pairs compared to the DZ twin pairs. We did not observe a significant decrease in the intraclass correlation in elderly MZ twins compared to young MZ twins, which would be expected if age-related skewing were due to stochastic factors. We conclude that the increased skewing with age implies that a genetically dependent selection of blood cells take place."
Aggregation of thyroid autoantibodies in first-degree relatives of patients with autoimmune thyroid disease is mainly due to genes: a twin study.Brix
TH, Hansen PS, Kyvik KO, Hegedus L. [abstract only]
"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.
Evidence for a major role of heredity in Graves' disease: a population-based study of two Danish twin cohorts.Brix TH, Kyvik KO, Christensen K, Hegedus L. J Clin Endocrinol Metab. 2001 Feb;86(2):930-4.
"The etiology of Graves' disease (GD), affecting up to 2% of a population in iodine-sufficient areas, is incompletely understood. According to current thinking, the development of GD depends on complex interactions among genetic, environmental, and endogenous factors. However, the relative contributions of the genetic and environmental factors remain to be clarified. In this study we report probandwise concordance rates for GD in a new cohort of same sex twin pairs born between 1953 and 1976 (young cohort), ascertained from the nationwide population-based Danish Twin Register. To elucidate the magnitude of the genetic and environmental influence in the etiology of GD, these new twin data were pooled with our previously published twin data on GD (old cohort). The old cohort consisted of 2338 same sex twin pairs born between 1870 and 1920 who had participated in questionnaire surveys during the 1950s, 1960s, and 1970s. The young cohort included 6628 same sex twin pairs born between 1953 and 1976 who had participated in a questionnaire survey in 1994. In the young cohort there were four monozygotic (MZ) pairs and one dizygotic (DZ) pair concordant for clinically overt GD, giving an overall probandwise concordance rate of 0.35 [95% confidence interval (CI), 0.16--0.57] for MZ pairs and 0.07 (95% CI, 0.01--0.24) for DZ pairs (P < 0.02). In the combined twin cohorts there were eight MZ pairs and one DZ pair concordant for clinically overt GD, giving a crude concordance rate of 0.35 (95% CI, 0.21--0.50) for MZ pairs and 0.03 (95% CI, 0.01--0.12) for DZ pairs (P < 0.02). Model-fitting analysis on the pooled twin data showed that 79% of the liability to the development of GD is attributable to genetic factors. Individual specific environmental factors not shared by the twins could explain the remaining 21%. In conclusion, our study strongly supports the idea that genetic factors play a major role in the etiology of GD and suggest that a further search for susceptibility genes is worthwhile."
A population-based study of chronic autoimmune hypothyroidism in Danish twins.Brix
TH, Kyvik KO, Hegedus L.
"Hashimoto's thyroiditis (HT), atrophic thyroiditis (AT), and Graves' disease are autoimmune thyroid diseases in which genetic factors are suspected to play an important role in disease susceptibility. In a recent population-based twin study we rendered it probable that a substantial part of the susceptibility to Graves' disease is attributable to genetic factors. At present there are no population-based twin studies supporting such a genetic influence in the etiology of HT/AT. To elucidate whether there is a genetic influence in the etiology of HT/AT, we studied the distribution of HT/AT in a population-based sample of 2945 Danish female-female twin pairs (5890 individuals) born between 1953 and 1972. Information on hypothyroidism was obtained from a nationwide questionnaire survey in 1994. Information from hospitals, out-patient clinics, general practitioners, and specialists was sought to verify the diagnosis. The overall prevalence of autoimmune hypothyroidism was 0.41% (24 of 5890). The prevalence did not differ between monozygotic and dizygotic twins (0.42% and 0.40%, respectively). The crude proband-wise concordance rates were significantly higher for monozygotic compared to dizygotic twin pairs: 0.55 (95% confidence interval, 0.23-0.83) vs. 0.0 (95% confidence interval, 0.0-0.25; P = 0.01). All of the healthy cotwins (n = 15) of twins with clinically overt autoimmune hypothyroidism were biochemically euthyroid. Overall, regardless of zygosity 53% (8 of 15) of the healthy cotwins were positive for antithyroid antibodies. The prevalence of autoantibodies among the monozygotic cotwins was 80% (4 of 5) and 40% (4 of 10) among dizygotic cotwins (P = 0.36). In conclusion, the higher concordance rate in monozygotic compared to dizygotic pairs indicates that genetic factors play a role in the etiology of HT/AT among Caucasian women living in areas with borderline iodine deficiency. However, the fact that the concordance rate among MZ twins was below 1 suggests that environmental factors also are of etiological importance."
What is the evidence of genetic factors in the etiology of Graves' disease? A brief review.Brix
TH, Kyvik KO, Hegedus L. [abstract only]
"Graves' disease (GD) is generally thought of as a multifactorial disorder in which genetic susceptibility interacts with environmental and endogenous factors to cause disease. The importance of genetic factors is suggested by the clustering of GD within families and by a higher concordance rate for disease in monozygotic than dizygotic twins. This has, however, recently been shown to be less pronounced than previously thought. During the last decade, much effort has been put into characterization of the genetic background of GD. Until recently most studies have examined associations between GD and the human leukocyte antigen (HLA) region, but recent advances in molecular techniques have opened the way for whole-genome screening. A number of HLA and non-HLA candidate genes have been proposed, but despite several large investigations within multiplex families no major susceptibility genes have been identified. This brief review discusses relevant articles published from 1940 through 1997 regarding the influence of genetic factors in the etiology of GD. Ongoing studies will focus on whole genome screening in multiplex families as well as population based twin studies. However, the possibility of GD being a heterogeneous disease without a single well-defined genotype and phenotype should be left open.
A population-based study of Graves' disease in Danish twins.Brix
TH, Christensen K, Holm NV, Harvald B, Hegedus L.
"OBJECTIVE: The aetiology of Graves' disease (GD) is generally thought to fit a multi-factorial pattern of inheritance in which clinical disease develops on the basis of genetic susceptibility interacting with environmental and endogenous factors. In previous twin studies the probandwise concordance rates for hyperthyroidism were as high as 0.86 in monozygotic twins and 0.20 in dizygotic twins, indicating a very strong genetic influence. In these studies, however, no effort was made to distinguish between GD and non-autoimmune hyperthyroidism, and one study also included patients with simple non-toxic goitre, hampering if not invalidating any conclusions. The aim of the present study was to determine whether there is a genetic contribution in the aetiology of GD.
DESIGN: Historical cohort study of pairs of same-sex twins, with information on GD being gathered by questionnaire surveys in the 1950s and 1960s. All available hospital material was sought to verify the diagnosis, which was assigned on the basis of clinical and histopathological evidence. The healthy co-twins were followed through middle age by questionnaire surveys in the 1970s and 1980s. PATIENTS: Same-sex twin individuals born between 1870-1920, included in a population-based nationwide register. A total of 118 subjects indicated hospitalization due to GD. A hospital record was available in 76 subjects. Of these, 55 (46 females and 9 males) could be classified as having GD. MEASUREMENTS: Pairwise and probandwise concordance rates for GD in monozygotic and dizygotic twin pairs.
RESULTS: The probandwise concordance rates were 0.36 for monozygotic pairs and 0 for dizygotic pairs. The pairwise concordance rates were 0.22 and 0 for monozygotic and dizygotic pairs, respectively. The concordance rates were significantly (P = 0.012) higher in monozygotic than in dizygotic pairs.
CONCLUSIONS: These results confirm that genetic factors play an important role in the aetiology of Graves' disease. However, they may not be as powerful as previously thought."
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