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Original Studies |
Department of Endocrinology M, Odense University Hospital (T.H.B., L.H.), and the Danish Twin Register, Odense University (T.H.B., K.O.K.), DK-5000 Odense C, Denmark
Address all correspondence and requests for reprints to: Dr. Thomas Heiberg Brix, The Danish Twin Register, Odense University, Winsløwparken 15, DK-5000 Odense C, Denmark. E-mail: t-brix{at}win-chs.ou.dk
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Abstract |
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The crude probandwise concordance rates were 0.42 [95% confidence interval (CI), 0.26-0.59] and 0.13 (95% CI, 0.06-0.24) for female monozygotic and female dizygotic pairs, respectively. The age-adjusted cumulative probandwise risk for simple goiter from birth to age 43 yr was 0.53 (95% CI, 0.23-0.83) for female monozygotic twins and 0.18 (95% CI, 0.05-0.35) for female dizygotic twins (P = 0.003). The tetrachoric correlations were substantially higher in monozygotic (0.82; SE, 0.07) than in dizygotic twins (0.47; SE, 0.12). Model-fitting analysis suggested that the heritability of the liability to the development of simple goiter in women is approximately 82%. Individual-specific environmental factors not shared by cotwins seemed to explain the remaining 18%. We conclude that the etiology of clinically overt simple goiter is multifactorial. Genetic factors play a major role in the etiology of simple goiter in females, but environmental factors are also of importance.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A simple goiter is defined as a diffuse or nodular enlargement of the thyroid gland that is not the result of an inflammatory or neoplastic process in an individual who is euthyroid (3). Simple goiter occurs both endemically and sporadically. In areas with endemic goiter, more than 10% of the population has a generalized or localized thyroid enlargement, whereas the prevalence in nonendemic areas ranges from 0.4-5% (4).
Although simple goiter is one of the most common thyroid disorders, its etiology is incompletely understood. It is generally accepted that iodine deficiency contributes to both endemic and sporadic simple goiter (5, 6). However, a number of environmental factors, such as naturally occurring goitrogens, goitrogenic drugs, certain infections, and smoking, are also of importance (6, 7). The fact, however, that even in endemic areas, environment cannot alone account for the development of simple goiter suggests that individual factors that predispose a part of the population to goiter development must play a role in the etiology (6). Among the individual factors, the influences of genes should be considered. A role for genetic factors is suggested by the aggregation of goiter within families (8, 9). It has been hypothesized that the high familial prevalence of goiter is due to the inheritance of a predisposition or susceptibility to goiter development (10, 11). This hypothesis is supported by the existence of families with vertical transmission of goiter (10, 12, 13), suggesting an autosomal dominant pattern of inheritance of disease susceptibility. Furthermore, two recent studies indicate that a number of genetic markers with association and or linkage with simple sporadic goiter may exist (14, 15). However, the relative contribution of the genetic influence on disease susceptibility largely remains to be defined. The relative contribution of genes and environment to interindividual variation in disease susceptibility can be investigated in twins (16). A higher concordance rate in MZ than in DZ pairs suggests that genetic factors are important, whereas similar rates indicate an environmental cause.
Previous twin studies (17-20), dating back 30 yr or more and conducted in endemic goiter areas and selected populations, do not support the idea that genetic factors are of major importance. The aim of our study was to investigate the genetic and environmental contributions to the etiology of simple goiter in a large, well defined population of Danish twins living in a nonendemic goiter area.
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Subjects and Methods |
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The twins were recruited from the young part of the Danish Twin Register. The ascertainment procedure of this nationwide, population-based register was described in detail previously (21).
The study population consisted of 5.479 same sex twin pairs (10.958 individuals) born between 1953 and 1972, where both twins in a pair had participated in a questionnaire survey in 1994. This questionnaire survey was performed in all twins born between 1953 and 1982 as a part of a nationwide project about health and psychosocial conditions among twins. The response rate was 86%, and there was no difference in the response rate across the birth cohorts. All respondents were living in Denmark, which is a nonendemic goiter area with borderline iodine deficiency (median urinary iodine excretion of 85 µg/24 h) (22). The screening questions for thyroid disease were: do you have or have you ever had hyperthyroidism, hypothyroidism or goiter?
Two hundred and nine subjects (188 females and 21 males) indicated a
present or previous goiter. These subjects and their cotwins were sent
a second, more detailed questionnaire in 1996. This questionnaire
contained questions about signs and symptoms of thyroid disease in
general. The name and address of the general practitioner, specialists,
or hospitals attended by the twin because of thyroid disorders, were
also requested. After one reminder, 163 subjects (78%) had responded.
In 52 subjects the presence of goiter was excluded, the main reason
being errors when filling out the 1994 questionnaire (41 subjects) or
other thyroid diseases (11 subjects). In 46 subjects (22%)
verification of the self-reported goiter as stated in the 1994
questionnaire was impossible due to nonresponse to the goiter
questionnaire. However, in an attempt to verify or exclude the presence
of the self-reported goiter stated in the 1994 questionnaire,
information on thyroid disease was sought from the National Discharge
Register as part of a record linkage between the Twin Register and the
National Discharge Register. Three of the 46 nonresponders (6.5%) were
recorded in the National Discharge Register with a thyroid-specific
International Classification of Disorders, World Health
Organization code, 1 had thyroid cancer and 2 had postpartum
thyroiditis and coexisting goiter, but none had simple goiter. These
subjects were not considered further. Thus, a total of 111 subjects (98
twin pairs) with verified simple goiter were identified. Of these, 75
subjects (64 twin pairs) were classified as having or having had a
diffuse or multinodular goiter, and 36 subjects (35 twin pairs) were
classified as having or having had a solitary thyroid nodule. Table 1
gives the characteristics of these
subjects, stratified by gender and zygosity. Eight of these 111
subjects were males (7.2%). Due to this small number and because in
Denmark there is a huge difference in the prevalence of goiter between
the two sexes, the male twins were excluded from further analysis.
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Classification of the goiter
Information from hospitals, out-patient clinics, specialists, and general practitioners was reviewed by two of us (L.H. and T.H.B.), both blinded to the zygosity of the twins. On the basis of this review with special emphasis on blood tests and clinical criteria, the subjects were classified as having or having had diffuse nontoxic goiter, multinodular nontoxic goiter, or a nontoxic solitary thyroid nodule. In all cases, the goiter was described as visible and/or palpable. Where available, the results of isotope imaging, ultrasound, and thyroid histopathology of tissue from fine needle aspiration or surgery were reviewed.
Zygosity
Zygosity determination was based on self-reported answers to specific questions about similarity and mistaken identity, which is a well established and valid method in large twin populations (23). A comparison of this method with laboratory methods (serological markers) has shown that the misclassification rate is less than 5% (23). Determination of zygosity was made by an experienced twin researcher (K.O.K.), who was blinded to information about the thyroid status of the twins.
Analysis of data
We defined a proband as a goitrous subject (with a verified diagnosis) who was ascertained through the 1994 questionnaire survey independently of disease status in the cotwin. Cotwins who as a consequence of the 1996 questionnaire were found to be goitrous were classified as secondary cases (24).
The similarity in MZ and DZ twins was assessed by probandwise concordance rates and tetrachoric correlations. The probandwise concordance rate is defined as the proportion of affected cotwins of probands. It gives the risk that a twin individual is affected given that the cotwin is affected and is, thus, directly comparable to risk estimates reported for other relatives or in the background population (25). To adjust for variable age at last contact, the age-adjusted probandwise concordance rates were estimated by Kaplan-Meier survival analysis. This generally accepted method is based on analysis of the disease status of the proband’s cotwin (26). The difference in the age-adjusted probandwise concordance rates between MZ and DZ twin pairs were tested by the log rank test. Estimation of the 95% confidence intervals (CI) for the concordance rates were based on the binomial distribution.
The tetrachoric correlations for goiter were estimated under the assumption of the multifactorial threshold model (27). This assumes that there is an underlying, normally distributed liability (susceptibility) to a disease due to genetic and environmental factors. The manifestation of a disease appears when an individual exceeds the thresholds of affection on this liability distribution. The tetrachoric correlations were computed separately for MZ and DZ twins from 2 x 2 contingency tables of disease status in the twin pairs using the MX software package (28).
For a qualitative trait such as goiter there is no simple method by
which to assess heritability (proportion of variance of a disease
attributable to additive genetic effects) (29). We analyzed the data by
structural equation modeling for twin data as described in detail by
Neale and Cardon (30). In this approach, the phenotypic variance of the
liability to goiter is partitioned into genetic and environmental
components. The genetic variance may be due to additive (A) or dominant
(D) genetic influence. The environmental variance can be divided into
variance due to common environmental factors (C) shared by twins reared
in the same family and variance due to individual nonshared
environmental factors (E). Five different etiological models, ACE, ADE,
AE, CE, and E, were fitted to the data using MX programmed for analysis
of categorical twin data (28). The DE model is not taken into account,
because it is biologically rare to have genetic dominance in the
absence of additive genetic factors. The fit of each model was assessed
by a 
2 goodness of fit test that tested the agreement
between the observed and the predicted statistics (a small
2 value and a high P value indicates a good
agreement between the model and the observed data). The goal in model
fitting is to explain the observed data as well as possible with as few
parameters as possible (parsimony). We used Akaike’s information
criterion, which equals the 2 value minus twice the
degrees of freedom (31). The model with the lowest Akaike’s
information criterion value reflects the best balance of goodness of
fit and parsimony.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Prevalences and concordance rates
The prevalences and probandwise concordance rates are shown in
Table 2. The overall prevalence of
clinically overt simple goiter was 1.75% (103/5.890). The prevalences
did not differ between MZ and DZ twin individuals (1.5% in MZ
vs. 2.0% in DZ; P = 0.135). There were
eight MZ and five DZ pairs concordant for simple goiter, giving crude
probandwise concordance rates of 0.42 (95% CI, 0.26-0.59) and 0.13
(95% CI, 0.06-0.24), respectively (P < 0.001). The
age-adjusted cumulative probandwise risk for simple goiter from birth
to age 43 yr was significantly higher in MZ than in DZ twins (0.53
vs. 0.20; log rank test: 2 = 8.83,
df = 1, P = 0.003; Fig. 1). The mean follow-up time of the
probands cotwin was similar in MZ and in DZ cotwins (9.5 vs.
12.2 yr; P = 0.25). Among the eight MZ pairs concordant
for simple goiter, the time from diagnosis in the first affected twin
until diagnosis in the cotwin was less than 5 yr in seven pairs and 14
yr in the remaining pair. The discordance time for the five DZ pairs
concordant for simple goiter was less than 2 yr in two pairs and 6, 9,
and 18 yr in the remaining pairs.
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). Tetrachoric correlations, model fitting, and heritability
As shown in Table 2, the tetrachoric correlation for simple goiter
was substantially higher in MZ (0.82; SE, 0.07) than in DZ
twins (0.47; SE, 0.12). The outcome of the etiological
modelling is summarized in Table 3.
Etiological models that included only environmental factors (CE and E
models) provided a very poor fit to the data (P <
0.1). All three models, including both genetic and environmental
influences (ACE, ADE, and AE), fitted the data well (P
> 0.1). Among these etiological models, the AE model provided the best
overall fit to the data. As the 2 difference test
between the AE model and the ACE model was nonsignificant (0.29 -
0.02 = 0.27; 1 df; P = 0.60), C could be excluded.
The impact of dominant genetic effects could be excluded from the ADE
model in a similar way.
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). Again, expanding
the sample to also comprise self-reported goiter that could not be
classified or confirmed did not change the overall results (Table 3). |
Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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These results are in contrast with those of previous twin studies, which suggest that genetic factors play at best only a minor role in the etiology of (endemic) goiter (17-20). This discrepancy might be due to a number of methodological differences between our and previous studies. First, our study was nationwide and population based, whereas the ascertainment methods in the previous studies were volunteer based (19, 20) and case based (17, 18), respectively. Second, our sample size (5890 individuals, distributed among 2945 complete female-female twin pairs) was substantially greater than the number of samples investigated in the 4 previous studies. Malamos et al. (19) examined 108 female-female twin pairs. Greig et al. (20) examined 61 female-female twin pairs. Siemens (18) examined 70 same sex twin pairs. Weitz (17) examined 45 MZ pairs. Third, all previous studies were conducted in areas of endemic goiter and were performed 32-75 yr ago. In contrast, our study was performed in a nonendemic area. In endemic areas, the high prevalence of goiter in the background population is often due to one major environmental factor, iodine deficiency. If the environmental factor is marked, it may mask an underlying genetic contribution to disease etiology in these areas.
The results of this study should be interpreted in the context of a number of potential limitations. The data in this study were obtained from Caucasians living in Denmark, among whom cultural background and living conditions are generally homogeneous. Moreover, the present results were obtained in women only. Thus, the results of this study cannot uncritically be extrapolated to other groups or populations. In fact, heritability is specific to the population in which it is estimated. Other populations may differ in genetic or environmental variance, or both, and hence, the ratio of genetic to total phenotypic variance may differ too. It is also important to point out that heritability estimates based on quantitative genetic modelling or any other method does not take a possible gene-environment interaction into account. Gene-environment interactions may be important in goiter development, making the results of heritability difficult to interpret.
Simple goiter, whether endemic or sporadic, may not be a single entity (3). Most individuals with simple goiter have a diffuse or multinodular enlargement of the thyroid gland. In some individuals, however, a single nontoxic nodule may develop within an otherwise normal gland. Whether this condition represents a stage in simple goiter development or indicates a different disease is at present questioned (3). Unfortunately, the size of our material does not allow a meaningful estimate of the heritability of the liability to these subtypes of goiter.
Although the Danish Twin Register is population based, our final study sample is unlikely to be completely representative of the entire twin population. Twins who did not answer/return the questionnaires were not included. However, as we used the probandwise concordance rate, it is not crucial that all twins should be studied, as long as there is no systematic bias in the ascertainment procedure (25). The information on the presence or absence of goiter was based on self-reports. This may induce a bias, because of problems in recall or validity of the questionnaire. However, the diagnosis was confirmed by review of medical records. Additionally, record linkage between the Twin Register and the National Discharge Register did not suggest systematic underreporting of thyroid disease.
The prevalence of simple goiter in Denmark is unknown. However, in our study the prevalence of both self-reported (3.19%) and confirmed simple goiter (1.75%) is comparable with the prevalences (0.4 to 5% by palpation) of simple goiter reported from other nonendemic areas (4). Moreover, the prevalence of simple goiter was similar in MZ and DZ twins. Thus, there is no evidence of overrepresentation of either zygosity class.
The follow-up period of the healthy cotwins was rather short (9.5 yr in MZ and 12.2 yr in DZ cotwins). That is, not much time was allowed for the cotwin to develop goiter; hence, the concordance rates might change with increasing follow-up time. However, it seems unlikely that such a potential increased concordance should be restricted to DZ compared to MZ pairs. In addition, the fact that the follow-up time tended to be longer in the DZ pairs in whom concordance was lowest further strengthens our findings.
In twin studies it is assumed that the intrapair difference in environment is the same for MZ and DZ twins. It has, however, been argued that twins in MZ pairs are more likely to share more similar environments than twins in DZ pairs (32). This could result in an overestimation of the genetic influence on disease etiology. In our study, the AE model fitted the observed data better than the model that included shared environmental effects (ACE model). On the other hand, this may be due to an inadequacy of power to detect a small to modest effect of shared environment in this study. In fact, the ACE model fit the observed data nearly as well as the AE model regardless of phenotypic classification. Therefore, we can only conclude that in the best fitting model, we were unable to identify major shared environmental influences on the liability for goiter in women.
In conclusion, our study suggests a multifactorial etiology of simple goiter among Caucasian women living in areas with borderline iodine deficiency. It strongly supports the idea that genetic factors play a major etiological role in the development of simple goiter, but also indicates that environmental factors are of importance. We, therefore, propose that genetic predisposition (susceptibility) might be necessary for the development of simple goiter in females, and that environmental factors possibly have a predominant role in controlling whether a genetically predisposed subject progresses to clinically overt goiter, at least in nonendemic goiter areas.
The next step is to elucidate the molecular basis of the genetic susceptibility to simple goiter. Strategies for clarifying the molecular basis of the genetic susceptibility to simple goiter should be based on linkage and association studies of a large number of families.
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Footnotes |
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Received March 25, 1999.
Revised May 4, 1999.
Accepted May 20, 1999.
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