The AITDs are examples of complex genetic diseases affecting the thyroid. Classically, the AITDs encompass a spectrum of related disorders varying from hyperthyroid Graves’ disease (GD) to hypo thyroid Hashimoto’s thyroiditis (HT) and which are characterized by abnormal autoimmune responses to thyroid antigens. Additional variants of AITD include postpartum thyroiditis, drug induced thyroiditis, such as interferon induced thyroiditis (IIT), thyroiditis associated with polyglandular autoimmune syndromes and just the presence of thyroid anti bodies (TAb) with no apparent clinical disease but which simply indicates the presence of an intrathyroidal infiltrate but retention of normal thyroid function. The AITD are among the commonest human autoimmune disorders affecting more than 5% of the general population. The AITD, including Graves’ and Hashimoto’s diseases, are categorized as complex diseases because they are believed to be caused by an interaction between several genes and a variety of environmental factors. In recent years, sound epidemiologic evidence for a genetic susceptibility to AITD has been established. Box1 summarizes these main epidemiological data pointing to a genetic susceptibility to AITD.

Box1. Epidemiological evidence for a genetic susceptibility to Graves’ disease and Hashimoto’s thyroiditis (see text)

Geographic and Longitudinal Trends in the Incidence of the AITD

The annual incidence of GD in populations of different geographic locations, excluding extremes of iodine intake, is similar and ranges from 0.22 to 0.27 per 1000. A similar pattern has been observed for HT. In the UK Whickham survey the prevalence of spontaneous hypothyroidism was 15/ 1000 in females compared with less than 1/ 1000 in males. The mean annual incidence of spontaneous hypothyroidism in women was 3.5/ 1000 and in men was 0.6/ 1000. Similar prevalence and incidence data of spontaneous hypothyroidism have been reported by others in the United States, Finland, Japan, and Sweden. The comparable prevalence and incidence of the AITD in geographically different populations has suggested that the genetic contribution to the development of the AITD is more important than the environmental contribution because these populations are exposed to different environmental factors.

A longitudinal study from the Mayo clinic (1935– 1967) showed no significant change in the incidence of GD over the 33 years of the study. The stable incidence of GD with time once again points to strong genetic effects because the genetic makeup of a population did not appear to change over several decades, but environ mental factors most probably did. The Mayo clinic observations were supported by a more recent study from Sweden. However, the Swedish study found an increased incidence of GD in a subset of the population, demonstrating that environmental effects may still play a crucial role in the aetiology of GD. In the Mayo survey (1935– 1967) there was a significant increase in the incidence of HT over the 33 years of the survey. This could reflect a stronger environmental influence on the development of HT rather than GD or more likely a change in the diagnostic criteria over time.

Familial Clustering

 The familial occurrence of the AITD has been recognized by investigators for many years. More than 50 years ago it was recognized that a familial predisposition can be found in approximately 50% of cases with GD. Later studies have shown a high frequency of thyroid abnormalities in relatives of patients with AITD, most commonly the presence of thyroid autoantibodies which were reported in up to 50% of the siblings of patients with GD; 36% of GD patients with ophthalmopathy had a family history of AITD while 32% had a first- degree relative with AITD. Moreover, a study from Holland in which 790 healthy female relatives of AITD patients were followed for up to 5 years, showed that 7.5% of them developed overt hypothyroidism or hyperthyroidism.

Such familial clustering of a disease can be due to non- genetic factors including the shared environmental exposures (e.g. infections, diet). Therefore, methods have been developed to determine whether familial clustering of a disease is the result of genetic susceptibility or non- genetic factors. One method is to calculate the sib ling risk ratio (λs) which expresses the increased risk of developing the disease in an individual who has a sibling with the disease compared to the risk in the general population, and has been claimed as a quantitative measure of the genetic contribution to the disease. A λs of > 5 has been used to indicate a significant genetic contribution to the pathogenesis of a disease. We calculated the λs in AITD in a cohort of 155 AITD patients. The λs was 16.9 for AITD, 11.6 for GD, and 28.0 for HT. These high λs values indicate a strong familial influence on the development of AITD.

Twins Studies

Twin studies can provide information concerning the inheritance of a disease and may yield certain quantitative evaluations on the role of heredity in relation to exogenous factors. Twin analysis is based upon comparison of the concordance (simultaneous occurrence) of a disease among monozygotic (MZ) twins vs. dizygotic (DZ) twins. MZ twins have similar genetic makeup, whereas DZ twins share an average of 50% of their genes (like siblings). Therefore, if concordance is higher in the MZ twins when compared to the DZ twins it suggests that the disease has an inherited component. Any discordance among the MZ twin pairs is usually interpreted to mean that the gene or genes concerned show reduced penetrance (i.e. certain epigenetic or environmental factors must be present before the disease becomes manifest). However, this logic has its limits for autoimmune diseases. This is because MZ twins are not immunologically identical. Since the T- cell receptor and immunoglobulin V genes undergo random recombination, twins have different immune repertoires although they may be sculpted by the same environment.

Nevertheless, the concordance rate in MZ twins is taken as an estimate of the penetrance of the disease but this is only up to the age they are examined. For example, if the concordance rate among the MZ twins is 50%, this is taken to mean that the penetrance of the disease genes is approximately 50%. As discussed, however, it must be emphasized again that MZ twins are not identical and their individual immune experiences will influence their immune repertoire. Therefore, part of the observed discordance between MZ twins may also be due to the discordance in their immune repertoire.

The concordance rate for GD in MZ twins was found to be ap proximately 30– 35% while the concordance rate in DZ twins was reported to be about 3– 5%. These data indicated that there is a substantial inherited susceptibility to Graves’ disease, presumably related to both immune and non- immune genes. For HT the concordance rates were 55% and 0% for MZ and DZ twins, respectively, again pointing to a strong genetic component in the aetiology of the disease. Finally, for thyroid antibodies, MZ twins had 80% concordance and DZ twins had 40% concordance. Thus, the twin data support a substantial inherited susceptibility to AITD. Indeed, a recent study estimated that 80% of the liability to develop GD was due to genetic factors. A similar strong genetic contribution was estimated for the production of thyroid antibodies.

Thyroid Autoantibodies

 Autoantibodies to thyroglobulin (Tg) and thyroid peroxidase ([TPO] the microsomal antigen) have been widely used to show the population at most risk for the development of AITD. An in creased prevalence of thyroid autoantibodies has been reported in relatives of patients with AITD. Antithyroid autoantibodies (antithyroglobulin and antithyroid peroxidase) have been found in up to 50% of the siblings of patients with the AITD, in contrast to a prevalence of 7– 20% in the general population. These findings are true in different populations such as the Japanese and British populations. In one study, it was found that thy roid antibodies were almost always present in one of the parents of an affected individual with AITD. These data suggested an inherited influence on the production of antithyroid antibodies compatible with dominant inheritance. Indeed, segregation ana lyses in a panel of families with thyroid antibodies also suggested a Mendelian dominant pattern of inheritance for the tendency to develop antithyroid antibodies . In keeping with these observations, it was reported that recognition of particular thyroid per oxidase (TPO) epitopes within the autoantibody immunodominant region may be transmitted within families.

Graves’ orbitopathy

Depending on the definition of Graves’ ophthalmopathy (GO), it would appear to affect about 90% of patients with GD and so is an intrinsic part of the disorder although rarely it may be found without thyroid involvement and also is seen regularly in patients with HT who may or may not have experienced GD. However, the severe form of ophthalmopathy occurs in less than 10% of GD patients. Severe GO manifests by proptosis, conjunctival injection, eye muscle weakness to paralysis, and sometimes optic nerve damage. GO is considered pathognomonic of GD even when the individual is not thyrotoxic. It was speculated that the genetic influence on the development of Graves ophthalmopathy could be more pronounced because GO represents the most severe form of the disease. We, therefore performed a segregation analysis in patients selected for severe GO by studying the first- degree relatives of individuals with severe GO. If the disease is hereditary the first- degree relatives would be expected to be affected by the disease more often than individuals randomly selected from the general population. Our segregation analysis showed that GO did not have a major genetic component. Although a genetic contribution to the susceptibility to develop GO has been claimed such a non- specific gene association could simply enhance susceptibility to more severe GD.

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مواضيع ذات صلة

Maternal Inheritance of Disorders Caused by Variants in the Mitochondrial Genome

Genetic Screening in Populations

Genetic Counseling for Preconception and Prenatal Diagnosis and Screening

Fetal Surgical and Medical Interventions

X-Linked Inheritance

Preconception Genetic Screening and Testing

Problems in Prenatal Chromosome Analysis and Gene Sequencing

Introduction to Cytogenetics and Genome Analysis

Methods to Detect Fetal Chromosomal Abnormalities

The Origin and Frequency of Different Types of Mutation

Noninvasive Prenatal Screening by Analysis of Cell- Free Fetal DNA

Screening for Down Syndrome and Other Aneuploidies