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The Genetics of Autoimmune Thyroid Disease

School of Clinical Medical Sciences (B.V., P.K.-T., S.H.S.P.) and Institute of Human Genetics (S.H.S.P.), University of Newcastle upon Tyne, Newcastle upon Tyne NE1 3BZ, United Kingdom

Address all correspondence and requests for reprints to: Dr. Simon Pearce, Institute of Human Genetics, International Centre for Life, Central Parkway, Newcastle upon Tyne NE1 3BZ, United Kingdom. E-mail: spearce{at}hgmp.mrc.ac.uk.

Autoimmune thyroid disease (AITD) comprises a series of interrelated conditions including hyperthyroid Graves’ disease (GD), Hashimoto’s (goitrous) thyroiditis, atrophic autoimmune hypothyroidism, postpartum thyroiditis (PPT), and thyroid-associated orbitopathy (TAO). These different manifestations of AITD may occur synchronously, most frequently as the combination of GD and TAO. Different AITD phenotypes may also occur sequentially in the same individual, for instance, spontaneous hypothyroidism following an episode of GD or PPT. This clustering of different AITD phenotypes within an individual suggests that these conditions have a common pathophysiological basis. Together, AITDs are the commonest autoimmune disorders in the population, affecting between 2% and 4% of women and up to 1% of men (1, 2, 3). Furthermore, AITD prevalence increases with advancing age, with more than 10% of subjects over 75 yr of age having biochemical evidence of mild (subclinical) hypothyroidism, the majority of which is due to autoimmune disease (2, 3).

A widely accepted model for the pathogenesis of AITD suggests that each subject has a background inherited predisposition to autoimmunity, with additional environmental and hormonal factors that trigger or contribute to the development of disease. In support of this model, there is good evidence that both cigarette smoking and adverse psychosocial events are associated with the development of GD (4, 5, 6). Similarly, the female preponderance of human AITDs (1), the modulation of animal models of AITD with gonadal steroids (7), the amelioration of GD during pregnancy, and the occurrence of PPT all support the important role of sex steroids in these disorders. In contrast, there is little convincing evidence that infective agents, which are thought of as classical environmental precipitants for autoimmunity, trigger AITDs (8). A recent statistical model, based on data from a large twin study, found that 79% of the predisposition to GD is due to genetic factors, with only 21% due to nongenetic (environmental and hormonal) influences (9). This study has profound implications for the study of AITD and suggests that if we are to make progress in understanding the molecular basis for AITDs, the elucidation of the genetic factors is most likely to hold the key. Recent years have seen a flurry of activity in this research field, and in this article we will review these advances in understanding about the genetic basis of AITDs.

Genetic epidemiology of AITD

Twin studies.

Twin studies show increased concordance of GD and autoimmune hypothyroidism (AH) in monozygotic (MZ) twins compared with dizygotic (DZ) twins. Three historical series have shown high levels of concordance for hyperthyroidism in MZ twins, in the range 50–70%, compared with 3–25% in DZ twins (10, 11, 12). However, GD was not distinguished from other causes of hyperthyroidism in these studies, and phenotype determination was often made without reference to biochemistry. Furthermore, these studies may have been subject to ascertainment bias. A more recent investigation based on a population of 8,966 Danish twins and performed using stringent ascertainment criteria, has shown that concordance for GD in MZ twins was 35%, compared with 3% in DZ twins (9). A similar study of AH (combining both atrophic and goitrous AH) in Danish twins, showed 55% concordance in MZ twins, compared with no concordant DZ twins (13). These twin studies show that there is a clear genetic component to both GD and AH.

Familial risk of AITDs.

The familial occurrence of GD was first reported more than a century ago (14). Since this early observation, five historical series have reported the prevalence of GD in a sibling of an affected GD proband as between 4 and 13% (10, 15, 16, 17, 18, 19). A measure of the heritability of a disorder can be gained from the ratio of the risk to a relative of an affected proband compared with the background population prevalence (a value termed s for siblings and o for parents/offspring). A study by Stenszky et al. (20) from Hungary, in which the background population prevalence of GD was known, allows the calculation of the s for GD. In this study, 23 of 435 (5.3%) GD probands had siblings with GD (21 sisters, 2 brothers), compared with a background population frequency of GD of 0.65%. This allows estimation of the s for GD as 8.1 in the Hungarian population. A similar study performed at our own institution during 1998 and 1999 showed 15 of 190 (7.9%) GD probands had similarly affected siblings (9 sisters, 6 brothers; Vaidya, B, unpublished data). A further 10 subjects (5.3%) had a sibling with AH (all sisters). Estimating a background prevalence of GD as 0.8% from the local Whickham survey (1), the Newcastle figure for the s of GD is 9.9. To put these values into context, the s for type 1 diabetes (T1D) is 15, and for rheumatoid arthritis is 8 (21). Interestingly, the values of o (excess risk to offspring) for GD in both the Hungarian study (10.3) and our own study (11.8) were slightly in excess of the s values. This slight excess of GD cases among parents and offspring compared with sibs may reflect the effects of dominant genetic loci, or simply that the disease penetrance is greater in parental generations. An important message for subjects with GD is that their female siblings and children have a 5 to 8% chance of also being affected by GD and an approximately similar risk of developing AH. The corresponding risk to male relatives is less, although neither our study nor that of Stenszky et al. (20) is able to provide a reliable estimate of this.

Heritability of thyroid autoantibodies.

Soon after the first description of thyroid autoantibodies (22), their occurrence in 22 of 39 (56%) siblings of AITD probands was noted, and a dominant pattern of inheritance was suggested (23). The finding of thyroid autoantibodies in 30–50% of first-degree female relatives was subsequently replicated for subjects with both AH and GD (18, 24) and has been confirmed more recently using sensitive direct thyroglobulin (Tg) and thyroid peroxidase (TPO) antibody assays (25). The prevalence of these antibodies in male relatives is less than that of female relatives (10–30%), and this pattern has been attributed to dominant inheritance with reduced penetrance in males (23, 25). A dominant pattern of transmission of Tg and TPO antibodies has been observed even in families with no overt clinical AITD (26). Naturally occurring TPO antibodies are not uniform in specificity and tend to be directed against certain defined immunodominant epitopes of TPO. Interestingly, these patterns of TPO antibody response (epitopic fingerprints) can also be shown to be inherited in a dominant fashion (27). Although this may reflect the coinheritance of major histocompatibility complex (MHC) or Ig gene alleles that may restrict the range of antigenic determinants that the immune system can recognize (27). It is striking that even in families in which several members have antibodies to TPO or Tg, clinically overt AITD is not the rule. This demonstrates that the generation of a B cell immune response to thyroid antigens is not in itself sufficient to cause AITD, and that other tissue-specific responses or immune system factors are also necessary.

Association of AITD with other autoimmune disorders.

The occurrence of Hashimoto’s thyroiditis in subjects with T1D and in their family members is well recognized. In large T1D family collections from the United Kingdom and the United States, at least one case of AITD was reported in relatives of 22% and 40% of T1D subjects, respectively (28, 29). A higher than expected prevalence of AITD has been found in subjects with other autoimmune disorders and in their families (30). Thus, two small UK studies of families with two or more rheumatoid arthritis cases found that close to 50% of pedigrees had a rheumatoid arthritis subject or relative with AITD (31, 32). AITD is also very frequently found in subjects with autoimmune Addison’s disease, being present in 40–50% of sporadic Addison’s subjects [i.e. those who do not have the autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy (APECED) or type 1 polyendocrinopathy syndrome; Refs. 33 and34 ]. However, Addison’s disease is rare among subjects with AITD. In our Newcastle cohort of 68 families with 2 or more sibs affected with GD, there were 2 families with a member who had Addison’s disease. Other weaker associations exist between AITD and other autoimmune endocrinopathies (e.g. autoimmune premature ovarian failure) and nonendocrine autoimmune disorders (e.g. pernicious anemia, celiac disease, myasthenia gravis, multiple sclerosis; Ref. 35). An important message from the clustering of different autoimmune conditions is that this suggests that several different autoimmune disorders are likely to have a disease susceptibility allele (or alleles) in common. It is also of note that this clustering of autoimmune diseases is not limited to conditions that are believed to have similar pathogenic mechanisms, such as organ-specific and nonorgan-specific autoimmune disorders, or predominantly B cell- or T cell-mediated disorders (28). Thus, these traditional classifications of autoimmune disease groups based on their suspected immunopathology may ultimately prove to have little molecular basis.

Molecular genetics of AITD

Monogenic disorders with AITD as a component.

Two monogenic autoimmunity syndromes have AITD as a component. The commonest of these rare disorders is the APECED syndrome, which has a prevalence of about 3 per million in the UK population (36). The cardinal features of this condition are autoimmune hypoparathyroidism, Addison’s disease, and chronic mucocutaneous candidiasis, which begin in childhood or early adolescence (see Ref. 37 for a comprehensive review). Other autoimmune disorders such as T1D, pernicious anemia, and hypogonadism occur in 15–30% of subjects with the APECED syndrome, but AH is comparatively uncommon, affecting only about 5% of subjects. The extreme rarity of GD in APECED is notable. APECED is an autosomal recessive syndrome caused by mutations in the autoimmune regulator (AIRE) gene on chromosome 21 (38). AIRE is a nuclear transcription factor that is expressed predominantly in dendritic antigen-presenting cells in the thymus and peripheral lymphoid tissues. AIRE gene mutations lead to defective negative selection of potentially autoreactive thymocytes and ineffective peripheral antigen presentation for some antigens (e.g. candida). A second rarer disorder is the immune dysregulation, polyendocrinopathy and enteropathy (X-linked) syndrome. This is a devastating condition of male infants with failure to thrive due to autoimmune enteropathy. AH and T1D develop in the first year of life in about 50% and 90% of males, respectively. Immune dysregulation, polyendocrinopathy and enteropathy (X-linked) syndrome is caused by mutations in the FOXP3 gene on Xp11 that lead to inappropriate activation and proliferation of CD4 lymphocytes (39, 40). These monogenic syndromes point us toward two cell types, namely the dendritic antigen presenting cell and the CD4 lymphocyte, whose normal functioning is critical to the maintenance of immune tolerance to thyroid tissues.

Chromosomal disorders with AITD as a component.

Down’s syndrome patients, with trisomy of chromosome 21, have a high prevalence of both autoimmune and congenital thyroid disease. AH is the commonest thyroid problem, affecting 15–20% of adults with Down’s syndrome (41, 42, 43). GD occurs less frequently, with a prevalence of 1–2%, which may not be increased compared with the general population (41, 42). Turner’s syndrome, which is characterized by complete or partial loss of X chromosome material in a phenotypic female, is also associated with AITD. About 15% of Turner’s patients have AH, with 30–40% having positive thyroid antibodies (44, 45, 46). There is a correlation between cytogenetic abnormalities and AITD in Turner’s syndrome, with an Xq isochromosome (deleted short arm and duplicated long arm) being associated with a prevalence of AH of up to 40% (45, 47, 48). GD prevalence is not increased in Turner’s syndrome (44, 45). DiGeorge syndrome (cardiac outflow tract defects, thymic hypoplasia, hypoparathyroidism, and facial anomalies) and the overlapping chromosome 22q11 deletion syndromes are associated with GD (49, 50, 51). One small study suggests that GD may occur in up to 20% of subjects with these chromosome 22q11 deletion syndromes (50). Overall, the association of AITD with these chromosomal disorders suggests that chromosomes 21, 22, and X may each harbor important AITD susceptibility or resistance genes. Alternatively, in the 22q11 deletion syndromes, the consequences of thymic hypoplasia on T lymphocyte maturation may have a specific but secondary effect to predispose to GD.

AITDs as complex genetic traits.

In contrast to the unusual monogenic forms of autoimmunity mentioned above, most cases of AITD, along with other common autoimmune disorders, are now thought to have a complex genetic basis; that is, the genetic predisposition to AITD is determined by a series of interacting susceptibility alleles of several different genes. These various genetic loci may also have differing influences on the predisposition to AITD in different populations (locus heterogeneity), which makes the identification of disease susceptibility genes a more difficult task. There are two standard approaches for identifying disease genes for either monogenic or complex traits (52). Firstly, candidate gene studies involve examining polymorphic markers within a particular gene, which has been selected because it is thought that disruption of its function may result in the phenotype. There has been significant success in using this approach to identify AITD susceptibility genes. A second approach is linkage scanning, in which widely spaced anonymous genetic markers (generally repeat polymorphisms between genes) are used to detect chromosomal segments with evidence for linkage in affected families. Luckily for investigators interested in AITDs, linkage studies of T1D have led the field of complex trait mapping. It is now clear from genomewide linkage studies encompassing more than 750 T1D families that there are 7 loci in which there is firm or suggestive evidence of genetic linkage (53, 54, 55, 56). Of the seven loci, one is the MHC on 6p21, another is the insulin gene region on 11p15, and a third is the cytotoxic T lymphocyte antigen-4 (CTLA4) on 2q33 (see CTLA4 section). The other 4 linked loci and a further 12 putative T1D loci are all defined on the basis of linkage to anonymous markers, and there is no defined allelic association. These studies of T1D have advanced the field by demonstrating that a common autoimmune disorder does have a complex (multigenic) genetic basis (21, 57). Indeed, similar findings have subsequently been made for rheumatoid arthritis, multiple sclerosis, and systemic lupus erythematosus, albeit with smaller numbers of families (58, 59). Furthermore, AITDs are likely to have a similar number of genetic loci implicated in their pathogenesis, and because of the familial clustering of AITD with T1D, some susceptibility alleles will be shared by both disorders.

Once linkage to an anonymous genetic marker is established, a major problem is to refine the region of linkage and determine which allele of a particular gene is responsible. Because chromosomal intervals identified by linkage are always large, encompassing at least 5–10 centiMorgan regions and often contain upward of 100 gene transcripts, disease allele identification is currently a limiting step. In monogenic disorders, fine-mapping studies can make enormous leaps by the identification of critical meiotic recombination events in a family. However, this strategy is not valid for a complex trait because genetic heterogeneity is expected even within families (52). Thus, for complex traits, a laborious association analysis of regularly spaced markers [most frequently single nucleotide polymorphisms (SNPs)] within an area of linkage is the general approach to identify a disease-associated haplotype and an interval of linkage disequilibrium, which contains the disease allele. One stringent method of detecting such association examines the probability of transmission of a candidate disease allele from parents to an affected child (known as the transmission disequilibrium test or TDT). Thus far, these approaches have been used with some success to identify disease alleles for type 2 diabetes and for Crohn’s disease (60, 61, 62). However, even though T1D loci were the first to be identified by linkage scanning, there has still not been a novel T1D disease gene identified by these classical genetic approaches. The limiting factors are small sample sizes, disease loci with small effects, and the expense and relatively slow speed of genotyping large sample cohorts for multiple markers. We review the progress made in these studies of AITD below.

MHC

MHC: a strong candidate locus for AITD.

The MHC, which contains the human leukocyte antigen (HLA) genes, is located on chromosome 6p21. It is subdivided into three regions: 1) the class I region, which encodes HLA antigens A, B, and C; 2) the class II region, which encodes HLA antigens DR, DQ, and DP, each with one or more and ß chains; and 3) the class III region, encoding several immunoregulatory molecules including complement components, heat shock protein 70 (HSP70), and TNF. The class II region also contains the peptide transporters associated with antigen processing (TAP) and large multifunctional protease (LMP) genes. Tight linkage disequilibrium (i.e. conserved haplotypes) exists between the alleles of the MHC region. The MHC class II molecules play a critical part in the initiation of adaptive immune responses. Peptide antigens can only be recognized by T cell receptors when they are attached to the binding groove of an MHC molecule on the surface of an antigen-presenting cell. This, together with the presence of several other immunoregulatory genes in the region, makes the MHC a strong candidate locus for AITD and other autoimmune diseases.

Association of HLA with GD.

Grumet et al. (63) first showed the association between GD and the alleles of MHC class I, with a higher frequency of HLA-B8 in GD patients (47%) compared with controls (21%). Several studies in white populations confirmed this association (64, 65, 66). However, a stronger association of GD was found with the MHC class II allele, HLA-DR3, which is in strong linkage disequilibrium with HLA-B8 (67). Many case-control studies in white populations have since consistently shown the association of GD with HLA-DR3, with relative risks between 2.5 and 5 (reviewed in Refs. 19, 68 and69). More recently, Heward et al. (70) have confirmed the association of MHC with GD in a TDT study that showed preferential transmission of the HLA DRB1*0304-DQB1*02-DQA1*0501 haplotype. Although there is now little doubt about the association of GD with the HLA DR3-carrying haplotype in whites, the primary disease susceptibility allele in the region remains unknown. Yanagawa et al. (71, 72) have reported an association of GD, particularly in males, with the HLA-DQA1*0501 allele, which was stronger than, and independent of, the HLA DR3 status. This independent association of HLA-DQA1*0501 with GD has been supported by some studies (69, 73, 74), but not by others (75, 76, 77, 78). Due to tight linkage disequilibrium in the region, association studies with a large number of cases and controls are necessary to clarify this issue.

In nonwhite populations, GD has been found to be associated with different HLA alleles. For example, GD has been shown to be associated with HLA B35, B46, A2, and DPB1*0501 in Japanese (79, 80, 81); A10, B8, and DQw2 in Indians (82); DR1 and DR3 in South African blacks (83); the DRB3*020/DQA1*0501 haplotype in African Americans (84); and B46, DR9, DRB1*303, and DQB1*0303 in Hong Kong Chinese (85, 86).

Association of MHC-linked genes with GD.

Case-control studies have also shown an association of GD with alleles of several different genes within the MHC, including the HSP70, TNF, TAP, and LMP genes (77, 87, 88, 89, 90). Due to the strong linkage disequilibrium of genes within the region, it is difficult to determine the independent effect of a particular allele in disease susceptibility. A reported association of the TNF alleles in Japanese TAO patients awaits confirmation (91).

Association of HLA with different GD phenotypes.

Over the past two decades, many studies have examined the association of TAO with MHC alleles. However, due to inconsistent criteria for the diagnosis of TAO, different allelotyping methodologies, and small sample sizes, these studies have yielded contradictory results. Early studies of white populations reported an increased frequency of the HLA-B8 and DR3 alleles in TAO patients compared with GD patients without TAO (92, 93, 94). However, other studies have not replicated this result (95, 96, 97). Likewise, reports suggesting a protective role of HLA-DR4 (particularly in the subset with B35+DR4+) and HLA-DR7 (in the absence of the HLA-B8 allele) have not been confirmed (98, 99).

Studies analyzing the association between MHC alleles and other GD phenotypes have also shown conflicting results. McGregor et al. (100) have suggested that GD patients with HLA-DR3 are more likely to relapse after antithyroid treatment, but this was not confirmed by later studies (101, 102, 103, 104). Similarly, associations have been reported between HLA-DR3 and resistance to radioiodine therapy (102), HLA-DR4 with an increased rate of remission after antithyroid drugs (105), and HLA-DRB1*08032 with methimazole-induced agranulocytosis (106), although none of these have been confirmed.

Association of MHC with AH and PPT.

MHC association studies in AH, in contrast to the studies in GD, have revealed less consistent results. In whites, association of AH has been reported with various HLA alleles, including B8, DR3, DR4, DR5, DQA1*0201/*0301, and DQB1*03 (77, 107, 108, 109, 110, 111, 112, 113, 114). Small sample sizes and phenotypic heterogeneity (for example, goitrous vs. atrophic AH) make it difficult to draw a firm conclusion from these studies, but they suggest a weak association of AH with HLA DR3, DR4, and DR5. Interestingly, PPT has also been shown to be associated with HLA DR4 (110, 115, 116) and DR5 (117, 118, 119), suggesting a close relationship between AH and PPT.

Linkage of MHC with AITD.

Although case-control studies in whites have consistently demonstrated an association of GD with HLA alleles, familial linkage studies of the HLA locus in GD have shown discrepant results (Table 1). Several early small studies found excess allele sharing at HLA in sibs affected with GD, suggesting linkage (20, 120, 121, 122). In contrast, three parametric linkage studies from Davies and coworkers (123, 124, 126) were unable to confirm linkage of GD to HLA. However, these studies had small sample sizes, and the families predominantly had members affected with AH rather than GD. Because the HLA associations are known to be different for GD and AH, it stands to reason that linkage was difficult to demonstrate in families with members affected by both GD and AH due to the presence of allelic heterogeneity. Recently, by using a TDT approach in a large cohort of GD families, Heward et al. (70) showed that GD is linked to HLA. Linkage analysis in a cohort of UK sib-pairs with GD also found modest evidence to support linkage of GD to the MHC region [a peak nonparametric linkage (NPL) score of 1.95; Ref. 127 ]. However, two recent genomewide scans in AITD have failed to detect linkage at 6p21 markers (128, 129). Therefore, the contribution of MHC to the genetic susceptibility to GD is comparatively small, perhaps accounting for 10–20% of the inherited susceptibility (127). This is in marked contrast to T1D, in which MHC has been demonstrated to be the most important locus, accounting for 30–40% of the total genetic susceptibility (53, 54, 55, 56).

CTLA4: a negative regulator of T cell activation.

The CTLA4 is an immunoregulatory molecule that is expressed on the surface of activated T lymphocytes. Several observations indicate that CTLA4 is a key inhibitor of T cell activation. Firstly, CTLA4 knockout mice develop a rampant lymphoproliferative disorder resulting in splenomegaly, lymphadenopathy, and death from autoimmunity before 3–4 wk of age (130). Secondly, the administration of CTLA4-blocking antibodies exacerbates murine experimental allergic encephalitis (131) and precipitates the onset of diabetes in the T cell receptor transgenic nonobese diabetic mice (132). Thirdly, a soluble fusion protein of CTLA4 and the Ig G1 Fc region (CTLA4Ig) ameliorates different experimental autoimmune disorders, including diabetes (133). Finally, the engagement of CTLA4 with its ligands inhibits IL-2 production, arrests the progression of activation-induced T cell cycling (134), and possibly also induces apoptosis of activated T cells (135, 136). The regulatory role of CTLA4 in T cell activation makes the CTLA4 gene an attractive candidate locus for autoimmune disorders.

CTLA4 gene and its polymorphisms.

In the human, the CTLA4 gene is located on chromosome 2q33. Three CTLA4 polymorphisms have been extensively studied for linkage and association in various autoimmune disorders: 1) an A to G SNP (CTLA4(49)A/G) at position 49 in exon 1, encoding a threonine to alanine substitution at codon 17; 2) a C to T SNP (CTLA4(-318)C/T) in the promoter region at position -318 relative to exon 1 start site; and 3) a microsatellite polymorphism CTLA4(AT)n, which is a dinucleotide (AT) repeat in the 3' untranslated region of exon 4. Recently, several other SNPs within the CTLA4 gene have been identified (137). It has been suggested that the CTLA4(AT)n polymorphism may be functionally important because larger-sized alleles of this polymorphism may adversely affect the stability of the mRNA transcript (138). A recent study in myasthenia gravis has shown that patients with longer CTLA4(AT)n alleles have a higher serum level of IL-2 soluble receptor -chain (IL-2 sR) and higher proliferative responses after stimulation, suggesting relative hyperactivity of T cells in patients with longer alleles (139). Kouki et al. (140) have studied the functional role of the CTLA4(49)A/G polymorphism in AITD. They showed an increased proliferation of T cells from subjects with GG genotypes (compared with AA genotypes) after stimulation. These results suggest that the G allele is associated with higher levels of T cell proliferation. Furthermore, the G allele at CTLA4(49)A/G and the T allele at CTLA4(-318)C/T have been shown to correlate with an increased expression of cell-surface CTLA4 after stimulation of lymphocytes (141). However, these polymorphisms are in linkage disequilibrium, and it is difficult to dissect out the independent functional effect of each allele (142).

Association of CTLA4 with GD.

In 1995, Yanagawa et al. (138) reported an association of GD with an allele of the CTLA4 gene, which was the first report showing allelic association of CTLA4 with any human autoimmune disorder. They found a significantly higher prevalence of the 106 mobility unit (m.u.) allele of the CTLA4(AT)n polymorphism in white GD patients compared with controls. Subsequently, the G allele of CTLA4(49)A/G was also found to be associated with GD (143). The association of these two CTLA4 polymorphisms with GD has been reproduced by several subsequent studies in different populations, with relative risks between 1.4 and 3.2 (Table 2). It is interesting to note that in the Tunisian population, GD was found to be associated with the A allele at CTLA4(49)A/G, in contrast to the G allele in other populations (147). The association of GD with the promoter polymorphism CTLA4(-318)C/T is less consistent than with the CTLA4(AT)n and CTLA4(49)A/G polymorphisms (Table 2), suggesting that in white populations the minor allele at this polymorphism may be carried on a different haplotype to the disease susceptibility allele.

Association of CTLA4 with severity and manifestations of GD.

Recent studies have shown that CTLA4 alleles may influence the severity or manifestations of several autoimmune disorders. For example, CTLA4 genotypes have been shown to correlate with pretreatment serum free T₄ levels in GD (152). A similar investigation of autoimmune hepatitis has shown an association of CTLA4 genotypes with serum aspartate transaminase levels (153).

Six studies have examined whether CTLA4 alleles confer susceptibility to TAO in patients with GD. Two of these found evidence to suggest that the G allele at CTLA4(49)A/G is associated with an increased risk of TAO (154, 155). In contrast, two subsequent studies have failed to replicate this result (97, 156). Notably, a similar case-control study in the Korean population did not find an association of TAO with the alleles of CTLA4(49)A/G, but found an association with the CC genotype of the promoter polymorphism, CTLA4(-318)C/T (157). A recent small study of 67 newly diagnosed Slovenian GD patients did not show any association of CTLA4(49)A/G genotypes with TAO but did suggest a link with thyroid antibody production (158). These discrepant results may be due to differences in the definition of TAO, the severity of TAO cases, or the duration of clinical follow-up.

A stronger association of CTLA4 alleles with autoimmune Addison’s disease and rheumatoid arthritis has been found in the presence of other autoimmune disorders, such as T1D and AITD (34, 159). In addition, the allelic association of CTLA4 is stronger in patients with both AITD and T1D than in patients with GD or T1D alone (150). Therefore, it is likely that different CTLA4 alleles, by modulating immune responses differentially, may influence both the development and severity of GD phenotypes and the manifestations of many other forms of autoimmunity.

Association of CTLA4 with AH.

The CTLA4(49)A/G and CTLA4(AT)n polymorphisms have been found to be associated with AH in different populations (Table 3). However, the allelic association of CTLA4 with AH appears to be less consistent than with GD. This is most likely to be due to the small sample sizes of the studies. Recently, Nithiyananthan et al. (164), by combining four published association studies of CTLA4(49)A/G in AH, showed a highly significant association of the G allele with AH. However, because control allele frequencies of CTLA4(49)A/G vary greatly in different populations (for example, the G allele frequency in whites is 31–36% compared with 63–68% in Korean and Japanese) and different studies have analyzed a widely varying number of cases and controls, the validity of such meta-analysis is questionable. One case-control study found no association between the CTLA4(AT)n polymorphism and PPT (165).

Despite the finding of association of CTLA4 alleles with GD and AH in many studies from different populations, initial linkage studies from Davies and coworkers (126, 128, 166) failed to detect linkage at CTLA4. However, these studies combined families from a mixed ethnic background (from the United States, Italy, Israel, and the United Kingdom), used a phenotypically varied population, with many families having only AH-affected subjects, and examined a sparse genetic map. Recently, linkage of CTLA4 to thyroid autoantibody status has been reported in the same population (167). Analysis of the CTLA4 locus in UK AITD sib-pairs showed evidence of linkage at CTLA4 (peak NPL score, 3.4), conferring up to one third of the total genetic susceptibility to GD in this population (127). However, a recent genomewide scan in the Japanese AITD families did not show linkage at CTLA4 (129).

CTLA4: linkage and association in other autoimmune disorders.

Since CTLA4 alleles were demonstrated to be associated with AITD (138), the CTLA4 locus has also been found to be linked or associated with a wide range of autoimmune disorders, including T1D (designated IDDM12; Refs. 143 and168), autoimmune Addison’s disease (34, 163, 169), autoimmune hepatitis (153), primary biliary cirrhosis (170), multiple sclerosis (171), rheumatoid arthritis (159, 172), celiac disease (173, 174), systemic lupus erythromatosus (175), and myasthenia gravis with thymoma (176). These results demonstrate that CTLA4 is an important locus for autoimmunity in general.

Other immunoregulatory genes

Studies of other immunoregulatory genes in AITD have produced conflicting results. Uno et al. (120) first suggested linkage of the Ig heavy chain (Gm) allotype (chromosome 14q32) in 15 Japanese families with GD; however, this was not supported by studies in other populations (125, 126). An association of the T cell receptor ß-chain polymorphism (chromosome 7q35) with GD (177) has also not been reproduced (178, 179). Blakemore et al. (180) reported an association of GD with an IL-1 receptor antagonist allele (chromosome 2q14), but this was not confirmed by others (77, 160, 181, 182, 183). Likewise, association studies of the IL-4 polymorphism (chromosome 5q31) in GD have yielded conflicting results (77, 184). Recently reported associations of GD with the polymorphisms of the interferon- (chromosome 12q14; Ref. 185) and vitamin D receptor (186) genes also await confirmation.

TSH receptor (TSH-R) and other thyroid-specific genes

The TSH-R is a major autoantigen for GD, and the TSH-R gene (chromosome 14q31) has therefore been extensively studied in GD. Bohr et al. (187) first described a C to A SNP at codon 52 of TSH-R gene (Pro52Thr) in a GD patient with TAO. A subsequent study found the 52Thr allele in 2 of 22 patients with severe TAO, but none in 17 normal subjects studied (188). The same group reported an association of this 52Thr allele in female patients with GD, which was stronger in patients with extrathyroidal manifestations of GD (189). However, in contrast to the initial reports, several subsequent studies were unable to confirm the association of the 52Thr allele with GD or TAO (160, 190, 191, 192, 193). Furthermore, de Roux et al. (194) did not find linkage between a microsatellite marker inside the TSH-R gene and GD.

A case-control study has shown a weak association of GD with a thyroid hormone receptor ß gene polymorphism (chromosome 3p24), which awaits replication in another dataset (195). Pirro et al. (196) found no association of GD with a TPO gene polymorphism (chromosome 2p25). Recently, linkage of AITD with polymorphisms close to the Tg gene (chromosome 8q24) has been described (129, 197); this is discussed in more detail below.

Linkage scanning for novel AITD loci

Over the last 5 yr, three different cohorts of AITD families have been examined for genetic linkage to a large number of anonymous chromosomal markers by U.S., UK, and Japanese investigators. The results of these studies need to be viewed in the context that with 56 families (U.S. study), 82 sib-pairs (UK study), and 123 sib-pairs (Japanese study), no individual study has been appropriately powered to detect susceptibility loci with modest effects (198). Thus, only highly significant linkages, or those that are replicated in a second cohort of AITD or autoimmune patients, are likely to stand the test of time.

U.S. studies.

The first genome screen for AITD was completed by Tomer, Davies, and coworkers (128) using a cohort of 56 multiplex AITD families of various ethnic backgrounds (U.S., Italian, Israeli, and UK whites). This study has found significant evidence for linkage to GD at one locus on chromosome 20 (20q11.2) and suggestive evidence for a further five loci (two for GD alone, two for AH alone, and one for AITD). The chromosome 20 locus, referred to by the investigators as GD2, shows a multipoint LOD score of 3.5 for GD under a recessive model (128, 199). This value is greater than the threshold for significant linkage (LOD score 3.3) for complex trait analysis determined by Lander and Kruglyak (200), and there is also weaker evidence (NPL score, 2.0) to support linkage of GD to this locus in a subset of the UK sib-pair cohort (201). The remaining five intervals on chromosomes 6, 12, 13, 14, and Xq, in which lesser evidence for linkage was found by this study, remain putative AITD loci only with LOD scores between 2 and 3 (Table 4).

The largest study to date investigated genomewide markers in 123 ethnically homogeneous Japanese sib-pairs with AITD and found highly significant evidence of linkage to markers on chromosome 8q23-q24 in AH sib-pairs, with a nonparametric maximum LOD score (MLS) of 3.8 (129). Evidence suggestive of linkage was also found in AITD sib-pairs to markers on chromosome 5q31-q33, with an MLS of 3.1 (129). This Japanese study did not confirm linkage to any of the six putative loci found in the U.S. genome screen, with MLS scores being less than 1 at each of these loci (Table 4). Of particular interest, the region of chromosome 8 found to have significant linkage to AH in this Japanese study contains the Tg gene (129). A subsequent U.S. study, using an enlarged cohort of AITD families, has confirmed evidence for linkage at the 8q23-q24 interval (heterogeneity LOD score, 3.5) and has also provided weak evidence (P = 0.002) for association of an allele of an intragenic Tg marker with AITD (197). Thus, Tg, or perhaps an adjacent gene on 8q23-q24, probably harbors an important susceptibility allele(s) for AH (129, 197). The second region defined by this Japanese study as having suggestive linkage, 5q31-q33, is known to contain a cluster of cytokine genes, including the IL-3, -4, -5, -9, -12B, and -13 genes, and there is also evidence suggestive of linkage and association of T1D to an overlapping region (203). Thus, despite the lack of evidence for linkage to this region in other AITD studies (128, 184), this is still a candidate region for an AITD susceptibility gene.

UK studies.

Our group has performed linkage analyses over candidate genomic regions (see MHC and CTLA4 above) in a cohort of 82 AITD sib-pairs, all from white UK families with at least two sibs with GD (127, 193, 201, 202). This study has found linkage of AITD (NPL score, 3.5) to markers on chromosome 18q21 and some evidence for association at one anonymous marker in this region (202). This locus was originally identified as being linked to T1D (designated IDDM6; Refs. 204 and205), and there is corroborative evidence from the Japanese AITD study (129) and from linkage analyses of rheumatoid arthritis and systemic lupus erythematosus for an autoimmunity susceptibility gene in this region (58, 59). No evidence for linkage of GD to the loci on chromosome 14 or Xq was found in the UK cohort, although weak evidence for linkage to GD was found on Xp11 (Table 4; Ref. 193).

Thus, studies in these three populations have been able to replicate linkage for two novel loci, one close to Tg on chromosome 8q23-q24 for AH and the other on chromosome 20q11 for GD (Table 4). Two further loci, on chromosomes 5q31-q33 and 18q21, provide suggestive evidence for linkage to AITD with supporting evidence from similar studies of different autoimmune disorders. In the future, it is likely that some of these results will turn out to be false-positive linkages. However, as AITD patient cohorts increase in size, more of the loci identified by these initial linkage studies will be replicated. Furthermore, because of the relatively low sensitivity of linkage analysis for detecting disease alleles with small effects, once these susceptibility alleles are identified, it is likely that their effects will be apparent, even in AITD populations in which there was initially little or no evidence for linkage.

Summary and future directions

The last five years have seen a significant gain in knowledge about the genetics of AITD, although we are still some way from identifying novel disease susceptibility genes for these disorders. There is now good evidence for an AITD susceptibility allele or alleles at CTLA4. Furthermore, it is likely that Tg will turn out to be an important locus for AH. The relatively minor contribution of the MHC locus to AITD susceptibility has also been clarified. In addition, there are nine other putative AITD loci that have been identified with varying degrees of certainty by genome-scanning studies. As fine-mapping studies progress at these various loci, it is highly probable that novel AITD genes will be identified in the next 5 yr. It is likely that these genes will be implicated in the function of several different tissues or systems, including those that determine the thyroidal response to immune attack and those involved in both immune surveillance (antigen presentation) and the effector limbs of the adaptive immune response (including those that permit autoantibody formation). These novel genes will identify biochemical pathways involved in AITD susceptibility that had not hitherto been suspected and lead to the possibility of new therapeutic compounds for these common disorders. A knowledge of these pathways will also open up our understanding of the way environmental risk factors may influence the risk of AITD and its manifestations. Finally, because AITDs are the commonest autoimmune disorders, it is certain that the susceptibility alleles for AITD will be common risk factors for autoimmunity in the population and that their identification will have a major impact on our understanding of other important autoimmune disorders.

Acknowledgments

We are grateful to all of the patients and their families who have allowed us to collect DNA samples and to all of the physicians who have identified suitable subjects for our studies. We thank Helen Imrie for invaluable laboratory work and Dr. W. F. Kelly for helpful comments on the manuscript.

Footnotes

The work of S.H.S.P. has been supported by The Wellcome Trust and the British Thyroid Foundation.

Abbreviations: AH, Autoimmune hypothyroidism; AIRE, autoimmune regulator; AITD, autoimmune thyroid disease; APECED, autoimmune polyendocrinopathy, candidiasis, ectodermal dystrophy; CTLA4, cytotoxic T lymphocyte antigen-4; DZ, dizygotic; GD, Graves’ disease; HLA, human leukocyte antigen; MHC, major histocompatibility complex; MLS, maximum LOD score; m.u., mobility unit; MZ, monozygotic; NPL, nonparametric linkage; PPT, postpartum thyroiditis; SNP, single nucleotide polymorphism; TAO, thyroid-associated orbitopathy; T1D, type 1 diabetes; TDT, transmission disequilibrium test; Tg, thyroglobulin; TPO, thyroid peroxidase; TSH-R, TSH receptor.

Received March 28, 2002.

Accepted September 10, 2002.

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