Graves Disease, Susceptibility To, 1

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A locus for susceptibility to Graves disease (GRD1) has been mapped to chromosome 14q31.

Other loci for Graves disease include GRD2 (603388) on chromosome 20q13, GRDX1 (300351) on Xp11, and GRDX2 (see 300351) on Xq21.33-q22.

Graves disease has also been mapped to several loci that confer susceptibility to autoimmune thyroid diseases, including Hashimoto thyroiditis (HT; 140300): AITD1 (608173) on 6p11; AITD2 (608174) on 5q31-q33; AITD3 (608175) on 8q24; AITD4 (608176) on 10q, and AITD5 (601941) on 18q21.

Description

Graves disease is an autoimmune disorder in which antibodies to the thyrotropin receptor (TSHR; 603372) result in constitutive activation of the receptor and increased levels of thyroid hormone. Wilkin (1990) reviewed endocrine disorders of hormone excess and hormone deficiency resulting from receptor autoimmunity.

Inheritance

Several lines of evidence have suggested that Graves disease occurs in families. Bartels (1941) suggested that Graves disease is inherited as a simple autosomal recessive with relative sex limitation to females and reduced penetrance (70 to 80%) in homozygotes. Martin and Fisher (1945) postulated a recessive factor predisposing to exophthalmic goiter; however, Martin and Fisher (1951) could find no evidence of hereditary basis of toxic nodular goiter. Ingbar et al. (1956) found abnormalities of thyroid metabolism in euthyroid relatives of a thyrotoxic patient. Levit, in early studies in the U.S.S.R., was more inclined toward dominant inheritance (Fraser, 1967). Neither the recessive nor the dominant hypothesis had satisfactory proof.

Skillern (1972) favored polygenic inheritance for hyperthyroidism and for Hashimoto thyroiditis.

Horwitz and Refetoff (1977) found that Graves disease has an increased frequency in patients with familial deficiency of thyroxine-binding globulin (314200).

Clinical Management

Wit et al. (1986) found that neonatal thyrotoxicosis, which they observed in sibs, was caused by transplacental passage of thyroid-stimulating immunoglobulins (TSI) from the mother with Graves disease. It was a transient phenomenon. (This disorder is distinct from congenital nonautoimmune hyperthyroidism (609152).) The first infant was treated with exchange transfusion and potassium iodide; the second with intrauterine prophylthiouracil (given to the mother) to control fetal heart rate, followed by potassium iodide. The mother was euthyroid as a result of subtotal thyroidectomy. Neonatal thyrotoxicosis simulates mendelism. Wit et al. (1986) stated that mortality from neonatal thyrotoxicosis as well as intellectual impairment in later life is considerable.

Marcocci et al. (2001) treated 82 consecutive patients with moderate to severe and active Graves ophthalmopathy randomly with orbital radiotherapy combined with either oral or intravenous glucocorticoids. A significant reduction in proptosis and in lid width occurred, with no difference between the 2 groups. Diplopia significantly improved in both groups: it disappeared in 13 of 27 (48.1%) intravenous glucocorticoid patients (p less than 0.005) and in 12 of 33 (36.4%) oral glucocorticoid patients. The authors concluded that high-dose intravenous glucocorticoid and oral glucocorticoid (associated with orbital radiotherapy) are effective in the management of severe Graves ophthalmopathy, but the intravenous route seems to be more effective and better tolerated than the oral route and associated with a lower rate of side effects.

Robertson et al. (2003) conducted a prospective study to determine whether external ionizing radiation could favorably influence the orbital manifestations of Graves ophthalmopathy. Prior to orbital radiation, retinal microvascular abnormalities were identified in 2 patients, bilaterally in 1 and unilaterally in the other. During the course of the study, microvascular abnormalities developed de novo in the unaffected retina of the latter patient while the retinopathy in the fellow eye progressed. Retinal microvascular abnormalities and their sequelae developed de novo in both eyes of 2 more patients. The findings led the authors to discourage further treatment of Graves ophthalmopathy with radiation.

Barbero et al. (2004) described 3 patients with choanal atresia (608911) whose mothers received methimazole during pregnancy for the treatment of thyrotoxicosis (Graves disease; Hashimoto thyroiditis, 140300).

Pathogenesis

By immunizing mice with fibroblasts transfected with both the human thyrotropin-stimulating hormone receptor (TSHR; 603372) and an MHC class II molecule, but not by either alone, Shimojo et al. (1996) induced immune hyperthyroidism that had the major humoral and histologic features of Graves disease: stimulating TSHR antibodies, thyrotropin binding-inhibiting immunoglobulins (which are different from the stimulating TSHR antibodies), increased thyroid hormone levels, thyroid enlargement, thyrocyte hypercellularity, and thyrocyte intrusion into the follicular lumen. The results suggested that aberrant expression of MHC class II molecules on cells that express a native form of TSHR can result in the induction of functional anti-TSHR antibodies that stimulate the thyroid. Shimojo et al. (1996) concluded that the acquisition of antigen-presenting ability on a target cell containing the TSHR can activate T and B cells normally present in an animal and induce a disease with the major features of autoimmune Graves disease.

In both Graves disease and Hashimoto thyroiditis, thyroid-reactive T cells are formed and infiltrate the thyroid gland. In Graves disease, most of the T cells undergo a Th2 differentiation and activate B cells to produce TSHR antibodies, which stimulate the thyroid and cause clinical hyperthyroidism, as reviewed by Davies (2000). In contrast, Hashimoto thyroiditis is caused by Th1 switching of the thyroid-infiltrating T cells, which induces apoptosis of thyroid follicular cells and clinical hypothyroidism, as reviewed by Weetman (1996).

Bahn and Heufelder (1993) reviewed the pathogenesis of Graves ophthalmopathy.

Biochemical Features

Cardiovascular manifestations are frequent findings in patients with thyroid hormone disorders. Nitric oxide (NO) plays a key role in vascular, endothelial-mediated relaxation. NO is synthesized from L-arginine by NO synthase, an enzyme inhibited by endogenous compounds, mainly ADMA. Hermenegildo et al. (2002) investigated whether plasma L-arginine and dimethylarginine concentrations and NO production are altered in hypo- and hyperthyroid patients, compared with control subjects. L-arginine, ADMA, and symmetric dimethylarginine (SDMA) were analyzed by HPLC. NO was measured as plasma nitrite plus nitrate (NOX) concentration by a colorimetric method based on Griess reagent. L-arginine, ADMA, and SDMA plasma levels in the hypothyroid group were similar to those of the control group, whereas these values were significantly increased in patients with hyperthyroidism, most of whom had Graves disease. The L-arginine/ADMA ratio was decreased in hyperthyroid patients, resulting in diminished NOX production. When all subjects were analyzed together, free T4 levels were directly correlated with ADMA and inversely correlated with NOX.

Mapping

GRD1 Locus on Chromosome 14q31

By linkage analysis, De Roux et al. (1996) excluded the TSHR gene (603372) as a candidate gene in large multiply affected Welch and English families segregating Graves disease.

To identify susceptibility genes for Graves disease, Tomer et al. (1997) studied DNA markers in the regions of 8 candidate loci: the HLA region, TSHR, thyroid peroxidase, thyroglobulin (188450), IDDM4 (600319), IDDM5 (600320), immunoglobulin heavy chain gene (147100), and CTLA4. In patients with Graves disease, negative lod scores were obtained for all the candidate loci, except for markers in the TSHR region on chromosome 14q31. Marker D14S81 gave the highest score (maximum lod = 2.05, theta = 0.01) assuming a dominant mode of inheritance and a penetrance of 0.8. This locus was termed GRD1. These data confirmed the authors' previous observations of a lack of a necessary disease locus for Graves disease in the HLA gene region, and suggested the presence of an important susceptibility gene on 14q31, but at a considerable distance from the TSHR gene.

Additional Linkage and Association Studies

Barbesino et al. (1998) studied a total of 45 multiplex families containing at least 2 members with either Graves disease (55 patients) or Hashimoto thyroiditis (72 patients). They used linkage analysis to evaluate candidate susceptibility genes involved in estrogen activity, such as ESR1 (133430), ESR2 (601663), and ARO (107910). They concluded that their data excluded a major role for ESR1 and ARO in the genetic predisposition to autoimmune thyroid disease, but that ESR2 remained a candidate locus.

Association with the IFIH1 Gene on Chromosome 2q24

Sutherland et al. (2007) studied the A946T substitution (rs1990760) in 602 Graves disease patients, 214 Addison disease (240200) patients, and 446 healthy controls. The ala946 allele was present in 796/1204 (66%) Graves disease patient alleles compared with 508/892 (57%) control alleles (odds ratio = 1.47; 5-95% CI, 1.23-1.76; p = 1.9 x 10(-5)). In contrast, there was no association of alleles at this marker in Addison disease.

Association with the CTLA4 Gene on Chromosome 2q33

Vaidya et al. (1999) genotyped 77 affected sib pairs with autoimmune thyroid disease for 8 polymorphic markers spanning the CTLA4 (123890) region of 2q31-q33, and for 5 markers spanning the MHC region of 6p21. Nonparametric analysis showed linkage of Graves disease to the CTLA4 region with a peak nonparametric linkage (NPL) score of 3.43 (p = 0.0004) at the marker D2S117. The proportion of affected full sibs sharing zero alleles reached a minimum of 0.113 close to D2S117. Families with brother-sister sib pairs showed a peak NPL score of 3.46 at D2S117, compared with 2.00 in the families with only affected females, suggesting a stronger influence in families with affected males. Lesser evidence for linkage was found at the MHC locus, with a peak NPL score of 1.95, between the markers D6S273 and TNFA (191160). Vaidya et al. (1999) concluded that the CTLA4 locus and the MHC locus together confer approximately 50% of the inherited susceptibility to Graves disease in the population studied.

Donner et al. (1997) determined the frequency of the CTLA4 49A-G (T17A; 123890.0001) polymorphism in 305 patients with Graves disease, 293 patients with insulin-dependent diabetes mellitus (IDDM; 222100), and 325 controls. Patients with Graves disease had significantly more ala17 alleles than controls, both as homozygotes (21% vs 13%) and as heterozygotes (53% vs 46%), and fewer thr17 alleles as homozygotes (26% vs 42%; P less than 2 x 10-4). The phenotypic frequency of ala-positive patients (73%) was significantly higher than that of controls (58%; p = 10-4; relative risk = 2).

Ueda et al. (2003) identified polymorphisms of the CTLA4 gene as candidates for primary determinants of risk for the common autoimmune disorders Graves disease, autoimmune hypothyroidism, and type I diabetes (see 601388). In humans, disease susceptibility was mapped to a noncoding 6.1-kb 3-prime region of CTLA4, the common allelic variation of which (see 123890.0002) was correlated with lower mRNA levels of the soluble alternative splice form of CTLA4. In a mouse model of type I diabetes, susceptibility was also associated with variation in CTLA4 gene splicing with reduced production of a splice form encoding a molecule lacking the CD80 (112203)/CD86 (601020) ligand-binding domain.

Association with the GC Gene on Chromosome 4q13

The immunomodulatory effects of the vitamin D endocrine system and the importance of GC for systemic 1,25-dihydroxyvitamin D led Pani et al. (2002) to genotype families with an offspring affected by Graves disease (95 pedigrees) or by Hashimoto thyroiditis (140300) (92 pedigrees), encompassing 561 individuals of Caucasian origin, for the T420K (139200.0001), D416E (139200.0002), and intron 8 GC (139200.0003) polymorphisms. There was a significant transmission disequilibrium of the intron 8 polymorphism in patients with Graves disease (p less than 0.03) but not of the exon 11 polymorphisms. They found that allele 8 was significantly more often inherited to patients than was allele 10; the observed frequency of allele 6 was too low for a statistical evaluation. In contrast, neither the IVS8 nor the exon 11 polymorphisms were associated with Hashimoto thyroiditis. Maternal and paternal transmission as well as allele frequencies in DQ2+ and DQ2- (see 146880) patients did not differ in either disease. The authors concluded that allelic variants of the DBP gene confer susceptibility to Graves disease but not to Hashimoto thyroiditis in their population. They also concluded that these findings support a role of the vitamin D endocrine system in thyroid autoimmunity.

Association with the HLA Region on Chromosome 6p21

Sasazuki (1981) presented data suggesting that 2 major genes, one linked to HLA (on chromosome 6) and one linked to Gm (on chromosome 14), contributed to susceptibility to Graves disease. He studied 30 Japanese families with 2 or more affected first-degree relatives. All affected sibs, except for 1 female, shared both HLA and Gm haplotypes. The exceptional case was explicable on the basis of recombination between HLA and an HLA-linked susceptibility gene for Graves disease. The HLA-linked gene appeared to be in strong linkage disequilibrium with HLA-DR5, but no significant association was noted between Graves disease and a particular immunoglobulin allotype. From statistical analysis using the estimated incidence of Graves disease in Japanese as 0.008, Sasazuki (1981) concluded that both the HLA- and the Gm-linked genes appeared to be recessive, and that their gene frequencies were 0.18 and 0.20, respectively, with a penetrance between 0.45 and 1.0. Uno et al. (1981) presented evidence that one of these genes was closely linked to HLA-DR and that the other was linked to the gene coding for the Gm allotype.

Payami et al. (1989) confirmed a positive association of Graves disease with HLA-DR3. In addition, they found a negative association between DR5 and Graves disease; this was not a result of the increase in DR3. When patients with or without eye disease were considered separately, a significant increase in the frequency of DR4 was found in those without eye disease. When the authors applied the sib-pair method to the data, they found frequencies of haplotype sharing that deviated significantly from the expected one-fourth, one-half, one-fourth distribution that is expected if the disease is not linked to HLA. The findings indicated the presence of a disease gene in or near the HLA region in both the Caucasian and the Chinese populations studied.

Heward et al. (1998) genotyped 228 Graves disease patients, 364 controls, and 98 families (parents, patients, and unaffected sibs) at the DRB1 (142857), DQB1 (604305), and DQA1 (146880) loci. The case-control study showed an increased frequency in Graves disease, compared to controls, of DRB1*0304 (47% vs 24%; pc less than 1.4 x 10-5), DQB1*02 (58% vs 46%; pc less than 0.035), DQB1*0301/4 (42% vs 28%; pc less than 3.5 x 10-3) and DQA1*0501 (67% vs 39%; pc less than 7 x 10-6). The DRB1*0304-DQB1*02-DQA1*0501 haplotype was increased in Graves disease (47%) compared with controls (24%; pc less than 1.8 x 10-5; odds ratio of 2.72). No independent association of these alleles was observed. Preferential transmission of DRB1*0304-DQB1*02-DQA1*0501 from parents heterozygous for the haplotype to affected sibs (72%) was seen in the families (chi square = 11.95; 1 d.f.; p = 0.0005). Lack of preferential transmission to unaffected sibs (53%; chi square of 0.19; 1 d.f.; p = NS) excluded segregation distortion. These results suggested to Heward et al. (1998) that linkage disequilibrium between Graves disease and the HLA class II region was due to the extended haplotype DRB1*0304-DQB1*02-DQA1*0501.

Chen et al. (1999) examined HLA genotypes of DRB1 and DQB1 plus DRB3 (612735) subtypes using PCR-based sequence-specific priming in 2 groups of North American (Gainesville, Florida and Toronto, Canada) Caucasian patients with Graves disease. They stratified patients into those with either early age at onset (less than 20 years, 13.1 +/- 4.8 years; 30 patients) or later age at onset (38.8 +/- 9.7 years; 62 patients) and compared the results to 192 normal controls. Chen et al. (1999) found that DRB1*03 was associated with Graves disease, but at a higher odds ratio for early-onset than late-onset patients (3.7 vs 2.2). The frequency of DRB1*08 was also increased in both groups of patients, but significantly so only in patients with early-onset Graves disease (p = 0.001; chi square = 10.8). DRB3 was highly associated with Graves disease in both groups of patients (p = 0.009; chi square = 6.83, and p = 0.0015; chi square = 10.1, respectively); however, the subtypes of DRB3 revealed differential susceptibilities. While the frequencies of both DRB3*0101 and DRB3*0202 were increased over the entire cohort, that of DRB3*0301 was not. Significant P values were found for DRB3*0101 in patients with early-onset and for DRB3*0202 in patients with late-onset Graves disease. When the haplotypes of DRB1*03-DRB3 of all subtypes were removed for analysis (all DRB1*03-positive also had DRB3*0101), the frequency of DRB3*0202 remained significantly higher in the patients with late-onset Graves disease than in controls (p = 0.0043; chi square = 8.13), but DRB3 was no longer positively associated with the early-onset group. In addition, Chen et al. (1999) found that DRB1*07 was negatively associated with both groups of patients (p = 0.024; chi square = 5.10, and p = 0.0085; chi square = 6.93, respectively). The authors concluded that DRB3*0202 is more likely than DRB1*03 to be the primary susceptibility locus for patients with late-onset Graves disease.

Chen et al. (2000) studied DRB1, DQB1, DRB3 subtypes, DQA1*0501, DQA1*0201, and CTLA4 polymorphisms in 49 African American patients with adult-onset Graves disease and in 47 racially-matched controls using PCR-based sequence-specific priming methods. They found that the frequency of DRB3 was significantly increased in the patients (75.5% vs 57.4%, p = 0.006, chi square = 3.52), especially for the DRB3*0202 subtype (53.1% vs 23.4%, p = 0.003, chi square = 8.91). In addition, while the frequency of DQA1*0501 was increased (p = 0.018, chi square = 5.63) in their patients, the haplotype of DRB3/DQA1*0501 or DRB3*0202/DQA1*0501 was found to be more strongly associated (P = 0.008, chi square = 7.0; p = 0.0008, chi square = 11.34, respectively). The authors concluded that DRB3*0202, particularly when found with DQA1*0501 in a haplotype, is a susceptible gene(s) for Graves disease in adult African Americans. Considering these data with those in Caucasian patients, they concluded that the primary Graves susceptible locus is likely DRB3 and not DRB1.

The HLA class II genes DRB1, DQB1, and DQA1 are associated with Graves disease, but, because of strong linkage disequilibrium within this region, which etiologic variant is primarily involved has been difficult to determine. Simmonds et al. (2005) genotyped 871 patients with Graves disease and 621 control subjects at these 3 loci, all of which were found to be associated with the disease. Stepwise logistic-regression analysis showed that the association could be explained by either DRB1 or DQA1 but not by DQB1. To extend previous results, the amino acid sequence of the exon 2-encoded peptide-binding domain of DRB1 was predicted for each subject, and, by use of logistic regression, each position was analyzed for association with GD. Of 102 amino acids, 70 were uninformative; of the remaining 32 amino acids, 13 were associated with GD. The strongest association was at position beta-74. This analysis was consistent with the possibility that position beta-74 of exon 2 of the DRB1 molecule may have a specific and central role in autoantigen presentation by DRB1 to T lymphocytes. However, Simmonds et al. (2005) could not exclude a primary role for DQA1 or for other polymorphisms that affect DRB1 function or expression.

Chu et al. (2011) conducted a genomewide association study in 1,536 individuals with Graves disease and 1,516 controls, and then evaluated a group of associated SNPs in a second set of 3,994 cases and 3,510 controls. Chu et al. (2011) confirmed an association with rs6903608 at the HLA-DR-DQ gene. The C allele is the risk allele (odds ratio = 1.34; 95% CI 1.26-1.41; combined P value = 5.12 x 10(-24)). Chu et al. (2011) also confirmed association with rs6457617, also at the HLA-DR-DQ gene; T is the risk allele (odds ratio = 1.40; 95% CI 1.32-1.48; P = 7.38 x 10(-33)). Chu et al. (2011) also confirmed association with rs2281388 in the HLA-DPB1 gene; T is the risk allele (odds ratio = 1.64; 95% CI 1.55-1.74; combined P = 1.50 x 10(-65)). Additionally, Chu et al. (2011) demonstrated association with rs4947296 at the MUC21 gene (616991) on chromosome 6p21, somewhat upstream of the HLA locus (position 31,166,157); C is the risk allele. Chu et al. (2011) found an odds ratio of 1.77 with 95% CI 1.65-1.91, combined P = 3.51 x 10(-51).

Association with the Vitamin D Receptor Gene on Chromosome 12q12-q14

Ban et al. (2000) investigated the distribution of a vitamin D receptor (VDR; 601769) gene polymorphism in 180 Japanese patients with Graves disease (48 males and 132 females) and 195 controls (67 males and 128 females). A VDR polymorphism was defined by BsmI endonuclease restriction yielding genotypes BB (no restriction site on both alleles), bb (restriction site on both alleles), or Bb (heterozygous). There was a 1.5 relative risk for Graves disease conferred by at least 1 B allele. The authors concluded that there was an association between the VDR gene and Graves disease in Japanese.

Association with the SLC27A4 Gene on Chromosome 7q31

Kacem et al. (2003) analyzed polymorphic microsatellite markers around the SLC26A4 gene (605646), which encodes pendrin, an apical transporter of iodide to the thyroid, to investigate the role of SLC26A4 in the genetic control of AITDs. Using case-control and family-based designs in a sample from Tunisia, Kacem et al. (2003) found evidence that SLC26A4 may be a susceptibility gene for AITDs, with varying contributions in Graves disease and Hashimoto thyroiditis.

Association with the TSHR Gene on Chromosome 14q31

Dechairo et al. (2005) identified linkage disequilibrium blocks encompassing the TSHR gene (603372) and SNPs that captured the majority of intra-block haplotype diversity, then genotyped 1,059 Caucasian patients with autoimmune thyroid disease and 971 Caucasian controls for these and other common SNPs. The authors identified a haplotype across 2 linkage disequilibrium blocks that was significantly associated with Graves disease. Dechairo et al. (2005) replicated these findings by genotyping the SNP with the strongest association with Graves disease, rs2268458, in a separate Caucasian group of 1,366 patients with autoimmune thyroid disease and 1,061 controls, and they suggested that TSHR is a Graves disease-specific locus.

Hiratani et al. (2005) reported significant associations between autoimmune thyroid disease (AITD)/Graves disease (GD)/Hashimoto thyroiditis and multiple SNPs. Specifically, the SNP JST022302 and several adjacent SNPs in intron 7 of the TSHR gene were significantly associated with GD (P = 0.039-0.0004) but not Hashimoto thyroiditis. Furthermore, they identified 3 haplotype blocks around intron 7 by linkage disequilibrium analysis. A single SNP haplotype [AATG(CT)6(TT)AG] in the haplotype block including JST022302 showed significant association with GD in haplotype case-control analysis (P = 0.0058). The authors concluded that alleles of intron 7 of the TSHR gene contribute to GD susceptibility.

Brand et al. (2009) investigated a combined panel of 98 SNPs, including 70 tag SNPs, across an extended 800-kb region surrounding the TSHR gene to refine association in a cohort of 768 GD subjects and 768 matched controls. Strongest associations were with rs179247 (p = 8.9 x 10(-8), OR = 1.53) and rs12101255 (p = 1.95 x 10(-7), OR = 1.55), which are both located in intron 1 of the TSHR gene. Association of rs179247 was replicated in 303 additional GD families (p = 7.8 x 10(-4)). Quantitative RT-PCR analysis of 12 thyroid tissue samples suggested that the disease-associated genotypes, AA for rs179247 and TT for rs12101255, showed reduced mRNA expression ratios of full-length TSHR relative to 2 TSHR splice variants ST4 and ST5.

Association with the ICAM1 Gene on Chromosome 19p13.3-p13.2

Because ICAM1 (147840) plays a key role in lymphocyte infiltration into the thyroid gland and the concentration of soluble ICAM1 correlates significantly with the clinical activity and treatment status in Graves disease, Kretowski et al. (2003) evaluated the frequency of the 721G-A (G241R) and the 1405A-G (K469E) polymorphisms of the ICAM1 gene in subjects with Graves disease compared with that in healthy controls. In a group of 235 patients with Graves disease and 211 healthy controls, Kretowski et al. (2003) found that the 721G-A polymorphism was associated with an earlier age of Graves disease onset (before age 40) and that the 1405A-G polymorphism could predispose to Graves ophthalmopathy. Kretowski et al. (2003) concluded that G241R and K469E amino acid substitutions in the ICAM1 molecule could influence the intensity/duration of the autoimmunity process and the infiltration of orbital tissues.

Animal Model

Using an adenovirus-mediated mouse model of Graves disease, Chen et al. (2003) demonstrated that goiter and hyperthyroidism occurred to a significantly greater extent when the adenovirus expressed the free alpha subunit as opposed to a genetically modified TSHR that cleaves minimally into subunits (p less than 0.005). Chen et al. (2003) concluded that shed alpha subunits induce or amplify the immune response leading to hyperthyroidism in Graves disease.