Further Evidence for a Strong Genetic Influence on the Development of Autoimmune Thyroid Disease: The California Twin Study

Ringold, Daniel A.; Nicoloff, John T.; Kesler, Matthew; Davis, Heather; Hamilton, Ann S.; Mack, Thomas M.

doi:10.1089/105072502760258613

Cited by 96 publications

(41 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Environmental factors play also an important role in the development of AITD, as the concordance rate for AITD in monozygotic twins is not 100% (27,28). Twin studies suggest that genetic factors account for about 70% of the risk of developing AITD leaving about 30% for the environmental factors (27)(28)(29)(30). Identified environmental factors are iodine intake, smoking, stress, pregnancy, estrogens, and possibly infections.…”

Section: Discussionmentioning

confidence: 99%

Natural history of the transition from euthyroidism to overt autoimmune hypo- or hyperthyroidism: a prospective study

Effraimidis¹,

Strieder²,

Tijssen

et al. 2011

European Journal of Endocrinology

View full text Add to dashboard Cite

Objective: To evaluate the progression in time from euthyroidism to overt autoimmune hypothyroidism or to overt autoimmune hyperthyroidism. Subjects and methods: The design is that of a nested case-control study within the prospective Amsterdam autoimmune thyroid disease (AITD) cohort study in which 790 healthy euthyroid women with at least one first or second degree relative with documented AITD were followed for 5 years. Thyroid function tests were assessed annually. Contrast between cases (overt hypothyroidism -TSHO 5.7 mU/l and free thyroxine (FT 4 )!9.3 pmol/l and overt hyperthyroidism -TSH!0.4 mU/l and FT 4 O20.1 pmol/l, also referred to as events) and controls (matched for age and duration of follow-up). Results: At baseline, the 38 hypothyroid cases had already higher TSH and lower FT 4 concentrations than their 76 controls, and the difference between both the groups persisted 1 year before occurrence of the event. In contrast, neither TSH nor FT 4 values differed between the 13 hyperthyroid cases and their 26 controls at baseline or 1 year before the event. The prevalence of thyroid peroxidase-Ab was higher in both hypothyroid and hyperthyroid cases than in controls. At the time of event, hypothyroid cases were less common among current smokers (PZ0.083) and more common in the postpartum period (PZ0.006) than their controls, whereas hyperthyroid cases were pregnant more frequently (PZ0.063). Conclusions: The data suggest that progression toward overt autoimmune hypothyroidism is a gradual process taking several years, but in contrast overt autoimmune hyperthyroidism develops faster in terms of months.

show abstract

Section: Discussionmentioning

confidence: 99%

Natural history of the transition from euthyroidism to overt autoimmune hypo- or hyperthyroidism: a prospective study

Effraimidis¹,

Strieder²,

Tijssen

et al. 2011

European Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…AITDs are complex diseases, which are caused by an interaction between susceptibility genes (6)(7)(8) and nongenetic factors, such as infection (9)(10)(11)(12). This paradigm is based on solid epidemiologic evidence demonstrating a genetic predisposition to AITDs, including: (i) familial clustering (13); (ii) a sibling risk ratio ( s ) of Ͼ10 (7,14); (iii) a high concordance rate in monozygotic twins when compared with dizygotic twins (15)(16)(17)(18); and (iv) the presence of thyroid autoantibodies, which are markers of subclinical AITD, in up to 50% of siblings of patients with AITD (19,20).…”

mentioning

confidence: 99%

Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

Ban

Greenberg

Concepcion

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

172

131

View full text Add to dashboard Cite

The 8q24 locus, which contains the thyroglobulin (Tg) gene, was previously shown to be strongly linked with autoimmune thyroid disease (AITD). We sequenced all 48 exons of the Tg gene and identified 14 single-nucleotide polymorphisms (SNPs). Case control association studies demonstrated that an exon 10 -12 SNP cluster and an exon 33 SNP were significantly associated with AITD (P < 0.01). Haplotype analysis demonstrated that the combination of these two SNP groups was more significantly associated with AITD (P < 0.001). Gene-gene interaction studies provided evidence for an interaction between HLA-DR3 and the exon 33 SNP, giving an odds ratio of 6.1 for Graves' disease. We then sequenced exons 10,12, and 33 of the mouse Tg gene in 19 strains of mice. Fifty percent of the strains susceptible to thyroiditis had a unique SNP haplotype at exons 10 and 12, whereas none of the mouse strains that were resistant to thyroiditis had this SNP haplotype (P ‫؍‬ 0.01). We concluded that Tg is a susceptibility gene for AITD, both in humans in and in mice. A combination of at least two Tg SNPs conferred susceptibility to human AITD. Moreover, the exon 33 SNP showed evidence for interaction with HLA-DR3 in conferring susceptibility to Graves' disease.Graves' disease ͉ Hashimoto's disease ͉ thyroiditis T he autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are among the most common human autoimmune diseases with recent data showing a prevalence of clinical AITD of up to 1% in the U.S. population (1, 2). The hallmark of GD is the production of thyroid-stimulating hormone receptor (TSHR)-stimulating antibodies causing hyperthyroidism, whereas HT is characterized by the apoptosis of thyrocytes, leading to hypothyroidism (reviewed in refs. 3 and 4). However, despite their contrasting clinical presentations, GD and HT share many features in common, mainly, infiltration of the thyroid by T cells and production of antithyroid autoantibodies [antithyroglobulin and anti-thyroid peroxidase (TPO) antibodies] (3-5). AITDs are complex diseases, which are caused by an interaction between susceptibility genes (6-8) and nongenetic factors, such as infection (9-12). This paradigm is based on solid epidemiologic evidence demonstrating a genetic predisposition to AITDs, including: (i) familial clustering (13); (ii) a sibling risk ratio ( s ) of Ͼ10 (7, 14); (iii) a high concordance rate in monozygotic twins when compared with dizygotic twins (15-18); and (iv) the presence of thyroid autoantibodies, which are markers of subclinical AITD, in up to 50% of siblings of patients with AITD (19,20).We have previously performed a whole-genome scan in a dataset of 102 multiplex, multigenerational AITD families (540 individuals; refs. 21-23). Three loci on chromosomes 6p, 8q, and 10q showed evidence for linkage with the entire AITD dataset giving maximum multipoint heterogeneity logarithm of odds (lod) scores of 2.0, 3.5, and 4.1, respectively. The 8q24 locus was also reported to be linked with AITD in a dat...

show abstract

“…Studies with twins have indicated a higher concordance of autoimmune disorders in monozygotic twins compared to dizygotic twins [31][32][33]. In addition to these findings in humans, certain inbred murine strains show a consistent susceptibility to particular spontaneous or experimentally induced autoimmune diseases [34,35].…”

Section: Genetic Basis Of Autoimmunitymentioning

confidence: 95%

Autoimmunity and Apoptosis - Therapeutic Implications

Rashedi

Panigrahi²,

Ezzati³

et al. 2007

CMC

View full text Add to dashboard Cite

Acquisition of a complex immune system during evolution provided organisms with the most effective defense mechanism against "foreign" or "non-self" invaders. This efficient protection against pathogens, however, has been achieved at the expense of a higher risk for "self"-directed reaction or autoimmunity. Establishment of self-tolerance and homeostasis in the immune system is regulated at different physiological stages of immune cells development. The breakdown in discrimination between "self" and "non-self" causes an aberrant immune response against autoantigens that promote damage to the "self" cells and tissue(s), resulting in various autoimmune phenotypes. Whereas activation and clonal proliferation of autoreactive T-and B-lymphocytes underlies the pathogenesis of autoimmune diseases, the mechanism by which self-tolerance is lost and autoimmune responses are induced is not clear yet. Autoimmunity is a multi-step process that occurs as a consequence of complex interaction between genetic susceptibility and non-genetic factors. Programmed cell death, as a key mechanism to regulate immune system function, has a crucial influence on both the selection process of immune cells and the maintenance of this immune tolerance in peripheral repertoire. Thus, defects in apoptotic death pathways may contribute to the development of autoimmune response in susceptible individuals in certain conditions.

show abstract

Further Evidence for a Strong Genetic Influence on the Development of Autoimmune Thyroid Disease: The California Twin Study

Cited by 96 publications

References 40 publications

Natural history of the transition from euthyroidism to overt autoimmune hypo- or hyperthyroidism: a prospective study

Natural history of the transition from euthyroidism to overt autoimmune hypo- or hyperthyroidism: a prospective study

Amino acid substitutions in the thyroglobulin gene are associated with susceptibility to human and murine autoimmune thyroid disease

Autoimmunity and Apoptosis - Therapeutic Implications

Contact Info

Product

Resources

About