Novel single-nucleotide polymorphisms in the calsequestrin-1 gene are associated with Graves&amp;rsquo; ophthalmopathy and Hashimoto&amp;rsquo;s thyroiditis

Lahooti, Hooshang; Cultrone, Daniele; Edirimanne, Senarath; Walsh, John P.; Delbridge, Leigh; Cregan, Patrick; Champion, Bernard; Wall, Jack R.

doi:10.2147/opth.s87972

Cited by 11 publications

(9 citation statements)

References 27 publications

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“…In previous publications 43 , 45 , 46 we suggested that CASQ1 gene SNPs rs3838216, rs74123279, and rs2275703 are possible genetic markers for GO and HT, in addition to those that are already known. They are potentially pathogenic genetic markers for the eye muscle component of GO.…”

Section: Discussionmentioning

confidence: 92%

“…1) MassARRAY SNP analysis using iPLEX technology of SEQUENOM has been described in detail in previous publications of this laboratory. 43 , 45 , 46 2) Functional analysis: T4, T3, thyroid receptors antibodies (TRAB), TSI, TSHr, TG antibody, and TPO antibody were measured by established radio immunoassay methods in pathology laboratories.…”

Section: Methodsmentioning

confidence: 99%

“…Comprehensive demographic, clinical details, and genotypes of SNP rs180195 for patients with GO, Graves’ hyperthyroidism (GH), HT, and control subjects without autoimmune diseases have been described in detail 43 in an earlier publication, summarized in Table 1 . Briefly, partici pants were recruited from outpatients’ clinics at Nepean and Royal North Shore Hospitals in New South Wales and the Sir Charles Gairdner Hospital in Western Australia.…”

Section: Clinical Subjectsmentioning

confidence: 99%

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Single nucleotide polymorphism 1623 A/G (rs180195) in the promoter of the Thyroglobulin gene is associated with autoimmune thyroid disease but not with thyroid ophthalmopathy

Lahooti¹,

Edirimanne²,

Walsh³

et al. 2017

OPTH

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BackgroundOur studies over recent years have focused on some new ideas concerning the pathogenesis for the orbital reaction that characterizes Graves’ ophthalmopathy namely, that there are antigens expressed by thyroid tissue and orbital tissue where they are targeted by autoantibodies and/or sensitized T cells, leading to orbital inflammation. While this has been well studied for the thyroid stimulating hormone-receptor, the possible role of another major thyroid antigen, Thyroglobulin (TG), has been largely ignored.MethodsWe identified novel variant 1623 A/G single nucleotide polymorphism (SNP) (rs180195) in the promoter of TG gene associated with autoimmune thyroid disorders. We genotyped the TG SNPs rs2069566, rs2076739, rs121912646, rs121912647, rs121912648, rs121912649, rs121912650, rs137854433, rs137854434, and rs180195 by MassARRAY SNP analysis using iPLEX technology in a cohort of 529 patients with thyroid autoimmunity with and without ophthalmopathy, and controls.ResultsWe showed that variant 1623 A/G SNP (rs180195) in the promoter of TG gene is a marker for thyroid autoimmunity, but not for ophthalmopathy. We showed that there was a significant difference in the distribution of the major allele (G) vs minor allele (A) in patients with Hashimoto’s thyroiditis (HT). In HT the wild-type (GG) genotype was less common. We showed that the genotypes homozygous AA and heterozygous GA rs180195 SNP in the promoter of TG gene were more closely associated with thyroid autoimmunity than the wild-type (GG) polymorphism, and are thus, markers of autoimmunity.Conclusionrs180195 SNP was previously identified by Stefan et al independently of us, who showed that this TG SNP predisposed to autoimmune thyroid diseases. However, this is the first study to explore the association between TG SNPs and HT. Our findings support the notion that the thyroid and orbital disorders are not part of the same disease, ie, “Graves’ disease” or “Hashimoto’s disease”, but separate autoimmune disorders.

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Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Clinical Subjectsmentioning

confidence: 99%

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Single nucleotide polymorphism 1623 A/G (rs180195) in the promoter of the Thyroglobulin gene is associated with autoimmune thyroid disease but not with thyroid ophthalmopathy

Lahooti¹,

Edirimanne²,

Walsh³

et al. 2017

OPTH

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“…So these results strongly suggest that the occurrence of thyroid dysfunction in teenagers can be caused by family history, which means the genetic background. The eye disorder associated with AITD, called thyroid-associated ophthalmopathy, drastically reduces the quality of life in affected patients and even contributes to the disability of patients [ 20 ]. Enormous amounts of documents have shown that TAO is a complex disease with multifaceted mechanism including smoking history, thyroid dysfunction, and positive TRAb [ 21 , 22 ].…”

Section: Discussionmentioning

confidence: 99%

Variants of Interleukin-22 Gene Confer Predisposition to Autoimmune Thyroid Disease

Song

Wang

et al. 2017

International Journal of Endocrinology

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As there are no previous studies on the interleukin-22 (IL-22) variants in autoimmune thyroid disease (AITD), the present study aimed to explore the association between polymorphisms of IL-22 and the predisposition to AITD. The study had 975 AITD patients, including 639 Graves' disease (GD) and 336 Hashimoto's thyroiditis (HT) individuals and 851 healthy cohorts. Ligase detection reaction (LDR) and direct sequencing method were used for genotyping the IL-22 gene polymorphisms at rs2046068, rs2227478, rs2227485, rs11611206, and rs1179251. In comparison to female controls, genotype CC of rs1179251 was increased in the female AITD patients. Alleles C at rs2046068, C at rs2227478, and C at rs1179251 linked to the susceptibility of HT males. Genotype CC in rs1179251 was higher in male HT. Variants at rs2046068, rs2227478, and rs1179251 were associated with the AITD teenagers. Besides, genotype GG in rs11611206 was correlated with thyroid-associated ophthalmopathy (TAO). Moreover, allele G at rs11611206 was associated with decreased risk for TAO by 28.9%. Similarly, genotype CC of rs1179251 and genotype GG of rs11611206 were associated with Graves' ophthalmopathy (GO). Allele G in rs11611206 increased people with HT towards the predisposition of hypothyroidism. In conclusion, genetic variants of IL-22 are associated with the occurrence of AITD.

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“…Moreover, several susceptibility genes for Graves’ ophthalmopathy have been proposed over the years based on small case–control association studies. These include CTLA-4 , tumor necrosis factor-α ( TNF- α), intercellular adhesion molecule-1 ( ICAM-1 ), interferon-γ ( IFN- γ) ( 8 ), insulin-like growth factor-1 receptor ( IGF-1R ) ( 9 ), suppressor of cytokine signaling 3 ( SOCS3 ) ( 10 ), thyroid peroxidase ( TPO ) ( 11 ), calsequestrin 1 ( CASQ1 ) ( 12 ), cysteine-rich angiogenic inducer 61 ( CYR61 ), zinc finger protein 36 C3H type homog mouse ( ZFP36 ), and stearoyl-coenzyme A desaturase ( SCD ) ( 13 ). However, none of the Graves’ ophthalmopathy specific genes have been confirmed.…”

Section: Introductionmentioning

confidence: 99%

Dissecting the Genetic Susceptibility to Graves’ Disease in a Cohort of Patients of Italian Origin

et al. 2016

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Graves’ disease (GD) is an autoimmune oligogenic disorder with a strong hereditary component. Several GD susceptibility genes have been identified and confirmed during the last two decades. However, there are very few studies that evaluated susceptibility genes for GD in specific geographic subsets. Previously, we mapped a new locus on chromosome 3q that was unique to GD families of Italian origin. In the present study, we used association analysis of single-nucleotide polymorphism (SNPs) at the 3q locus in a cohort of GD patients of Italian origin in order to prioritize the best candidates among the known genes in this locus to choose the one(s) best supported by the association. DNA samples were genotyped using the Illumina GoldenGate genotyping assay analyzing 690 SNP in the linked 3q locus covering all 124 linkage disequilibrium blocks in this locus. Candidate non-HLA (human-leukocyte-antigen) genes previously reported to be associated with GD and/or other autoimmune disorders were analyzed separately. Three SNPs in the 3q locus showed a nominal association (p < 0.05): rs13097181, rs763313, and rs6792646. Albeit these could not be further validated by multiple comparison correction, we were prioritizing candidate genes at a locus already known to harbor a GD-related gene, not hypothesis testing. Moreover, we found significant associations with the thyroid-stimulating hormone receptor (TSHR) gene, the cytotoxic T-lymphocyte antigen-4 (CTLA-4) gene, and the thyroglobulin (TG) gene. In conclusion, we identified three SNPs on chromosome 3q that may map a new GD susceptibility gene in this region which is unique to the Italian population. Furthermore, we confirmed that the TSHR, the CTLA-4, and the TG genes are associated with GD in Italians. Our findings highlight the influence of ethnicity and geographic variations on the genetic susceptibility to GD.

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Novel single-nucleotide polymorphisms in the calsequestrin-1 gene are associated with Graves’ ophthalmopathy and Hashimoto’s thyroiditis

Cited by 11 publications

References 27 publications

Single nucleotide polymorphism 1623 A/G (rs180195) in the promoter of the Thyroglobulin gene is associated with autoimmune thyroid disease but not with thyroid ophthalmopathy

Single nucleotide polymorphism 1623 A/G (rs180195) in the promoter of the Thyroglobulin gene is associated with autoimmune thyroid disease but not with thyroid ophthalmopathy

Variants of Interleukin-22 Gene Confer Predisposition to Autoimmune Thyroid Disease

Dissecting the Genetic Susceptibility to Graves’ Disease in a Cohort of Patients of Italian Origin

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