Dataset Information

Association of BTG2, CYR61, ZFP36, and SCD gene polymorphisms with Graves' disease and ophthalmopathy.

ABSTRACT: BACKGROUND: Environmental and genetic factors predispose an individual to the development of Graves' disease (GD). In an expression study of intraorbital tissue, adipocyte-related immediate early genes (IEGs) and immunomodulatory genes were found to be overexpressed in patients with Graves' ophthalmopathy (GO). We hypothesized that genetic variations in these genes could be associated with GD and/or GO. METHODS: A total of 98 single nucleotide polymorphisms (SNPs) in 12 genes were genotyped in 594 GD patients with (n=267) or without (n=327) GO and 1147 sex- and ethnicity-matched controls from Malmö, Sweden. RESULTS: Ten SNPs in four genes (BTG family, member 2 [BTG2], cysteine-rich, angiogenic inducer 61 [CYR61], zinc finger protein 36, C3H type, homolog mouse [ZFP36], and stearoyl-coenzyme A desaturase [SCD]) showed an association with GD and/or GO. SNPs rs12136280 (odds ratio [OR] 1.29, p=0.002), rs6663606 (OR 1.26, p=0.004), and rs17534202 (OR 1.21, p=0.02) in BTG2 and rs3753793 (OR 1.21, p=0.03) in CYR61 were associated with GD. An association with GO was shown for SNPs rs3753793 (OR 1.45, p=0.008), rs6682848 (OR 1.55, p=0.03), rs12756618 (OR 1.77, p=0.049), and rs1378228 (OR 1.29, p=0.049) in CYR61, rs1057745 (OR 1.56, p=0.03) and rs11083522 (OR 1.32, p=0.04) in ZFP36, and rs1393491 (OR 1.38, p=0,048) in SCD. Smoking and CYR61 rs12756618 interacted to increase the risk of GO. CONCLUSIONS: We found associations of SNPs in IEGs and SCD with GD and/or GO; however, confirmation in a different population is required.

SUBMITTER: Planck T

PROVIDER: S-EPMC4080864 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Association of BTG2, CYR61, ZFP36, and SCD gene polymorphisms with Graves' disease and ophthalmopathy.

Planck Tereza T Shahida Bushra B Sjögren Marketa M Groop Leif L Hallengren Bengt B Lantz Mikael M

Thyroid : official journal of the American Thyroid Association 20140603 7

<h4>Background</h4>Environmental and genetic factors predispose an individual to the development of Graves' disease (GD). In an expression study of intraorbital tissue, adipocyte-related immediate early genes (IEGs) and immunomodulatory genes were found to be overexpressed in patients with Graves' ophthalmopathy (GO). We hypothesized that genetic variations in these genes could be associated with GD and/or GO.<h4>Methods</h4>A total of 98 single nucleotide polymorphisms (SNPs) in 12 genes were g ...[more]

PMID: 24780075

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Project description:BackgroundA large gene region, called GD-1, was first described by this laboratory as linked to Graves' disease (GD) and included the gene for the thyroid-stimulating hormone receptor (TSHR). Recent studies have now suggested an association of TSHR intronic polymorphisms with GD. We have taken the opportunity to examine a population of well-characterized patients with autoimmune thyroid disease (AITD) typed for an additional thyroid susceptibility gene, the immunoregulatory gene for cytotoxic T-lymphocyte antigen 4 (CTLA-4), to examine its relationship with the susceptibility to GD endowed by TSHR gene polymorphisms.MethodsWe used TSHR-SNP-rs2268458, located in intron 1 of the TSHR gene, measured using standard PCR-RFLP procedures, as our marker for the TSHR gene association. We genotyped 200 patients with GD, 83 patients with Hashimoto's thyroiditis (HT), and 118 healthy controls (all female Caucasians).ResultsThe allele and genotype frequencies from GD patients, but not HT patients, were significantly different from controls. The frequency of the combined genotype (allele) CC + TC was significantly higher in GD patients versus controls, suggesting that the C-containing genotype increased the risk for GD in a dominant manner (p = 0.018, odds ratio [OR] = 1.8). When compared with CTLA-4 (A/G)(49) single-nucleotide polymorphism (SNP), we were unable to demonstrate additive risk in patients with established AITD. Further, subsetting the patients (n = 120) into those with clinically significant Graves' ophthalmopathy (GO) showed no association with the TSHR SNP.ConclusionsThese results demonstrated that the intronic TSHR-SNP-rs2268458 was associated with GD, but not with HT, thus indicating that the TSHR gene has the potential to increase susceptibility to GD. However, we were not able to demonstrate any additive risk with the CTLA-4 (A/G)(49) SNP, which is, therefore, an independent risk factor for AITD. This suggested that, within the limits of the study population, each of these two genes provided a small contribution to GD susceptibility and that neither was essential. In addition, there was no evidence for the TSHR gene association adding to the risk of developing GO. Direct functional analyses are now needed to help explain the mechanisms of this TSHR gene susceptibility to GD.

Project description:BACKGROUND:The eye disorder associated with Graves' disease, called Graves' ophthalmopathy (GO), greatly reduces the quality of life in affected patients. Expression of the calsequestrin (CASQ1) protein in thyroid tissue may be the trigger for the development of eye muscle damage in patients with GO. We determined the prevalence of rs74123279, rs3747673, and rs2275703 single-nucleotide polymorphism (SNPs) in patients with autoimmune thyroid disorders, GO, Graves' hyperthyroidism (GH), or Hashimoto's thyroiditis (HT) and control subjects with no personal or family history of autoimmune thyroid disorders. Furthermore, we measured the concentration of the CASQ1 protein in normal and Graves' thyroid tissue, correlating levels with parameters of the eye signs, CASQ1 antibody levels, and the CASQ1 gene polymorphism rs74123279 and rs2275703. METHODS:High-quality genomic DNA was isolated from fresh blood samples, assayed for identification of rs74123279, rs3747673, and rs2275703 SNPs in CASQ1 gene by MassARRAY SNP analysis using iPLEX technology of SEQUENOM. RESULTS:DNA samples from 300 patients and 106 control subjects (100 males, 306 females) with GO (n=74), GH (n=130), HT (n=96) and control subjects (n=106) were genotyped for the SNPs rs74123279, rs3747673 (n=405), and rs2275703 (n=407). The SNP rs74123279, rs3747673, and rs2275703 were identified as 1) common homozygous or wild type, 2) heterozygote, and 3) rare homozygous. Minor allele frequency for rs74123279, rs3747763, and rs2275703 were 21%, 40%, and 44%, respectively. Multiple comparisons of genotype frequency for rs74123279, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed P=0.06, 0.641, and 0.189, respectively. These results were substantiated by multiple comparison of alleles frequency for rs74123279, rs3838216, rs3747763, and rs2275703 in the GO, GH, HT, and control groups showed, P=0.36, 0.008, 0.66, and 0.05, respectively. Pairwise analysis of alleles frequency distribution in patients with GO showed significant probability for rs2275703, P=0.008. CONCLUSION:Based on their evolutionary conservation and their significant prevalence, we suggest that CASQ1 gene SNPs rs74123279, rs3838216, and rs2275703 may be considered as genetic markers for GO.

Dataset Information

Association of BTG2, CYR61, ZFP36, and SCD gene polymorphisms with Graves' disease and ophthalmopathy.

Publications

Association of BTG2, CYR61, ZFP36, and SCD gene polymorphisms with Graves' disease and ophthalmopathy.

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