Although stressful events are known to trigger Graves’ disease (GD), the mechanisms involved in this process are not well understood. The NR3C1 gene, encoding for the glucocorticoid receptor (GR), presents single nucleotide polymorphisms (SNPs) that are associated with stress-related diseases. To investigate the relationship between NR3C1 SNPs, GD susceptibility, and clinical features, we studied 792 individuals, including 384 patients, among which 209 presented with Graves’ orbitopathy (GO), and 408 paired healthy controls. Stressful life events were evaluated in a subset of 59 patients and 66 controls using the IES-R self-report questionnaire. SNPs rs104893913, rs104893909, and rs104893911 appeared at low frequencies and presented similar profiles in patients and controls. However, variant forms of rs6198 were rarer in GD patients, suggesting a protective effect. Stressful events were more common in patients than controls, and were reported to have clearly occurred immediately before the onset of GD symptoms in 23 cases. However, no association was found between these events and rs6198 genotypes or GD/GO characteristics. We suggest that the NR3C1 rs6198 polymorphism may be an important protective factor against GD, but its relationship with stressful events needs further investigation.

Objective: Abnormalities involving the TGFB1 gene and its receptors are common in several types of cancer and often related to tumor progression. We investigated the role of single nucleotide polymorphisms (SNP) in the susceptibility to cancer, their impact on its features, as well as the role of mRNA expression of these genes in thyroid malignancy. Materials and methods: We genotyped TGFB1, TGFBR1, and TGFBR2 SNPs in 157 papillary thyroid cancer (PTC) patients and 200 healthy controls. Further, we investigated RNA samples of 47 PTC and 80 benign nodules, searching for differential mRNA expression. Results: SNPs rs1800472 and rs1800469 were associated with characteristics of PTC aggressiveness. Effect predictor software analysis of nonsynonymous SNP rs1800472 indicated increasing protein stability and post-translational changes. TGFB1 mRNA expression was upregulated in PTC and downregulated in benign samples, differentiating malignant from benign nodules (p<0.0001); PTC from goiter (p<0.0001); and PTC from FA (p<0.0001). TGFBR1 mRNA expression was upregulated in goiter and PTC, but downregulated in FA, distinguishing PTC from goiter (p=0.0049); PTC from FA (p<0.0001); and goiter from FA (p=0.0267). On the other hand, TGFBR2 was downregulated in all histological types analyzed and was not able to differentiate thyroid nodules. Conclusion: TGFB1 polymorphism rs1800472 may confer greater activity to TGF-beta 1 in the tumor microenvironment, favoring PTC aggressiveness. Evaluation of TGFB1 and TGFBR1 mRNA levels may be useful to identify malignancy in thyroid nodules.

Understanding the complex mechanisms involved in diseases caused by or related to important genetic variants has led to the development of clinically useful biomarkers. However, the increasing number of described variants makes it difficult to identify variants worthy of investigation, and poses challenges to their validation. We combined publicly available datasets and open source robust bioinformatics tools with molecular quantum chemistry methods to investigate the involvement of selectins, important molecules in the cell adhesion process that play a fundamental role in the cancer metastasis process. We applied this strategy to investigate single nucleotide variants (SNPs) in the intronic and UTR regions and missense SNPs with amino acid changes in the SELL, SELP, SELE, and SELPLG genes. We then focused on thyroid cancer, seeking these SNPs potential to identify biomarkers for susceptibility, diagnosis, prognosis, and therapeutic targets. We demonstrated that SELL gene polymorphisms rs2229569, rs1131498, rs4987360, rs4987301 and rs2205849; SELE gene polymorphisms rs1534904 and rs5368; rs3917777, rs2205894 and rs2205893 of SELP gene; and rs7138370, rs7300972 and rs2228315 variants of SELPLG gene may produce important alterations in the DNA structure and consequent changes in the morphology and function of the corresponding proteins. In conclusion, we developed a strategy that may save valuable time and resources in future investigations, as we were able to provide a solid foundation for the selection of selectin gene variants that may become important biomarkers and deserve further investigation in cancer patients. Large-scale clinical studies in different ethnic populations and laboratory experiments are needed to validate our results.

Objective: We aimed to investigate the role of DIO2 polymorphisms rs225014 and rs12885300 in Graves' disease patients, mainly for controlling body weight following treatment. Subjects wid methods: We genotyped 280 GD patients by the time of diagnosis and 297 healthy control individuals using a TaqMan SNP Genotyping technique. We followed up 141 patients for 18.94 +/- 6.59 months after treatment. Results: There was no relationship between the investigated polymorphisms with susceptibility to GD and gain or loss of weight after GD treatment. However, the polymorphic inheritance (CC+CT genotype) of DIO2 rs225014 was associated with a lower body weight variation after GD treatment (4.26 +/- 6.25 kg) when compared to wild typeTT genotype (6.34 +/- 7.26 kg; p = 0.0456 adjusted for the follow-up time).This data was confirmed by a multivariate analysis (p = 0.0138) along with a longer follow-up period (p = 0.0228), older age (p = 0.0306), treatment with radioiodine (p-value = 0.0080) and polymorphic inheritance of DIO2 rs12885300 (p = 0.0306). Conclusion: We suggest that DIO2 rs225014 genotyping may have an auxiliary role in predicting the post-treatment weight behavior of GD patients.