Genetic and Epigenetic Association of FOXP3 with Papillary Thyroid Cancer Predisposition.

Papillary thyroid cancer (PTC) is the most common type of thyroid malignancy with an increased female incidence ratio. The specific traits of X chromosome inheritance may be implicated in gender differences of PTC predisposition. The aim of this study was to investigate the association of two X-linked genes, Forkhead Box P3 (FOXP3) and Protein Phosphatase 1 Regulatory Subunit 3F (PPP1R3F), with PTC predisposition and gender disparity. One hundred thirty-six patients with PTC and an equal number of matched healthy volunteers were enrolled in the study. Genotyping for rs3761548 (FOXP3) and rs5953283 (PPP1R3F) was performed using polymerase chain reaction-restriction fragment length polymorphism assay (PCR-RFLP). The methylation status of FOXP3 was assessed using the combined bisulfite restriction analysis (COBRA) method. The SPSS software was used for statistical analyses. Gender stratification analysis revealed that the CA and AA genotypes and the A allele of FOXP3 rs3761548 variant are associated with PTC predisposition only in females. Moreover, different methylation status was observed up to the promoter locus of FOXP3 between PTC female patients, carrying the CA and CC genotype, and controls. Both revealed associations may explain the higher PTC incidence in females through reducing FOXP3 expression as reported in immune related blood cells.

Sporadic Parathyroid Adenoma: A Pilot Study of Novel Biomarkers in Females.

Background and Objectives: Parathyroid adenoma is a distinct cause of primary hyperparathyroidism, with the vast majority being sporadic ones. Proteomic analysis of parathyroid adenomas has proposed a large number of related proteins. The aim of this study is to evaluate the immunohistochemical staining of ANXA2, MED12, MAPK1 and VDR in parathyroid adenoma tissue. Materials and Methods: Fifty-one parathyroid adenomas were analyzed for ANXA2, MED12, MAPK1 and VDR expressions. Tissue was extracted from formalin-fixed paraffin-embedded parathyroid adenoma specimens; an immunohistochemical study was applied, and the percentage of allocation and intensity were evaluated. Results: ANXA2 stained positively in 60.8% of all cell types, while MED12 had positive staining in 66%. MAPK1 expression was found to be negative in total, although a specific pattern for oxyphil cells was observed, as they stained positive in 17.7%. Finally, VDR staining was positive at 22.8%, based on nuclear staining. Conclusions: These immunohistochemical results could be utilized as biomarkers for the diagnosis of sporadic parathyroid adenoma. It is of great importance that a distinct immunophenotype of nodule-forming cells in a positive adenoma could suggest a specific pattern of adenoma development, as in hereditary patterns.

Type 2 Diabetes Mellitus is Associated with Increased Risk of Sarcopenia: A Systematic Review and Meta-analysis.

Diabetes mellitus (DM) is associated with an increased risk of fractures, mainly due to impaired bone architecture and microvascular complications. Whether DM is also associated with increased risk of sarcopenia is not yet known, with studies yielding inconclusive results. The aim of this study was to systematically review and synthesize the best available evidence regarding the association between DM and sarcopenia risk. A comprehensive search was conducted in PubMed, CENTRAL and Scopus databases. Data are expressed as odds ratio (OR) with 95% confidence intervals (CI). The I2 index was employed for heterogeneity. Only studies which had implemented at least two of the three criteria for sarcopenia diagnosis (low muscle mass, muscle strength and/or muscle performance), as defined by the international studying groups, were included. Fifteen studies fulfilled eligibility criteria, yielding a total of 1832 patients with type 2 DM (T2DM) and 1159 cases of sarcopenia. Patients with T2DM demonstrated a higher risk of sarcopenia compared with euglycemic subjects (OR 1.55, 95% CI 1.25-1.91, p < 0.001; I2 34.6%). This risk remained significant when analysis was restricted to studies matched for age and sex. Sarcopenia risk was independent of disease definition or study design. Notably, T2DM patients presented lower muscle performance and strength compared with euglycemic subjects, whereas no difference in muscle mass was observed between groups. Patients with T2DM have an increased risk of sarcopenia compared with euglycemic subjects.

The Association of Vitamin D Receptor Polymorphisms with COVID-19 Severity.

BACKGROUND: Association studies of vitamin D receptor (VDR) polymorphisms with COVID-19 severity have produced inconsistent results in different populations. Herein we examined VDR gene polymorphisms in a Caucasian Greek cohort of COVID-19 patients. METHODS: This was a case-control study in a tertiary university hospital in Greece including 137 COVID-19 patients with varying disease severities and 72 healthy individuals. In total 209 individuals were genotyped for the FokI (rs10735810), ApaI (rs7975232), TaqI (rs731236) and BsmI (rs1544410) single-nucleotide polymorphisms (SNP) of the VDR gene by polymerase chain reaction and restriction fragment length polymorphism analysis (PCR-RFLPs). Statistical analyses were performed to determine the association between genotype and disease severity, adjusting for various confounding factors. RESULTS: Genotype distribution of the studied VDR SNPs in the control group was in Hardy-Weinberg equilibrium. The TaqI variant was differentially distributed between controls and COVID-19 patients according to the additive model (p = 0.009), and the CC genotype was significantly associated with an increased risk for severe COVID-19 according to the recessive model [OR: 2.52, 95%CI:1.2-5.29, p = 0.01]. Multivariate analysis demonstrated a robust association of COVID-19 severity and TaqI polymorphism in the recessive model even after adjusting for multiple confounders, including age, sex and CRP levels [Adj.OR:3.23, 95%CI:1.17-8.86, p = 0.023]. The distribution of FokI, ApaI and BsmI genotypes was similar between COVID-19 patients and controls. CONCLUSIONS: The CC genotype of TaqI polymorphism is significantly associated with an increased risk for severe COVID-19 independently of age, sex or degree of inflammation.

A Pilot Study of the Association VDR Polymorphisms With Primary Hyperparathyroidism.

BACKGROUND/AIM: Primary hyperparathyroidism (PHPT) is the third most common endocrine disorder characterized by autonomous parathyroid hormone (PTH) production from one or more parathyroid glands and hypocalcemia. Vitamin D through its receptor is a principal regulator of parathyroid glands function. VDR gene polymorphisms, which affect the expression or structure of VDR protein, may be involved in the genetic pathogenesis of PHPT. The aim of this study was to investigate the role of FokI, ApaI, TaqI, and BsmI VDR gene polymorphisms as genetic predisposing factors for PHPT. PATIENTS AND METHODS: Fifty unrelated patients with sporadic PHPT and an equal number of corresponding ethnicity, sex and age range healthy volunteers were enrolled in the study. Genotyping was performed with polymerase chain reaction and restriction fragment length polymorphism assay. RESULTS: Statistically significant difference was observed in TaqI genotype distribution between PHPT patients and controls, while no association was detected for the other studied polymorphisms. CONCLUSION: TaqI TT and TC genotypes may be associated with PHPT risk in Greek population. Further independent studies are needed to replicate and validate the role of VDR TaqI polymorphism in PHPT predisposition.

Sporadic parathyroid adenoma: an updated review of molecular genetics.

Introduction: Primary HPT (PHPT) is a common disorder, affecting approximately 1% of the general population. Parathyroid adenomas emerge as non-familial sporadic in 90% of cases. The aim of this review is to give a detailed update of molecular genetics of sporadic parathyroid adenoma reported in international literature. Methods: A bibliographic research was conducted in PubMed, Google Scholar, and Scopus. Results: Seventy-eight articles were included in our review. CaSR, MEN1, CCND1/PRAD, CDKI, angiogenic factors like VEGF, FGF, TGFß, and IGF1, and apoptotic factors are important genes in parathyroid adenomas pathogenesis that have been established by several studies. A huge list of proteins is differently expressed in parathyroid adenomas measured by Western Blotting, MALDI/TOF, MS spectrometry, and immunohistochemistry. These proteins take part in several cell processes such as cell metabolism, cytoskeleton structural stability, cell oxidative stress regulation, cell death, transcription, translation, cell connection, and cell signaling transmission, while they can be found over- or underexpressed in abnormal tissues. Conclusion: This review gives a detailed analysis of all reported data on genomics and proteomics of parathyroid adenoma. Further studies should be applied on understanding parathyroid adenoma pathogenesis and introducing new biomarkers for early detection of primary hyperparathyroidism.

The Implication of X-Linked Genetic Polymorphisms in Susceptibility and Sexual Dimorphism of Cancer.

The X-chromosome is implicated in cancer development through various mechanisms, including X-inactivation defects, loss of heterozygosity, and germline and somatic alterations of X-linked genes. Sex is a key factor which influences cancer susceptibility as many cancer types show sexual dimorphism in their incidence. The aim of this review was to summarize the germline genetic polymorphisms lying on the X-chromosome that have been associated with cancer susceptibility and to evaluate their possible implication in cancer-related sexual dimorphism. PubMed and Web of Science were searched using the terms "X-chromosome", "polymorphism" and "cancer". The literature review revealed 39 articles reporting 33 genetic variants in 22 X-linked genes as being associated with cancer risk. Most of these genes interact with each other in a direct or indirect way, as GeneMANIA software revealed, demonstrating the complication of the mechanisms through which they are involved in tumorigenesis. Polymorphisms in eight genes [androgen receptor (AR), fibroblast growth factor 13 (FGF13), forkhead box P3 (FOXP3), L1 cell adhesion molecule (L1CAM), nudix hydrolase 11 (NUDT11), Shroom family member 2 (SHROOM2), transcription elongation factor A-like 7 (TCEAL7) and TIMP metallopeptidase inhibitor 1 (TIMP1)] are reported to have a sex-specific association with cancer susceptibility, which might explain the sexual dimorphism of certain cancer types. All of the above eight mentioned genes, with the exception of L1CAM, exhibit differences in their expression pattern between breast tumor (sex-specific)/thyroid tumor (sex-influenced) vs. normal tissues according to our analysis using GENT2 software. Additionally, differences in breast or thyroid tumor compared with normal tissues were also observed in five genes analyzed with GENT2 software that were previously related to sex-influenced cancer according to literature. Finally, the present review points out the need for the development of appropriate free and user-friendly statistical software in order to reduce bias/errors in statistical analyses and overcome researchers' reluctance to include X-chromosome variants in their genetic-association studies.