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Polycystic ovary syndrome and hyperandrogenism in adolescents
Published in Joseph S. Sanfilippo, Eduardo Lara-Torre, Veronica Gomez-Lobo, Sanfilippo's Textbook of Pediatric and Adolescent GynecologySecond Edition, 2019
Andrea E. Bonny, Asma Javed Chattha
Genome-wide association studies have revealed overexpression of a protein (DENND) in theca cells, producing an in vitro PCOS phenotype.20 Other genes identified by genome-wide association studies include FSHR, LHCGR, RAB5B/SUOX, INSR, THADA, YAP1, HMGA2, and SUMO1P1.21
Thyroid nodules and multinodular goiter
Published in David S. Cooper, Jennifer A. Sipos, Medical Management of Thyroid Disease, 2018
Poorani N. Goundan, Stephanie L. Lee
Currently, there is a move toward incorporating the use of adjunctive genetic testing for indeterminate cytology results – Bethesda III and IV nodules (Table 7.4). Given the already high pre-test probability for cancer in lesions in the Bethesda V (suspicious for malignancy) category, molecular testing is generally not indicated. The Cancer Genome Atlas provided a comprehensive characterization of genetic alterations in papillary thyroid cancer (90). It classified papillary cancers based on the genetic mutation, associated downstream signaling pathways, and histopathologic characteristics into two categories—“BRAF V600E-like” and “RAS-like” tumors. Similarly, the genetic landscape of other thyroid cancers — medullary and poorly differentiated cancer — has been studied. Follicular adenomas and carcinomas, which are clonal expansions, have been associated with mutations in the RAS proto-oncogenes and PAX8-PPAR gamma 1 fusion. Other mutations including PTEN, RET proto-oncogene (can be seen with radiation), and THADA are seen. Mutations and gene rearrangements leading to activation of the MAPK pathway can be seen in papillary thyroid cancers. These include NTRK1 and RET proto-oncogene rearrangements, activating the mutation of BRAF and RAS and RAS-like genes. TERT mutations, when associated with other mutations such as BRAF V600E, are associated with more aggressive thyroid malignancy (91).
The Role of Epigenetics in Skeletal Muscle Adaptations to Exercise and Exercise Training
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
It is generally well accepted that repeated bouts of acute exercise and corresponding dynamic alterations in the expression of exercise-responsive genes play an important role in skeletal muscle adaptations to exercise training. However, a key question is whether exercise training induces stable epigenetic alterations that could confer a persistent memory of muscle adaptation. A number of studies have observed hypomethylation of exercise-responsive genes in skeletal muscle following exercise training interventions (28, 35, 46), which were generally associated with gene expression patterns. Gene ontology analysis found that many of the gene regions that displayed reduced methylation following exercise training were associated with various metabolic processes and insulin signalling (46). Interestingly, many of these same pathways were also identified in ontology analysis of gene regions that displayed increased methylation after training (46). The functional significance of these findings remains unclear, but could be explained by other findings that have questioned the extent to which methylation contributes to the global control of gene expression levels in differentiated tissue (20, 69). Nitert and colleagues (46) directly addressed this question by analysing the effect of methylation on promoter reporters of a number of genes found to be hypomethylated in skeletal muscle following exercise training. These experiments showed that methylation of the promoters of the NDUFC2, RUNX1, MEF2A, and THADA genes significantly reduced reporter expression (46), providing strong evidence that hypomethylation of these gene regions enhances the transcription of these genes. The concept of an exercise training transcriptional memory has also been examined more directly in a well-controlled study where subjects completed two 3-month training periods, separated by a 9-month period of detraining (34). Following the 9-month detraining period, there was no retention of the training-induced transcriptional profile, although there were subtle differences in the transcriptional response to the second training period (34). At present no studies have rigorously assessed whether histone modifications are persistently altered following exercise training. However, given the short half-life and enzymatic reversibility of these modifications, it is difficult to envisage a scenario where persistent histone modifications contribute to maintenance of a training phenotype. On balance, these data collectively suggest that there is not a clearly defined epigenetic memory of exercise training that is retained beyond the termination of training.
Replication study of THADA rs13429458 variant with PCOS susceptibility and its related traits in Indian women
Published in Gynecological Endocrinology, 2021
Roshan Dadachanji, Divya Sawant, Anushree Patil, Srabani Mukherjee
The role of THADA in diabetes and insulin sensitivity has been confirmed by observation of its altered methylation in pancreatic islets of T2D patients, and association of polymorphisms with altered apoptosis of β cells and diabetes susceptibility [20,21]. A GWAS carried out in Han Chinese women identified for the first time strong association of the intronic rs13429458 polymorphism of THADA with PCOS [3], which was weakly corroborated in GWAS performed in European women [6]. Studies in Hainan Chinese [22], Han Chinese [15,16], Uygur Chinese [23], western Saudi [24] women and cross-ethnic meta-analysis of Dutch, US and Chinese women [25] confirmed similar association. Zhao et al. substantiated rs13429458 polymorphism as a robust genetic marker for PCOS risk using transmission disequilibrium test in 276 Han Chinese family trios having a proband with PCOS [19]. A recent meta-analysis using five genetic models and stratifying by ethnicity into Asian and non-Asian sub-groups, concluded that only Asian women carrying the minor allele were at increased risk of PCOS considering the dominant model, which may contribute to increased insulin resistance in affected women [9]. A study from South India showed association of this polymorphism with PCOS risk, and furthermore, in-silico analysis proposed that it could have deleterious effects [17]. In contrast we do not report such an association in this study, similar to other studies in Caucasian [10,13,26,27] and Hui Chinese [14] women. Thus, our study highlights that rs13429458 polymorphism of THADA may not determine PCOS susceptibility in women from Western India signifying that genetic predisposition patterns vary in different ethnic populations across India. Thus, it is imperative to delineate uniform genetic risk markers for PCOS for Indian women by surveying multiple populations.