Juxtaglomerular cell tumor (JxGCT) is a rare type of renal neoplasm demonstrating morphologic overlap with some mesenchymal tumors such as glomus tumor (GT) and solitary fibrous tumor (SFT). Its oncogenic drivers remain elusive, and only a few cases have been analyzed with modern molecular techniques. In prior studies, loss of chromosomes 9 and 11 appeared to be recurrent. Recently, whole-genome analysis identified alterations involving genes of MAPK-RAS pathway in a subset, but no major pathogenic alterations have been discovered in prior whole transcriptome analyses. Considering the limited understanding of the molecular features of JxGCTs, we sought to assess a collaborative series with a multiomic approach to further define the molecular characteristics of this entity. Fifteen tumors morphologically compatible with JxGCTs were evaluated using immunohistochemistry for renin, single-nucleotide polymorphism array (SNP), low-pass whole-genome sequencing, and RNA sequencing (fusion assay). In addition, methylation analysis comparing JxGCT, GT, and SFT was performed. All cases tested with renin (n=11) showed positive staining. Multiple chromosomal abnormalities were identified in all cases analyzed (n=8), with gains of chromosomes 1p, 10, 17, and 19 and losses of chromosomes 9, 11, and 21 being recurrent. A pathogenic HRAS mutation was identified in one case as part of the SNP array analysis. Thirteen tumors were analyzed by RNA sequencing, with 2 revealing in-frame gene fusions: TFG::GPR128 (interpreted as stochastic) and NAB2::STAT6 . The latter, originally diagnosed as JxGCT, was reclassified as SFT and excluded from the series. No fusions were detected in the remaining 11 cases; of note, no case harbored NOTCH fusions previously described in GT. Genomic methylation analysis showed that JxGCT, GT, and SFT form separate clusters, confirming that JxGCT represents a distinct entity (ie, different from GT). The results of our study show that JxGCTs are a distinct tumor type with a recurrent pattern of chromosomal imbalances that may play a role in oncogenesis, with MAPK-RAS pathway activation being likely a driver in a relatively small subset.

• MeSH
• Adult MeSH
• Epigenesis, Genetic MeSH
• Epigenomics MeSH
• Gene Fusion * MeSH
• Genetic Predisposition to Disease MeSH
• Genomics MeSH
• Immunohistochemistry MeSH
• Polymorphism, Single Nucleotide MeSH
• Juxtaglomerular Apparatus pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• DNA Methylation MeSH
• Biomarkers, Tumor * genetics   MeSH
• Kidney Neoplasms * genetics   pathology   chemistry   MeSH
• Whole Genome Sequencing MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH

Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10-8) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10-6). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

• MeSH
• Alzheimer Disease * genetics   MeSH
• Genome-Wide Association Study methods   MeSH
• Genetic Predisposition to Disease genetics   MeSH
• X Chromosome Inactivation genetics   MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Humans MeSH
• Chromosomes, Human, X * genetics   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BIDrs9604789 variant with an increased risk of developing the disease (ORMeta = 1.31, p = 9.67 × 10-6). We also confirmed the association of TP63rs1515496 and TP63rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10-8 and OR = 1.16, p = 2.74 × 10-5). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10-4 and p = 1.56 × 10-3), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10-4). These results were in agreement with research suggesting that the TP63rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC.

• MeSH
• Autophagy * genetics   MeSH
• White People genetics   MeSH
• Carcinoma, Pancreatic Ductal * genetics   pathology   MeSH
• Forkhead Transcription Factors MeSH
• Genetic Predisposition to Disease * MeSH
• Hepatocyte Nuclear Factor 3-alpha genetics   metabolism   MeSH
• Polymorphism, Single Nucleotide * MeSH
• Cohort Studies MeSH
• Humans MeSH
• Biomarkers, Tumor * genetics   MeSH
• Tumor Suppressor Proteins * genetics   MeSH
• Pancreatic Neoplasms * genetics   pathology   MeSH
• Case-Control Studies MeSH
• Transcription Factors genetics   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH

BACKGROUND: Colorectal cancer (CRC) is a common, fatal cancer. Identifying subgroups who may benefit more from intervention is of critical public health importance. Previous studies have assessed multiplicative interaction between genetic risk scores and environmental factors, but few have assessed additive interaction, the relevant public health measure. METHODS: Using resources from CRC consortia, including 45,247 CRC cases and 52,671 controls, we assessed multiplicative and additive interaction (relative excess risk due to interaction, RERI) using logistic regression between 13 harmonized environmental factors and genetic risk score, including 141 variants associated with CRC risk. RESULTS: There was no evidence of multiplicative interaction between environmental factors and genetic risk score. There was additive interaction where, for individuals with high genetic susceptibility, either heavy drinking (RERI = 0.24, 95% confidence interval [CI] = 0.13, 0.36), ever smoking (0.11 [0.05, 0.16]), high body mass index (female 0.09 [0.05, 0.13], male 0.10 [0.05, 0.14]), or high red meat intake (highest versus lowest quartile 0.18 [0.09, 0.27]) was associated with excess CRC risk greater than that for individuals with average genetic susceptibility. Conversely, we estimate those with high genetic susceptibility may benefit more from reducing CRC risk with aspirin/nonsteroidal anti-inflammatory drugs use (-0.16 [-0.20, -0.11]) or higher intake of fruit, fiber, or calcium (highest quartile versus lowest quartile -0.12 [-0.18, -0.050]; -0.16 [-0.23, -0.09]; -0.11 [-0.18, -0.05], respectively) than those with average genetic susceptibility. CONCLUSIONS: Additive interaction is important to assess for identifying subgroups who may benefit from intervention. The subgroups identified in this study may help inform precision CRC prevention.

• MeSH
• Diet MeSH
• Adult MeSH
• Genetic Predisposition to Disease * MeSH
• Body Mass Index MeSH
• Gene-Environment Interaction * MeSH
• Polymorphism, Single Nucleotide MeSH
• Colorectal Neoplasms * genetics   epidemiology   MeSH
• Smoking adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Logistic Models MeSH
• Alcohol Drinking MeSH
• Risk Factors MeSH
• Aged MeSH
• Case-Control Studies MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

In advanced prostate cancer (PC), in particular after acquisition of resistance to androgen receptor (AR) signaling inhibitors (ARSI), upregulation of AR splice variants compromises endocrine therapy efficiency. Androgen receptor splice variant-7 (ARV7) is clinically the most relevant and has a distinct 3' untranslated region (3'UTR) compared to the AR full-length variant, suggesting a unique post-transcriptional regulation. Here, we set out to evaluate the applicability of the ARV7 3'UTR as a therapy target. A common single nucleotide polymorphism, rs5918762, was found to affect the splicing rate and thus the expression of ARV7 in cellular models and patient specimens. Serine/arginine-rich splicing factor 9 (SRSF9) was found to bind to and increase the inclusion of the cryptic exon 3 of ARV7 during the splicing process in the alternative C allele of rs5918762. The dual specificity protein kinase CLK2 interferes with the activity of SRSF9 by regulating its expression. Inhibition of the Cdc2-like kinase (CLK) family by the small molecules cirtuvivint or lorecivivint results in the decreased expression of ARV7. Both inhibitors show potent anti-proliferative effects in enzalutamide-treated or -naive PC models. Thus, targeting aberrant alternative splicing at the 3'UTR of ARV7 by disturbing the CLK2/SRSF9 axis might be a valuable therapeutic approach in late stage, ARSI-resistant PC.

• MeSH
• 3' Untranslated Regions genetics   MeSH
• Alternative Splicing genetics   drug effects   MeSH
• Receptors, Androgen * metabolism   genetics   MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Humans MeSH
• Cell Line, Tumor MeSH
• Prostatic Neoplasms * genetics   metabolism   pathology   drug therapy   MeSH
• Protein Isoforms genetics   metabolism   MeSH
• Protein Serine-Threonine Kinases genetics   metabolism   antagonists & inhibitors   MeSH
• Gene Expression Regulation, Neoplastic * drug effects   MeSH
• Serine-Arginine Splicing Factors * metabolism   genetics   MeSH
• RNA Splicing genetics   MeSH
• Protein-Tyrosine Kinases * genetics   metabolism   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH

Plasma circulating donor-derived cell-free DNA (ddcfDNA) can be used to noninvasively monitor acute rejection of heart transplants (HTx). This study utilized digital droplet PCR to analyze ddcfDNA concentrations (measured in copies per milliliter) and the fractional abundance (%ddcfDNA) to differentiate between donor and recipient DNA on the basis of single nucleotide polymorphism (SNP) homozygosity. Seventy-seven patients participated in a study, providing 300 plasma samples. Both markers, mean ddcfDNA (cp/mL) and %ddcfDNA, showed similar decreasing trends following the HTx, (R2 < 0.2; p < 0.001). Significantly higher levels of ddcfDNA (cp/mL) and %ddcfDNA were observed during episodes of acute rejection (AR) compared to non-rejection samples (p < 0.001). Additionally, antibody-mediated rejection (AMR) was associated with increased %ddcfDNA levels compared to non-rejection and to acute cellular rejection samples (p < 0.001 and p < 0.01). A logistic regression model identified %ddcfDNA as an early predictor of AMR risk 10-19 days post-heart transplant (odds ratio 158, p < 0.02). Performance analysis established an optimal %ddcfDNA threshold of 0.125% for AMR detection, correctly identifying all patients without subsequent AMR. These findings suggest that early %ddcfDNA measurements post-HTx can accurately identify individuals unlikely to develop AMR during the first posttransplant year.

• MeSH
• Biomarkers * blood   MeSH
• Early Diagnosis MeSH
• Tissue Donors * MeSH
• Adult MeSH
• Isoantibodies * immunology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Graft Survival MeSH
• Prognosis MeSH
• Graft Rejection * diagnosis   etiology   blood   MeSH
• Risk Factors MeSH
• Heart Transplantation * adverse effects   MeSH
• Cell-Free Nucleic Acids * blood   genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Recent advances in avian melanogenesis have pinpointed multiple genetic loci associated with color polymorphisms, predominantly in the plumage of chickens, quails, and pigeons. However, the genetic basis of melaninization in parrot plumage remains elusive. Previously, we showed that mutations in the melanosomal ion-transporter SLC45A2 lead to a complete loss of blue structural color in green parrot feathers, leaving only yellow psittacofulvin. Yet, several color morphs involving partial or complete melanin reduction are common in captive-bred parrots that have not been studied. To bridge this gap, we investigated two new color morphs of parrot plumage: non-sex-linked recessive lutino (NSL), which entirely inhibits blue structural coloration, and the sex-linked recessive cinnamon, which reduces the intensity of blue structural coloration. Our genotypic analysis revealed that tyrosinase (TYR) variants are responsible for the NSL phenotype in Fischer's lovebird and green-cheeked parakeet, while tyrosinase related protein 1 (TYRP1) variants are associated with the cinnamon phenotype in the rose-ringed parakeet. When transfected into HEK293T cells, the candidate substitutions significantly affected tyrosinase enzymatic activity. This study underscores tyrosinase and related enzymes' role in parrot feather coloration, enhancing our understanding of avian melanogenesis as well as the conserved functions of melanogenic components across different species.

• MeSH
• Phenotype MeSH
• Humans MeSH
• Melanins metabolism   MeSH
• Oxidoreductases * metabolism   genetics   MeSH
• Parrots * genetics   metabolism   MeSH
• Feathers * enzymology   metabolism   MeSH
• Pigmentation * genetics   MeSH
• Avian Proteins * metabolism   genetics   MeSH
• Monophenol Monooxygenase * metabolism   genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH

BACKGROUND: Polymorphisms in thiopurine methyltransferase (TPMT) are a predominant cause of azathioprine-induced leucopenia in Western countries. The exact role of these polymorphisms in the Indian population with dermatological disorders is uncertain. OBJECTIVES: To evaluate the frequency of genetic polymorphism of TPMT and its impact on the safety of azathioprine in dermatological disorders. METHODS: We included consecutive patients on azathioprine who were initiated for dermatological disorders from South India. Three TPMT polymorphisms (c.238G>C, c.460G>A and c.719A>G) were assessed. The proportions of adverse events to azathioprine, especially myelosuppression, were compared between those with the wildtype genotype and those with TPMT polymorphisms. RESULTS: Of the 123 patients (61 male and 62 female, mean age 46 years), 65% had an autoimmune blistering disorder. Adverse events to azathioprine were noted in 25 (20.3%), of whom 16 (13.0%) had myelosuppression and 4 (3.2%) each had hepatotoxicity and gastrointestinal intolerance. TPMT polymorphisms were detected in 13 (10.6%), of whom 5 had experienced adverse events. The polymorphisms could explain 25% (4 of 16) of the cases of leucopenia. The odds of developing leucopenia in patients with TPMT polymorphism were not significant (odds ratio 3.63, 95% confidence interval 0.96-13.6; P = 0.06). CONCLUSIONS: The tested TPMT polymorphisms could not predict the adverse events of azathioprine, particularly the haematological toxicity, in dermatological use among the South Indian population.

• MeSH
• Azathioprine * adverse effects   therapeutic use   MeSH
• Adult MeSH
• Genotype MeSH
• Immunosuppressive Agents * adverse effects   therapeutic use   MeSH
• Clinical Relevance MeSH
• Skin Diseases * drug therapy   genetics   MeSH
• Leukopenia chemically induced   genetics   MeSH
• Middle Aged MeSH
• Humans MeSH
• Methyltransferases * genetics   MeSH
• Adolescent MeSH
• Young Adult MeSH
• Polymorphism, Genetic MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• India MeSH

BACKGROUND: The etiopathogenesis of atopic dermatitis is complicated, and it includes aspects such as dysfunction of the skin barrier, changes in immune responses, IgE-mediated hypersensitivity, and many characteristics of the environment. Regarding skin barrier dysfunction, a number of genetic changes have been described. This genetic predisposition could be related to the phenotypes of atopic dermatitis. AIM: In this study, several polymorphisms in five proinflammatory genes were associated with certain phenotypes of AD patients (genotype-phenotype study). METHODS: In total, 89 unrelated AD Czech (Caucasian) patients were genotyped regarding five proinflammatory gene polymorphisms (angiotensinogen AGT M235T, AGT-6 G/A, TNF-α-238 G/A, TNF-β Fok1, IL-6-174 C/G and IL-6-596 G/A). Genotyping was performed using PCR and restriction analysis. For phenotypes, patients' sex, age and personal and family history of atopy, aero- and food allergies and other complex diseases were evaluated. RESULTS: A significant association with transepidermal water loss (TEWL) measured on the forearm was found with the AGT M235T polymorphism (p = 0.02). For the AG genotype of TNF-α-238 G/A, a six-times higher risk for a family history of diabetes mellitus compared to other examined aspects of family history was found (p = 0.02). A family history of thyreopathy was associated with the IL-6-174 G/C polymorphism when compared to a family history of other complex diseases. The GG genotype had a ten-times higher risk for a family history of thyreopathy compared to the other genotypes (p = 0.004). This result was highly specific (0.914). The GG genotype of IL-6-596 G/A was associated with a family history of thyreopathy, with the same result (p = 0.004). Moreover, the G allele of IL-6-174 G/C was associated with a family history of thyreopathy compared to AD patients without a positive family history of complex diseases (p = 0.03). In AD men, the MM genotype of the AGT M235T gene was found to be associated with food allergies (p = 0.004). This result was highly sensitive (0.833). A family history of cardiovascular disease in AD men was associated with AGT-6 G/A variability. The A allele was found to be six times more frequent in patients with a positive family history of cardiovascular disease (p = 0.02, with high sensitivity and specificity (0.700 and 0.735, respectively)). A family history of diabetes mellitus was associated with the TNF-β Fok1 polymorphism, where the B1 allele was almost six times more frequent in AD men with a positive family history of diabetes mellitus (p = 0.02), with high sensitivity (0.85). A significant association between TEWL measured on the forearm and the AGT M235T polymorphism was found when AD women were carriers of the MM genotype, with a median of 25 and range 4-61; those patients with the MT genotype had a median of 10 and range of 0.3-39; and patients with the TT genotype had a median of 5 and range of 3-40, p = 0.003. The polymorphism AGT-6 G/A was associated with different ages of eczema onset. The AG genotype was almost nine times more risky for the youngest group (0-7 years) compared to the oldest group (more than 18 years) (p = 0.02), with high specificity for this result. CONCLUSIONS: Our results in the field of cytokine signaling in the immune system in patients with atopic dermatitis are in agreement with those of GWASs. We suggest that cost-effective and simple PCR tests may be the best approach for the rapid and optimal collection of valid genetic information in clinical practice.

• MeSH
• Dermatitis, Atopic * genetics   pathology   MeSH
• Adult MeSH
• Phenotype MeSH
• Genetic Predisposition to Disease MeSH
• Genotype MeSH
• Interleukin-6 genetics   MeSH
• Polymorphism, Single Nucleotide MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Tumor Necrosis Factor-alpha genetics   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Geographicals
• Czech Republic MeSH

Chronic bronchitis is increasingly reported as a healthcare challenge in clinical settings partially due to the disease's bad prognosis and unresponsiveness to therapy, including the ineffectiveness of glucocorticoids. The ineffectiveness could have a link with genetic polymorphism of receptor genes resulting in inappropriate glucocorticoid pharmacodynamics. We sought to identify the role of gene polymorphism in the response of patients with chronic bronchitis to prednisolone therapy. To do so, a total of 60 newly diagnosed chronic bronchitis patients enrolled in the present study. Prednisolone at a dose of 30mg/day for two weeks was given and respiratory parameters [forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC were measured before and after therapy. Blood samples were withdrawn for genetic profiling of genes involved in glucocorticoids pharmacodynamics, including BCII (rs41423247), N363S (rs56149945), and ER22/23EK (rs6189/rs6190) measured for their homozygous versus heterozygous gene splice variants.Results: Gene splice variants for BCII (rs41423247), N363S (rs56149945), and ER22/23EK (rs6189/rs6190) homozygous (73.3%, 98.7%, and 95%) represented a higher percentage than heterozygous (26.7%, 1.7%, and 5%). The respiratory parameters FEV1, FVC, and FEV1/FVC have shown significantly (p<0.05) better values at baseline in homozygous versus heterozygous, correspondingly, the responsiveness to therapy has shown significantly (p<0.05) better values in homozygous versus heterozygous.Conclusion: The study has provided a good template for genetic behaviour toward individualised medicine in our locality providing that these genes could be a cornerstone for discovering issues related to the pharmacodynamics profiling of drugs in clinical settings.

• MeSH
• Bronchitis, Chronic * diagnosis   genetics   MeSH
• Glucocorticoids pharmacology   MeSH
• Humans MeSH
• Polymerase Chain Reaction methods   MeSH
• Polymorphism, Genetic genetics   MeSH
• Prednisolone pharmacology   therapeutic use   MeSH
• Protein Isoforms genetics   MeSH
• Receptors, Glucocorticoid * genetics   drug effects   MeSH
• Respiratory Function Tests methods   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Clinical Study MeSH
• Research Support, Non-U.S. Gov't MeSH