Genetic Variants Research Articles

Identifying Genetic Mutations in Vascular Anomalies Using a Sequencing Panel for Childhood Cancers: A Pilot Study

Introduction: Genetic mutations have been identified in the pathogenesis of vascular anomalies. Due to overlaps in genetic variants causing vascular anomalies and cancer, we used a next-generation sequencing panel for genomic profiling of childhood cancers to detect somatic mutations in children with vascular anomalies. We aim to review the utility of an oncology panel for the molecular diagnosis of vascular anomalies. Methods: Nine patients with histologically confirmed vascular anomalies were included. DNA was extracted from formalin-fixed paraffin-embedded tissue specimens obtained from affected tissue following diagnostic punch biopsies of the skin and core biopsies of the vascular malformation or tumor during sclerotherapy or surgical excision. Molecular analysis of the tissue samples was performed using AmpliSeq for Childhood Cancer DNA Assay Panel. Results: Two patients had antenatally detected vascular anomalies. The median age at diagnosis for the remaining patients was 7.0 years (IQR, 0.6–10.0 years). Seven were diagnosed with vascular malformations, while 2 had vascular tumors. Pathological somatic mutations were identified in 4 patients, leading to a diagnostic yield of 44.4%. Two different PIK3CA mutations were identified in 3 cases: 1 in a case of macrocystic lymphatic malformation, the other in a case of Congenital Lipomatous Overgrowth, Vascular malformations, Epidermal nevus, Spinal/Skeletal anomalies syndrome and Klippel–Trenaunay syndrome. BRAF mutation was identified in a patient with a veno-lymphatic malformation. Conclusion: An oncology next-generation sequencing panel can be used for genetic profiling of vascular anomalies. However, a more customized and sensitive panel may be of better diagnostic yield, as detection of somatic mutations in vascular anomalies is challenging due to tissue mosaicism, low-abundant genetic variants, and specimen limitations.

The Value IRS-1 rs1801278G > A Polymorphism Testing in Evaluating Infertile Women with Polycystic Ovarian Syndrome: A Case-control Study

Background: Polycystic ovary syndrome (PCOS) is a leading cause of infertility. Insulin resistance is a key element in pathogenesis. The insulin receptor causes phosphorylation of the insulin receptor substrate (IRS); IRS-1 rs1801278G > A polymorphism variant is the most common genetic variant associated with IR and PCOS. Objective: We aimed to examine the frequency of IRS-1 rs1801278G > A polymorphism variant and test its value in evaluating infertile PCOS women. Methods: A case-control study recruited 140 age and body-mass-matched participants in the university hospital, subdivided according to Rotterdam criteria into PCOS cases (70/140) and healthy controls (70/140). We collected demographic data, ultrasonic [antral follicles and endometrial thickness], hormonal [FSH, LH, AMH, E2], and genetic data by polymerase chain reaction for analysis. Result: Wild GG SNP rs1801278 G was meaningfully higher among controls (58.57%, P<0.0001). Mutant AA SNP rs1801278 was significantly higher in PCOS women (37.14%, P-value =0.0001, an odds ratio of 20.50, 95% CI (9.42-28.63) to develop PCOS. Heterogenous GA gene SNP rs1801278 showed a trend of higher frequency in PCOS patients with 44.29%; OR of 3.91, 95% CI (1.37–7.55); P = 0.422. Upon correlating infertility parameters to SNP rs1801278 G>A polymorphism, statistical differences were found with AFC, LH/FSH ratio, and serum testosterone. As for the AMH, E2, and endometrial thickness, they failed to have a statistical value. Conclusion: The significant correlation of genetic polymorphism to infertility parameters among PCOS women opens a new therapeutic and prognostic avenue that helps gynecologists tailor manganate for a better and safer outcome.

The Influence of OCT3 and MATE2 Genetic Polymorphisms in Poor Response to Metformin in Type 2 Diabetes Mellitus.

The response of patients with Type 2 diabetes mellitus (T2DM) to metformin may be a variation because of genetic differences in solute carrier (SLC) transporter proteins and other effect factors, which have an important effect on how metformin is processed in the body and its efficiency for glycaemic control. This study was conducted to investigate the impact of certain genetic variants of the organic cation transporter genes OCT3 (SLC22A3 rs12194182 and rs8187722) and MATE2 (SLC47A2 rs12943590) and their association with glycaemic parameters in patients with T2DM who respond poorly to metformin. This cross-sectional study involved 150 Iraqi cases with T2DM who were prescribed a daily dose of (1000 mg/day) metformin for a minimum of 3 months. Various parameters included are as follows: demographic data, glycaemic parameters and three SNPs: rs12943590 variant of SLC47A2, rs12194182 and rs8187722 variant of SLC22A3 using the standard PCR-sequencing technique. Thirty-nine patients (26.17%) were responders, whereas 111 patients (73.82%) could not respond to metformin treatment. Upon analysing the genotypes of the rs12943590 variants of SLC47A2, rs12194182 and rs8187722 SNPs of SLC22A3, the present findings revealed a nonsignificant association of genetic variations in all SNPs with metformin response. SLC47A2 (rs12943590) showed nonsignificant associations of the GG, AA and AG genotyping; SLC22A3 (rs12194182) showed nonsignificant associations of the TT, TC and CC genotyping; and SLC22A3 (rs8187722) showed nonsignificant associations of the AA, CC and AC genotyping between two groups. Variations in genes SLC22A3 and SLC47A2 did not have a significant role in the response of patients with T2DM to metformin (1000 mg/day).

Exploring causal correlations between inflammatory cytokines and intervertebral disc degeneration: A Mendelian randomization.

Inflammatory cytokines have been reported to be related to intervertebral disc degeneration (IVDD) in several previous studies. However, it remains unclear about the causal relationship between inflammatory cytokines and IVDD. This study employs Mendelian randomization (MR) to analyze the causal link between inflammatory cytokines and the risk of IVDD. We used genetic variants associated with inflammatory cytokines from a meta-analysis of genome-wide association study (GWAS) in 8293 Finns as instrumental variables and IVDD data were sourced from the FinnGen consortium. The main analytical approach utilized Inverse-Variance Weighting (IVW) with random effects to assess the causal relationship. Additionally, complementary methods such as MR-Egger, weighted median, simple mode, weighted mode, and MR pleiotropy residual sum and outlier were employed to enhance the robustness of the final results. We found interferon-gamma (IFN-γ, p = 2.14 × 10-6, OR = 0.870, 95% CI = 0.821-0.921), interleukin-1 beta (IL-1b, p = 0.012, OR = 0.951, 95% CI = 0.914-0.989), interleukin-4 (IL-4, p = 0.034, OR = 0.946, 95% CI = 0.899-0.996), interleukin-18 (IL-18, p = 0.028, OR = 0.964, 95% CI = 0.934-0.996), granulocyte colony-stimulating factor (GCSF, p = 0.010, OR = 0.919, 95% CI = 0.861-0.980), and Stromal cell-derived factor 1a (SDF1a, p = 0.014, OR = 1.072, 95% CI = 1.014-1.134) were causally associated with risk of IVDD. Our MR analyses found a potential causal relationship between six inflammation cytokines (IFN-γ, IL-1b, IL-4, IL-18, SDF1a, and GCSF) and altered IVDD risk.

Clinical phenotype, genetic characteristics, and creation of immortalized cell lines for patients from a pedigree affected with Hunter syndrome

To explore the clinical phenotype and genetic variant in a Chinese pedigree affected with Hunter syndrome and create immortalized cell lines for the affected pedigree members. A pedigree of six members who had visited Xi'an Children's Hospital in July 2022 was selected as the study subject. Clinical data was collected. Whole exome sequencing was carried out for the pedigree members. Candidate variant was verified by Sanger sequencing. In addition, peripheral B lymphocytes were transfected with Epstein-Barr virus to create immortalized cell lines, which were then subjected to enzyme activity analysis. The patient, a five-year-and-seven-month-old boy, had exhibited stiff limbs and enlarged joints. He had developed hernia, scaphocephaly, and barrel chest from 3 months of age. His uncle also had stiff limbs, poor hearing, blindness, and right oblique inguinal hernia. Above features had resembled those of Hunter syndrome. Genetic testing revealed that both the child and his uncle had harbored an IDS (NM_000202.8): c.823G>A (p.D275N) variant, which was unreported previously. Bioinformatic analysis indicated that the D275 to be a highly conserved site, and the D275N variant may affect the stability of the protein's spatial conformation, thereby decrease the catalytic activity of the enzyme. The successfully constructed immortalized lymphoblastoid cell lines for the child and his parents showed increased volume, irregular shape, burr structure and cluster growth. And the value of IDS activity of the patient's immortalized lymphoblastoid cells was below the limit of detection. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as likely pathogenic (PS3+PM2_Supporting+PM5+PP1+PP3). Above finding has enriched the phenotypic and mutational spectra of Hunter syndrome, and provided a basis for the genetic counseling for this pedigree. The creation of immortalized cell lines has offered a model for further investigation of the impact of variant on the function of IDS and development of targeted drugs.

ГЕНЕТИЧЕСКАЯ ХАРАКТЕРИСТИКА Х-СЦЕПЛЕННОГО СИНДРОМА АЛЬПОРТА У ДЕТЕЙ: ДАННЫЕ ОДНОЦЕНТРОВОГО КОГОРТНОГО ИССЛЕДОВАНИЯ

X-linked Alport syndrome (XLAS) is a monogenic disease characterized by the progressive nephropathy development, sensorineural hearing loss and the lens and retina pathology. The clinical manifestations of the syndrome and the renal prognosis of patients are determined by the nature of the gene COL4A5 mutation. The range of COL4A5 genetic variants is different among populations. Information about the XLAS genetic structure in Russian pediatric cohort is insufficient. The purpose of this research was to determine the features of the spectrum of the gene COL4A5 genetic variants in children with XLAS. Materials and methods used: a single-center retrospective cohort study included children aged 2 to 17 y/o with genetically confirmed XLAS. Descriptions of variants in gene COL4A5 were performed using genome build GRCh37/hg19 in accordance with the reference sequence GRCh37/hg19 (Reference Sequence, HGVS) and the American College of Medical Genetics and Genomics (ACMG), AMP Clinical Practice Guidelines. Results: analysis of data from 174 probands from unrelated families showed that 108 (62%) children had missense variants in gene COL4A5 (62% v. 38%, missense v. non-missense variants, respectively, p=0.028), 24 (13.8%) had mutations leading to impaired RNA splicing, 17 (9.8%) had frameshift mutations, 14 (8%) had gene deletions and 10 (5.7%) had nonsense mutations. Missense variants were predominantly localized in the collagen domain compared to the non-collagen domain (n=102, 94.4%, p<0.001), in exons 18 to 41 (n=94; 94.8%) and were represented by glycine substitutions (n=90, 83.3%). Two common variants were identified in the cohort: NM_033380.3(COL4A5):c.1871G>A (p.Gly624Asp) in 28 (26%) and NM_033380.3(COL4A5):c.3319G>A (p.Gly1107Arg) in 4 (3.7%). Conclusion: the structure of COL4A5 genetic variants in the studied cohort was comparable with the current Worldwide data, such as two thirds of the examined had missense variants and ca. one-fifth had genetic variants leading to the protein synthesis absence. Two common missense variants in gene COL4A5 were identified, including the common variant NM_033380.3(COL4A5):c.1871G>A (p.Gly624Asp) that is of frequent occurrence in the European population.

СПЕКТР КЛИНИЧЕСКИХ ПРОЯВЛЕНИЙ Х-СЦЕПЛЕННОГО СИНДРОМА АЛЬПОРТА У ДЕВОЧЕК: ОДНОЦЕНТРОЕ КОГОРТНОЕ ИССЛЕДОВАНИЕ

X-linked Alport syndrome (XLAS) is an inherited disorder caused by genetic variants in gene COL4A5. The frequency and the severity of clinical manifestations as well as the risk of glomerulopathy progression are variable in XLAS in females, and the disease course features have not been sufficiently studied as yet. Since patient management tactics is determined by the disease course nature, studying the spectrum of XLAS clinical manifestations and prognosis in girls remains relevant. The purpose of this research was to determine the spectrum and the features of clinical manifestations of XLAS in girls. Materials and methods used: a single-center cohort prospective study was carried out by the Authors that included 74 girls aged 2 to 17 y/o with genetically proven XLAS diagnosis. Authors have analyzed the patients’ medical records identifying sensorineural hearing loss (SNHL), arterial hypertension (AH; blood pressure (BP) over 95% than at the patient’s age/height), albuminuria (Alb; norm<30 mg/mmol of creatinine), proteinuria (Pr; norm<100 mg/sq m/day) - with its degree, decrease in estimated glomerular filtration rate (eGFR, ml/min/1.73 sq m; norm≥90 ml/min/1.73 sq m) and angiotensin-converting enzyme inhibitors (ACEIs) therapy data. Results: all patients had hematuria with episodical macrohematuria in 27% of cases, proteinuria in 40%, eGFR decrease in 15%, SNHL in 8% and peripheral retinopathy in 7%. Girls with missense v. those with non-missense variants of COL4A5 more often had macrohematuria (0.15 v. 0.05; p=0.015) and albuminuria (1 v. 0.5; p<0.001) whilst no statistically significant difference was showed in proteinuria frequency and age of onset (0.48 v. 0.5 and 6.5 [3; 11] v. 5 [5; 8] y/o), eGFR decrease (0.15 v. 0.15; 12.4±2.6 v. 13.2 ±2.8 y/o), SNHL (0.07 v. 0.1; 13±2.8 v. 14.4±3.1 y/o) and retinopathy (0.04 v. 0.15; 14.3±3.5 v. 12.6±2.9 y/o). ACEIs therapy did not show any statistically significant effect on the cumulative proportion of patients with both proteinuria and eGFR decrease (log-rank test=1.25, p=0.213 and log-rank test=0.66, p=0.512, respectively). Conclusion: the results obtained demonstrate the need for a dynamic follow-up of girls with XLAS with the purpose of earliest possible detection of proteinuria and timely prescribing with nephroprotective therapy as well as hearing loss diagnosing and timely audiological correction.

GENEVIC: GENetic data exploration and visualization via intelli- gent interactive console.

The vast generation of genetic data poses a significant challenge in efficiently uncovering valuable knowledge. Introducing GENEVIC, an AI-driven chat framework that tackles this challenge by bridging the gap between genetic data generation and biomedical knowledge discovery. Leveraging generative AI, notably ChatGPT, it serves as a biologist's 'copilot'. It automates the analysis, retrieval, and visualization of customized domain-specific genetic information, and integrates functionalities to generate protein interaction networks, enrich gene sets, and search scientific literature from PubMed, Google Scholar, and arXiv, making it a comprehensive tool for biomedical research. In its pilot phase, GENEVIC is assessed using a curated database that ranks genetic variants associated with Alzheimer's disease, schizophrenia, and cognition, based on their effect weights from the Polygenic Score (PGS) Catalog, thus enabling researchers to prioritize genetic variants in complex diseases. GENEVIC's operation is user-friendly, accessible without any specialized training, secured by Azure OpenAI's HIPAA-compliant infrastructure, and evaluated for its efficacy through real-time query testing. As a prototype, GENEVIC is set to advance genetic research, enabling informed biomedical decisions. GENEVIC is publicly accessible at https://genevic- anath2024.streamlit.app. The underlying code is open-source and available via GitHub at https://github.com/bsml320/GENEVIC.git (also at https://github.com/anath2110/GENEVIC.git). Available at Bioinformatics online and at https://github.com/bsml320/GENEVIC_Supplementary.git (also at https://github.com/anath2110/GENEVIC_Supplementary.git).

Comprehensive single-cell analysis deciphered microenvironmental dynamics and immune regulator olfactomedin 4 in pathogenesis of gallbladder cancer

ObjectiveElucidating complex ecosystems and molecular features of gallbladder cancer (GBC) and benign gallbladder diseases is pivotal to proactive cancer prevention and optimal therapeutic intervention.DesignWe performed single-cell transcriptome analysis on 230...

Two genetic variants in the HIBCH and FTCDNL1 genes are associated with susceptibility to developmental dysplasia of the hips among the Han Chinese population of Southwest China

BackgroundDevelopmental dysplasia of the hip (DDH) is a common cause of childhood disability, and the incidence of DDH shows significant familial aggregation. As the genetic factors of DDH remain unknown, the correlation between five candidate single nucleotide polymorphisms (SNPs) and DDH was evaluated in the Han Chinese population of Southwest China.MethodsA case‒control association study was conducted in 276 patients with DDH and 318 healthy controls. SNP genotyping in the case and control groups was performed by SNPshot and multiple PCR. SNPs were genotyped in the case and control groups by multiplex PCR. The relationship between DDH and candidate SNPs was evaluated using the χ2 test.ResultsThe genotype distributions of rs291412 in HIBCH and rs769956 in FTCDNL1 were different between the case and control groups (P < 0.05). After genetic model analysis, logistic regression analysis revealed that the C allele of rs291412 had a protective effect on DDH (OR = 0.605, P = 0.010) and that the G allele of rs769956 was a risk factor (OR = 2.939, P = 0.010).s.ConclusionThese SNPs could be associated with susceptibility to DDH but larger population-based studies should confirm the current results.

Drug Response of Iranian Alzheimer's Patients to Rivastigmine Concerning Their Genotype for VDR rs11568820 and MTHFR C677T Variants: A Pharmacogenetic and Association Study.

Alzheimer's disease is a neurodegenerative disorder with polygenic etiology. Genetic risk variants for Alzheimer's disease differ among populations. Thus, discovering them in each population is clinically important. A total of 118 patients and 97 controls for VDR rs11568820 and 88 patients and 100 healthy controls for MTHFR C677T polymorphism were genotyped to evaluate the association of these polymorphisms with late-onset Alzheimer's disease in the Iranian population, along with their impacts on the response to Rivastigmine treatment. The VDR C allele was significantly associated with Alzheimer's disease and provided protection against it (P = 0.003, RR = 1.14, 95% CI 1.04-1.24), while the T allele increased susceptibility (P = 0.003, RR = 1.93, 95% CI 1.23-3.02). These results were also considerable upon excluding the effect of APOE ε4 allele. The Prevalence-corrected Positive Predictive Value was 1.71% for the VDR CC genotype and 4% for the VDR CT genotype, indicating lower and almost twofold higher chances of developing Alzheimer's disease, respectively. No significant correlation was observed between MTHFR C677T and Alzheimer's disease. Based on our pharmacogenetic study, MTHFR T allele carriers lacking APOE ε4 allele showed a better response to Rivastigmine treatment after a 2-year follow-up. Moreover, patients with VDR CC genotype displayed milder Alzheimer's disease, particularly when coincided with the APOE ε4 allele. The VDR rs11568820 polymorphism affects both Alzheimer's disease risk and the response to Rivastigmine in Iranian patients. Also, MTHFR C677T polymorphism may play a role in the response to Rivastigmine, through a pathway that needs to be elucidated in future studies.

Pharmacogenetics of Calcineurin inhibitors in kidney transplant recipients: the African gap. A narrative review.

Calcineurin inhibitors (CNIs) are the mainstay of immunosuppression in kidney transplantation. Interpatient variability in the disposition of calcineurin inhibitors is a well-researched phenomenon and has a well-established genetic contribution. There is great diversity in the makeup of African genomes, but very little is known about the pharmacogenetics of CNIs and transplant outcomes. This review focuses on genetic variants of calcineurin inhibitors' metabolizing enzymes (CYP3A4, CYP3A5), related molecules (POR, PPARA) and membrane transporters involved in the metabolism of calcineurin inhibitors. Given the genetic diversity across the African continent, it is imperative to generate pharmacogenetic data, especially in the era of personalized medicine and emphasizes the need for studies specific to African populations. The study of allelic variants in populations where they have greater frequencies will help answer questions regarding their impact. We aim to fill the knowledge gaps by reviewing existing research and highlighting areas where African research can contribute.

The kpc-1 3'UTR facilitates dendritic transport and translation efficiency of mRNAs for dendrite arborization of a mechanosensory neuron important for male courtship.

A recently reported Schizophrenia-associated genetic variant in the 3'UTR of the human furin gene, a homolog of C. elegans kpc-1, highlights an important role of the furin 3'UTR in neuronal development. We isolate three kpc-1 mutants that display abnormal dendrite arborization in PVD neurons and defective male mating behaviors. We show that the kpc-1 3'UTR participates in dendrite branching and self-avoidance. The kpc-1 3'UTR facilitates mRNA localization to branching points and contact points between sibling dendrites and promotes translation efficiency. A predicted secondary structural motif in the kpc-1 3'UTR is required for dendrite self-avoidance. Animals with over-expression of DMA-1, a PVD dendrite receptor, exhibit similar dendrite branching and self-avoidance defects that are suppressed with kpc-1 over-expression. Our results support a model in which KPC-1 proteins are synthesized at branching points and contact points to locally down-regulate DMA-1 receptors to promote dendrite branching and self-avoidance of a mechanosensory neuron important for male courtship.

The past 25 years in paediatric rheumatology: insights from monogenic diseases.

The past 25 years have seen major novel developments in the field of paediatric rheumatology. The concept of autoinflammation was introduced to this field, and medicine more broadly, with studies of familial Mediterranean fever, the most common autoinflammatory disease globally. New data on the positive evolutionary selection of familial Mediterranean fever-associated genetic variants might be pertinent to mild gain-of-function variants reported in other disease-associated genes. Genetic studies have unveiled the complexity of human heritability to inflammation and flourishing data from rare monogenic disorders have contributed to a better understanding of general disease mechanisms in paediatric rheumatic conditions. Beyond genomics, the application of other 'omics' technologies, including transcriptomics, proteomics and metabolomics, has generated an enormous dataset that can be applied to the development of new therapies and in the practice of precision medicine. Novel biomarkers for monitoring disease activity and progression have also emerged. A surge in the development of targeted biologic therapies has led to durable remission and improved prognosis for many diseases that in the past caused major complications. Last but not least, the COVID-19 pandemic has affected paediatric rheumatology practice and has sparked new investigations into the link between viral infections and unregulated inflammatory responses in children.

Highlights of Gene and Cell Therapy for Epidermolysis Bullosa and Ichthyosis.

Advancements in the molecular genetics of epidermolysis bullosa (EB) and ichthyosis, two rare inherited skin conditions, have enabled the identification of genetic variants that cause these diseases. Alongside technological advancements in genetic medicine, the identification of variants causal of these rare skin conditions has led to preclinical research and the clinical development of various in vivo and ex vivo gene and cell therapies for their treatment. Gene and cell therapies are considered to be the most advanced forms of personalized medicine, demonstrating safety and efficacy in numerous rare diseases. Although the orphan drug development boom has resulted in regulatory approval of multiple gene and cell therapies for various rare conditions, the application of these modalities to rare inherited skin conditions remains limited. Nonetheless, there are successful examples of both in vivo gene therapy- and ex vivo cell therapy-based approaches developed to treat EB and ichthyosis. This review highlights preclinical research and the clinical development of gene and cell therapies for multiple subtypes of these two devastating congenital skin conditions, including a gene therapy recently approved by the U.S. Food and Drug Administration for the treatment of recessive dystrophic EB.

T1R2/T1R3 polymorphism affects sweet and fat perception: Correlation between SNP and BMI in the context of obesity development.

Genetic variations in taste receptors are associated with gustatory perceptionand obesity, which in turn affects dietary preferences. Given the increasing tendency of people with obesity choosing sweet, high-fat meals, the current study assessed the cross-regulation of two polymorphisms of the sweet taste receptor (T1R2/T1R3), rs35874116 and rs307355, on fat sensitivity in Indian adults. We investigated the association between taste sensitivity and BMI in the T1R2, T1R3, and CD36 polymorphic and non-polymorphic groups. The general labelled magnitude scale (gLMS) was used to assess the taste sensitivity of 249 participants in addition to anthropometric data. TaqMan Probe-based RT-PCR was employedto determine the polymorphisms. Additionally, the colorimetric method utilizing 3, 5-dinitro salicylic acid was used to evaluate the participants' salivary amylase activity. The mean detection thresholds for linoleic acid (LA) and sucrose were greater in individuals with obesity (i.e., 0.97±0.08mM and 0.22±0.02M, respectively) than in healthy adults (p < 0.0001), indicating lower sensitivity. Moreover, it was found that a greater proportion of persons with obesity fall into the polymorphic groups (i.e., 52% with genotype CD36 AA, 44% with genotype T1R2 CC, and 40% with genotype T1R3 TT). All three single nucleotide polymorphisms support the Hardy-Weinberg equilibrium (p = 0.78). The Pearson correlation analysis between LA and the sucrose detection threshold revealed a significant (p < 0.0001) positive relationship with an rvalue of 0.5299. Moreover, salivary amylase activity was significantly (p < 0.05) higher in the polymorphic sub-groups. The results of our study imply that genetic variations in T1R2/T1R3 receptors affect perception of both sweetness and fat, which may have an effect on obesity.

Exploring the contribution of genetic variants to high sunitinib exposure in patients with cancer.

Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.5ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib. This was a genome-wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose-normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P-value ≤5 × 10-8 was considered significant and a P-value between 5 × 10-8 and 5 × 10-6 was considered suggestive. Sixty-nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon-like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10-19). Twelve SNVs were suggestive for an association with sunitinib exposure (P≤ 5 × 10-6). While rs6923671 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity.

Mendelian Randomization Study Reveals a Predicted Relationship between Sensorineural Hearing Loss and Mitochondrial Proteins.

Mitochondrial proteins assume a pivotal role in the onset and progression of diverse diseases. Nonetheless, the causal interconnections with sensorineural hearing loss (SNHL) demand meticulous exploration. Mendelian randomization analysis is a method used in observational epidemiological studies to predict the relationship between exposure factors and outcomes using genetic variants as instrumental variables. In this study, we applied this analytical approach to two distinct samples to predict the causal impact of mitochondrial proteins on SNHL. Two-sample Mendelian randomization analyses were executed to scrutinize the predicted associations between 63 mitochondrial proteins (nuclear-encoded) and SNHL, utilizing summary statistics derived from genome-wide association studies. Assessments of pleiotropy and heterogeneity were carried out to gauge the robustness of the obtained findings. Four mitochondrial proteins exhibited a suggestive causal relationship with the susceptibility to SNHL. Dihydrolipoamide dehydrogenase (DLD; OR = 0.9706, 95% CI = 0.9382-0.9953, p = 0.0230) was linked to a diminished risk of SNHL. Conversely, elevated levels of mitochondrial ribosomal protein L34 (MRPL34; OR = 1.0458, 95% CI = 1.0029-1.0906, p = 0.0362), single-pass membrane protein with aspartate-rich tail 1 (SMDT1; OR = 1.0619, 95% CI = 1.0142-1.1119, p = 0.0104), and superoxide dismutase 2 (SOD2; OR = 1.0323, 95% CI = 1.0020-1.0634, p = 0.0364) were associated with an elevated risk of SNHL. This research utilized Mendelian randomization analysis to predict the relationship between mitochondrial proteins and SNHL. It provides a potential viewpoint on the etiology and diagnosis.

Evaluation of the Behavioral Effect of Psychostimulants in Children with Autism Spectrum Disorder: A Cross-Sectional Study.

Autism spectrum disorder (ASD) is often accompanied by comorbid conditions such as attention deficit hyperactivity disorder and epilepsy. In this context, patients are often treated with psychostimulants in an attempt to control behavioral symptoms. This study aims to understand the behavioral effects of psychostimulants in children with ASD and investigate if interictal epileptiform discharges on electroencephalogram (EEG) can act as a modifying factor in this behavior. Sixty-eight patients with ASD who were being accompanied in the Department of Child and Adolescent Psychiatry of the Centro Hospitalar Universitário de São João and had previously done an EEG assessment answered a questionnaire regarding their behavioral response to psychostimulants. In total, 47.4% of patients reported improved agitation, 56.1% enhanced concentration, and 8.8% improved sleep. Conversely, 28.1% experienced worsened agitation, 15.8% worsened concentration, and 17.5% worsened sleep. The remaining reported no alterations. The age of diagnosis correlated significantly with improved agitation, with a higher diagnosis age being associated with a higher probability of improvement. Extended-release methylphenidate and genetic variations were significantly associated with worsening of agitation. Regarding speech, 86% exhibited no changes, while 14% showed alterations, mostly, 87.5%, characterized as negative. For other behavioral alterations, 45.6% reported negative changes, 3.5% reported positive changes, and 50.9% reported no additional alterations. Female gender was significantly associated with other negative behavioral changes. A significant correlation was found between treatment duration and the probability of improvement in agitation, concentration, and other behavioral changes.

Analysis of the Mitochondrial COI Gene and Genetic Diversity of Endangered Goose Breeds

The mitochondrial cytochrome c oxidase subunit I (COI) genes of six endangered goose breeds (Xupu, Yangjiang, Yan, Wuzong, Baizi, and Lingxian) were sequenced and compared to assess the genetic diversity of endangered goose breeds. By constructing phylogenetic trees and evolutionary maps of genetic relationships, the affinities and degrees of genetic variations among the six different breeds were revealed. A total of 92 polymorphic sites were detected in the 741 bp sequence of the mtDNA COI gene after shear correction, and the GC content of the processed sequence (51.11%) was higher than that of the AT content (48.89%). The polymorphic loci within the populations of five of the six breeds (Xupu, Yangjiang, Yan, Baizi, and Lingxian) were more than 10, the haplotype diversity &gt; 0.5, and the nucleotide diversity (Pi) &gt; 0.005, with the Baizi geese being the exception. A total of 35 haplotypes were detected based on nucleotide variation among sequences, and the goose breed haplotypes showed a central star-shaped dispersion; the FST values were −0.03781 to 0.02645, The greatest genetic differentiation (FST = 0.02645) was observed in Yan and Wuzong breeds. The most frequent genetic exchange (Nm &gt; 15.00) was between the Wuzong and Yangjiang geese. An analysis of molecular variance showed that the population genetic variation mainly came from within the population; the base mismatch differential distribution analysis of the goose breeds and the Tajima’s D and Fu’s Fs neutral detection of the historical occurrence dynamics of their populations were negative (p &gt; 0.10). The distribution curve of the base mismatches showed a multimodal peak, which indicated that the population tended to be stabilised. These results provide important genetic information for the conservation and management of endangered goose breeds and a scientific basis for the development of effective conservation strategies.