Impact Of Single Nucleotide Polymorphisms Research Articles

Phenotype wide association study links bronchopulmonary dysplasia with eosinophilia in children

Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth. Despite this, genetic drivers of BPD are poorly understood. The objective of this study is to better understand the impact of single nucleotide polymorphisms (SNPs) previously associated with BPD by examining associations with other phenotypes. We drew pediatric subjects from the biorepository at the Center for Applied Genomics to identify associations between these SNPs and 2,146 imputed phenotypes. Methylation data, external cohorts, and in silico validation methods were used to corroborate significant associations. We identified 60 SNPs that were previously associated with BPD. We found a significant association between rs3771150 and rs3771171 and mean eosinophil percentage in a European cohort of 6,999 patients and replicated this in external cohorts. Both SNPs were also associated with asthma, COPD and FEV1/FVC ratio. These SNPs displayed associations with methylation probes and were functionally linked to ST2 (IL1RL1) levels in blood and lung tissue. Our findings support a genetic justification for the epidemiological link between BPD and asthma. Given the well-established link between ST2 and type 2 inflammation in asthma, these findings provide a rationale for future studies exploring the role of type 2 inflammation in the pathogenesis of BPD.

Abstract We142: Identification of the Molecular Determinants for the Circadian Regulation of the Human KCNH2 promoter

Background: KCNH2 encodes a voltage-gated potassium channel (Kv11.1), which conducts the rapid delayed rectifier potassium current (IKr) critical for ventricular repolarization in the heart. Circadian clock factors regulate the expression of the KCNH2 mRNA transcript in the heart. However, the molecular mechanisms for the circadian expression of KCNH2 transcripts have yet to be defined. Hypothesis: A conserved cis-regulatory element in the core KCNH2 promoter drives circadian regulation of human KCNH2 (hKCNH2) promoter activity. Objective: Identify the molecular determinants of the circadian regulation of hKCNH2 promoter activity and determine the impact of single nucleotide polymorphisms (SNPs) in this region. Methods: Real-time bioluminescence (LumiCycle, Actimetrics) and Dual Glo luciferase assays were employed to identify critical cis elements that regulate the circadian expression of the human KCNH2 promoter using promoter-luciferase reporter constructs. We studied several deletion and mutant hKCNH2 promoter reporter vectors transiently transfected in a myogenic cell line (C2C12 cells). Bioluminescence was measured at 10-minute intervals for 7-10 days. Data were analyzed for circadian characteristics (period, phase and amplitude). Mutant constructs included both engineered and constructs containing naturally occurring rare and common SNPs. Results: Lumicycle data demonstrated that the hKCNH2 promoter reporter showed robust circadian and overall activity in C2C12 cells. Deletion and mutational analysis of the hKCNH2 promoter-reporter construct identified a highly conserved tandem E-box element within 1 Kb of the exon 1 start site that was critical for circadian and overall regulation of hKCNH2 promoter activity. Cells expressing hKCNH2 promoter-reporter constructs with different SNPs in this tandem E-box element showed SNP-specific effects. Surprisingly, a relatively common SNP decreased hKCNH2 circadian promoter activity by 66% (n = 6, p=0.0049). Conclusion: We identified a conserved tandem E-box in the proximal promoter of hKCNH2 Exon1 necessary for circadian and overall hKCNH2 promoter activity. Several SNPs in this region suggested a functional impact that might lead to decreased levels of IKr.

P-556 Genetic variation in genes related to folliculogenesis and steroidogenesis in Caucasian and Asian women: Baby steps towards a pharmacogenetic approach in assisted reproductive techniques

Abstract Study question What is the impact of single nucleotide polymorphisms (SNPs) in genes related to the folliculogenesis and steroidogenesis on ovarian response to stimulation? Summary answer SMAD2 rs13381619 and COMT rs4680 variants are associated with the follicular output rate (FORT). What is known already The prediction of ovarian response (OR) is crucial for an optimal and individualized management. Despite the good accuracy of ovarian reserve markers in the prediction of OR, a proportion of patients are unexpected hypo-responders. Therefore, a link between OR and individual genotype has been suggested. However, the available evidence is limited by small sample sizes and heterogeneous study designs, including patients with different profiles and allowing for dose adjustments during treatment. Our aim was to analyze the association between SNPs in genes related to folliculogenesis and steroidogenesis and OR in an ethnic diverse population treated with the same fixed-dose protocol. Study design, size, duration This is a secondary analysis of a multicenter multinational prospective study, including 368 patients from Vietnam, Belgium, and Spain (168 from Europe and 200 from Asia) recruited from 11/2016-06/2019. The study included predicted normal responders <38 years old undergoing their first or second ovarian stimulation (OS) cycle. All patients underwent OS in an antagonist protocol with a fixed daily dose of 150 IU rFSH until triggering. Participants/materials, setting, methods First, an interactome was developed using “FSHR” and “LHCGR” as keyword imputed in the Homo sapiens STRING database for protein network analysis. Genetic information from sixty-eight final SNPs involved in the folliculogenesis and steroidogenesis was obtained and used for clustering analysis. Secondly, genotype-phenotype analysis was performed. The prevalence of hypo-responders (<10 oocytes retrieved), number of oocytes retrieved, FORT and follicle to oocyte index (FOI) were compared between different SNPs genotypes. Main results and the role of chance Clustering analysis revealed four distinct genetic clusters according to the selected SNPs related to folliculogenesis and steroidogenesis. Principal component analysis (PCA) was used to display individuals’ distribution according to the fertility centre, resulting in an obvious distribution according to ethnicity. However, PCA failed to demonstrate a clinically significant association between our interactome and the outcomes of interest. We further refined our SNP panel by categorizing SNPs according to their physiological pathway and analyzed their individual impact on OR. Following multivariable linear regression adjusting for patient’s age, Anti-Mullerian hormone (AMH), duration of stimulation and ethnicity, SMAD2 rs13381619 genotype GC (estimated mean difference (EMD) 11.57, 95% Confidence interval (CI) 2.66-20.49), and COMT rs4680 genotype AA (EMD 18.31, 95% CI 4.91-31.72) were associated with improved FORT. No impact of the studied polymorphisms was found on the prevalence of hypo-response, number of oocytes retrieved nor FOI. Limitations, reasons for caution The study was performed in young women with a normal ovarian reserve to eliminate biases related to age-related fertility decline, precluding the extrapolation of the results to other populations. Moreover, the low prevalence of some genotypes might have limited the analysis of some of the included variants. Wider implications of the findings Our findings confirm the variation of SNPs prevalence according to ethnic diversity, highlighting the importance of the intercontinental design of our study. Moreover, a novel association between SMAD2 and COMT variants and OR was reported, opening new opportunities for further pharmacogenetics studies and paving the way towards personalized medicine. Trial registration number Not applicable

Probing the Association of EPCAM Gene Single Nucleotide Polymorphisms with Genetic Disorders

Background: Mutations in the EPCAM gene can lead to the absence of this protein from epithelial cell surfaces, resulting in various disorders such as Lynch syndrome, congenital tufting enteropathy, cholestatic liver disease, and a range of cancers. Therefore, analyzing mutations in this gene is significant from diagnostic and prognostic perspectives. This study examines the effect of various mutations in the EPCAM gene on different attributes of the encoded protein. Objective: The objective of this study was to analyze the impact of single nucleotide polymorphisms (SNPs) in the EPCAM gene on the protein's structural and functional properties, aiming to identify potential predictive biomarkers for EPCAM-associated diseases. Methods: The study focused on the EPCAM gene transcript EPCAM-201, with ENSEMBL transcript ID ENST00000263735.9 and NCBI Reference Sequence NM_002354.3. The gene sequence was retrieved from the NCBI database, and SNPs were selected from the ENSEMBL database. A total of 21 variants were selected to design twenty-one cases. These cases were analyzed using various bioinformatics tools, including EXPASY for nucleotide sequence translation, HOPE server for 3D structure analysis, CELLO2GO for sub-cellular localization, and PROTPARAM for physicochemical parameter prediction. Data collection adhered to the principles outlined in the Declaration of Helsinki. Statistical analyses were conducted using SPSS version 25, with descriptive statistics and appropriate tests to determine the significance of the observed variations. Results: Analysis revealed that sixteen SNPs, namely rs994384264, rs1280024892, rs1294456118, rs149875996, rs767811939, rs750826481, rs754293486, rs748292053, rs1460762372, rs1294456118, rs149875996, rs754293486, rs748292053, rs771063031, rs776854951, and rs267606785, significantly altered the 3D structure of mutated proteins. Among these SNPs, rs994384264 and rs149875996 also affected the sub-cellular localization of proteins. Additionally, four mutations—rs1280024892, rs1460762372, rs987919056, and rs771029207—caused alterations in extinction coefficient, isoelectric point (pI), aliphatic index, and instability index. Conclusion: These single nucleotide variants might serve as predictive biomarkers for EPCAM-associated diseases, aiding in diagnosis and prognosis. Variants predicted in this study require further experimental validation to confirm their clinical utility.

Association between Platelet-Derived Growth Factor Receptor Alpha Gene Polymorphisms and Platelet-Rich Plasma's Efficiency in Treating Lateral Elbow Tendinopathy-A Prospective Cohort Study.

Individual differences in the response to platelet-rich plasma (PRP) therapy can be observed among patients. The genetic background may be the cause of this variability. The current study focused on the impact of genetic variants on the effectiveness of PRP. The aim of the present study was to analyze the impact of single nucleotide polymorphisms (SNP) of the platelet-derived growth factor receptor alpha (PDGFRA) gene on the effectiveness of treating lateral elbow tendinopathy (LET) with PRP. The treatment's efficacy was analyzed over time (2, 4, 8, 12, 24, 52 and 104 weeks after the PRP injection) on 107 patients using patient-reported outcome measures (PROM) and achievement of a minimal clinically important difference (MCID). Four SNPs of the PDGFRA gene (rs7668190, rs6554164, rs869978 and rs1316926) were genotyped using the TaqMan assay method. Patients with the AA genotypes of the rs7668190 and the rs1316926 polymorphisms, as well as carriers of the T allele of rs6554164 showed greater effectiveness of PRP therapy than carriers of other genotypes. Moreover, the studied SNPs influenced the platelets' parameters both in whole blood and in PRP. These results showed that PDGFRA gene polymorphisms affect the effectiveness of PRP treatment. Genotyping the rs6554164 and the rs1316926 SNPs may be considered for use in individualized patient selection for PRP therapy.

Effects of pharmacogenetics on pharmacokinetics and toxicity of doxorubicin in Egyptian breast cancer patients

This study investigates the impact of single nucleotide polymorphisms in genes (SLC22A16 and CBR1) involved in the pharmacokinetics and toxicity of doxorubicin (DOX) in Egyptian female patients with breast cancer. Patients administered DOX (60 mg/m2) for 4 cycles every 3 weeks. The peak DOX plasma concentration was measured using a validated chromatographic method. The genotyping for the selected SNPs, SLC22A16 T > C (rs714368), and CBR1 C > T (rs20572), was performed by RT-PCR. Patients were monitored for hematological and cardiac toxicities. The variant carriers of CBR1 C > T (rs20572) exhibited significantly higher DOX concentration, but no significant association to DOX-induced hematological toxicity. On the other hand, SLC22A16 T > C (rs714368) had no significant influence on DOX plasma concentration, but was significantly correlated with lower risk of neutropenia (OR 0.31, 95% CI 0.12–0.75, p = 0.01) and leukopoenia (OR 0.18, 95% CI 0.07–0.5, p = 0.001). DOX-related cardiotoxicity was correlated with the cumulative dose of DOX (R = 0.238, p = 0.017), but not with any of the two examined SNPs. Genetic polymorphisms in SLC22A16 and CBR1 may explain the inter-individual variations in DOX pharmacokinetics and toxicity. Using pharmacogenetic testing is important to customise drug therapy for cancer patients treated with anthracyclines.

Probing RNA structural landscapes across Candida yeast genomes.

Understanding the intricate roles of RNA molecules in virulence and host-pathogen interactions can provide valuable insights into combatting infections and improving human health. Although much progress has been achieved in understanding transcriptional regulation during host-pathogen interactions in diverse species, more is needed to know about the structure of pathogen RNAs. This is particularly true for fungal pathogens, including pathogenic yeasts of the Candida genus, which are the leading cause of hospital-acquired fungal infections. Our work addresses the gap between RNA structure and their biology by employing genome-wide structure probing to comprehensively explore the structural landscape of mRNAs and long non-coding RNAs (lncRNAs) in the four major Candida pathogens. Specifically focusing on mRNA, we observe a robust correlation between sequence conservation and structural characteristics in orthologous transcripts, significantly when sequence identity exceeds 50%, highlighting structural feature conservation among closely related species. We investigate the impact of single nucleotide polymorphisms (SNPs) on mRNA secondary structure. SNPs within 5' untranslated regions (UTRs) tend to occur in less structured positions, suggesting structural constraints influencing transcript regulation. Furthermore, we compare the structural properties of coding regions and UTRs, noting that coding regions are generally more structured than UTRs, consistent with similar trends in other species. Additionally, we provide the first experimental characterization of lncRNA structures in Candida species. Most lncRNAs form independent subdomains, similar to human lncRNAs. Notably, we identify hairpin-like structures in lncRNAs, a feature known to be functionally significant. Comparing hairpin prevalence between lncRNAs and protein-coding genes, we find enrichment in lncRNAs across Candida species, humans, and Arabidopsis thaliana, suggesting a conserved role for these structures. In summary, our study offers valuable insights into the interplay between RNA sequence, structure, and function in Candida pathogens, with implications for gene expression regulation and potential therapeutic strategies against Candida infections.

Interaction between CYP1A1 gene polymorphism and environment factors on risk of endometrial cancer.

The purpose of this study was to investigate the impact of single nucleotide polymorphisms (SNPs) of the CYP1A1 gene and the gene-environment interaction on the susceptibility to endometrial cancer in Chinese women. Logistic regression was performed to investigate the association between the four SNPs of the CYP1A1 gene and the risk of endometrial cancer. Generalized multifactor dimensionality reduction (GMDR) was employed to analyze the gene-environmental interaction. A total of 934 women with a mean age of 61.7 ± 10.5 years were selected, including 310 endometrial cancer patients and 624 normal controls. The frequency of rs4646421- T allele was higher in endometrial cancer patients than normal controls, the T allele of rs4646421 was 28.1% in endometrial cancer patients and 21.0% in normal controls (p < 0.001). Logistic regression analysis showed that the rs4646421 - T allele was associated with increased risk of endometrial cancer, OR (95% CI) were 1.52 (1.11-1.97) and 1.91 (1.35-2.52), respectively. GMDR analysis found a significant two-locus model (p = 0.0107) involving rs4646421 and abdominal obesity (defined by waist circumference), indicating a potential gene-environment interaction between rs4646421 and abdominal obesity. Abdominal obese subjects with rs4646421- CT or TT genotype have the highest risk of endometrial cancer, compared to non-abdominal obese subjects with the rs4646421- CC genotype, the OR (95%CI) was 2.23 (1.62-2.91). Both the rs4646421- T allele and the interaction between rs4646421 and abdominal obesity were associated with increased risk of endometrial cancer.

Analysing the Functional and Structural Impact of Single Nucleotide Polymorphisms in Matrix Metalloproteinase 3 Gene: An In-silico Approach

Introduction: Matrix Metalloproteinase 3 (MMP3) is a vital member of the MMP family, known for its wide range of substrate specificity and proteolytic activity against Extracellular Matrix (ECM) components. The role of functional polymorphisms in the MMP genes has been previously investigated in relation to cancer susceptibility, particularly breast cancer. Several SingleNucleotide Polymorphisms (SNPs) in the MMP3 gene have been linked to a number of clinical illnesses, such as Coronary Artery Disease (CAD); however, the results were not entirely conclusive. Aim: To identify pathogenic missense SNPs in the human MMP3 gene and analyse their effects on structure and function. Materials and Methods: This was a record-based cross-sectional study performed using data retrieved from online resources. The analysis was conducted using a series of different bioinformatic tools, for which ethical clearance was obtained from the institution. The online tools used included Sorting Intolerant from Tolerant (SIFT), PolyPhen-2, PhD-SNP, PANTHER, PROVEAN, and SNPs and GO to predict harmful non synonymous SNPs (nsSNPs). Further analysis was performed using I-Mutant 2.0, MutPred2, Consurf, and HOPE software. These tools were able to filter out damaging SNPs and predict the impact of deleterious SNPs on the structure and function of the MMP3 protein. Results: This study predicted two potentially pathogenic SNPs (D175Y and Y116C) out of 443 missense SNPs from dbSNP, which is a database of SNPs available on the National Centre for Biotechnology Information website. Further analysis revealed that these SNPs were located in highly conserved regions and were predicted to decrease protein stability. Conclusion: In this study, two potentially pathogenic SNPs (D175Y and Y116C) were identified. Characterisation of these SNPs can help us gain a better understanding of the molecular basis of clinical conditions. The results of this study can be further validated by designing population-based studies and wet lab experiments. This will help in augmenting research and personalised medicine.

An Integrated Framework for Analysis and Prediction of Impact of Single Nucleotide Polymorphism Associated with Human Diseases.

Single nucleotide polymorphisms are most common type of genetic variation in human genome. Analyzing genetic variants can help us better understand the genetic basis of diseases and develop predictive models which are useful to identify individuals who are at increased risk for certain diseases. Several SNP analysis tools have already been developed. For running these tools, the user needs to collect data from various databases. Secondly, often researchers have to use multiple variant analysis tools for cross validating their results and increase confidence in their findings. Extracting data from multiple databases and running multiple tools at a time, increases complexity and time required for analysis. There are some web-based tools that integrate multiple genetic variant databases and provide variant annotations for a few tools. These approaches have some limitations such as retrieving annotation information, filtering common pathogenic variants. The proposed web-based tool, namely IPSNP: An Integrated Platform for Predicting Impact of SNPs is written in Django which is a python-based framework. It uses RESTful API of MyVariant.info to extract annotation information of variants associated with a given gene, rsID, HGVS format variants specified in a VCF file for 29 tools. The results are in the form of a CSV file of predictions (1) derived from the consensus decision, (2) a file having annotations for the variants associated with the given gene, (3) a file showing variants declared as pathogenic commonly by the selected tools, and (4) a CSV file containing chromosome coordinates based on GRCh37 and GRCh38 genome assemblies, rsIDs and proteomic data, so that users may use tools of their choice and avoiding manual parameter collection for each tool. IPSNP is a valuable resource for researchers and clinicians and it can help to save time and effort in discovering the novel disease-associated variants and the development of personalized treatments.

Impact of single nucleotide polymorphisms of immune checkpoint CTLA-4 (SNP rs231775 and rs5742909) in susceptibility to Hashimoto's thyroiditis patients

Background: Hashimoto thyroiditis is an autoimmune disorder causing thyroid cell destruction. This research aimed to evaluate CTLA-4 expression levels in patients with Hashimoto's thyroiditis, biochemical parameters. As well as understand the risk and protective effects of two CTLA-4 SNPs polymorphisms (rs231775 and rs5742909) in Iraqi patients. Methods: A case control study was conducted on 50 HT patients (5 men and 45 females) were assembled from Baghdad teaching hospital, Baghdad, Iraq. The relative Gene expression method was used to measure the gene expression of CTLA-4 using qRT-PCR. The single nucleotide polymorphisms of (318C/T (rs231775) and +49A/G (rs5742909) were sequenced for data analysis. Results: There was significant increase of serum CTLA-4 levels, similarity fold change of CTLA-4 was significant upregulated in HT patients compared to controls. The allele and genotypes frequencies according to HWB equilibrium showed significant differences in HT patients 318C/T (rs231775) AA genotypes, while no significant differences in the AG, GG genotypes, respectively compared to controls (p&lt;0.05), There were also no significant differences in the CTLA-4 SNP +49A/G (rs5742909), (CC, CT, TT) genotype, respectively. (p&gt;0.05). Both studied SNPs recoded higher upregulation of soluble and fold change of the immune check point (CTLA-4), respectively. Conclusion: The study reveals that CTLA-4 gene SNPs rs231775 and rs5742909 significantly influence soluble and the expression of CTLA-4 levels in HT patients, potentially causing Hashimoto disease and HT incidence and development.

Level of biochemical parameters in patients with type 2 diabetes mellitus depending on the genotype of the FokI polymorphism in the vitamin D3 receptor (VDR gene).

Diabetes mellitus type 2 (T2DM) is a multifactorial and polygenic disorder characterised by chronic hyperglycaemia accompanied by impaired lipid, carbohydrate, and protein metabolism. The disease is associated with several genetic polymorphisms, including the FokI polymorphism in the vitamin D receptor (VDR) gene. We conducted a study of 327 probands (191 T2DM patients, 136 controls), with a mean age 65.06 (SD ± 10.88) years of patients with T2DM and 58.89 (SD ± 6.59) years in the healthy probands. We investigated the association between FokI polymorphism and biochemical parameters in T2DM patients in the Slovak population. Anthropometric measurements, biochemical, and genetic analysis were statistically evaluated by Statistica ver.13 software using t-tests. Biochemical analysis confirmed significantly higher mean values of total cholesterol (TC), triglyceride (TG), glucose (GLU), and uric acid (UA) (p < 0.001) in T2DM probands and statistically significantly lower values of high-density lipoprotein (HDL), cholesterol and vitamin D (p < 0.001). Allele frequencies and genotype distributions of the FokI (rs2228570) polymorphism were not significantly different between T2DM patients and controls (p = 0.909). Patients with T2DM and TT genotype had the highest glucose level of 11.39 (SD ± 2.32) uU/ml (p < 0.001). Our study did not provide evidence for an association of the investigated FokI polymorphism of the VDR gene with T2DM in the Slovak population. Further research is needed to evaluate the impact of single nucleotide polymorphisms (SNPs) in the VDR gene, focusing on related genetic analyses in a larger T2DM cohort.

Pharmacokinetics (PK) of Deferasirox in Transfusion Dependent Thalassemia

Iron overload is a major cause of organ dysfunction and death in transfusion-dependent thalassemia (TDT) and advances in iron chelation are urgently needed. The iron chelator, deferasirox, is widely used in TDT, however, many patients accumulate iron despite taking maximum recommended doses and many experience dose-limiting toxicity, including renal and liver failure. There is high inter-individual variability in the plasma concentrations of patients taking comparable deferasirox doses and low exposure correlates with inadequate chelation response. The cause of variable drug levels remains unknown, in part because prior deferasirox PK studies primarily include limited sample sizes and/or homogenous patients. There is an urgent unmet need to determine (1) what patient characteristics contribute to the observed variability in deferasirox-plasma concentrations, and (2) how dosing strategies can be tailored to achieve optimal therapeutic plasma-drug concentrations in all patients. We initiated a 2 year, single center observational pharmacokinetic (PK) pilot study to describe the PK of deferasirox in a diverse group of TDT patients from 2 years old through adulthood with a goal accrual of 50 patients. Our aim is to develop a population PK (popPK) model of deferasirox that will be evaluated in a future prospective study to individualize dosing and optimize exposure. The eligibility criteria are broad to capture a diverse population. Patients are eligible if they: 1) have a diagnosis of TDT, 2) are taking deferasirox, and 3) are able to provide informed consent (or have a guardian provide informed consent). For quantification of plasma deferasirox concentrations, 0.5 ml of whole blood are collected prior to transfusions at 4 regularly scheduled transfusion visits. Samples are then analyzed by a validated high performance liquid chromatography assay. Baseline labs, liver iron concentration and information on concomitant chelators are collected at the start of the study and labs, fed/fasted state, time and dose of last deferasirox, deferasirox regimen, and concomitant chelators are collected at each study visit. The planned analysis is to use nonlinear mixed effect modeling to calculate drug exposure and develop the popPK model. We have enrolled 39 patients with TDT, including 27 patients with beta thalassemia major, 10 patients with hemoglobin E beta thalassemia, 12 patients with hemoglobin H constant spring and one patient with beta thalassemia intermedia. Median age is 28 years old, with a range from 6 - 63 years old. Pre-study iron status also varied considerably, with median liver iron concentration 4.5 mg/g (range 1.5 -30 mg/g) and median ferritin 1500 ug/L (range 460 - 5600 ug/L). Thirty one patients have completed the study and 141 samples have been collected. Initial analysis of the first 15 patients who completed the study show a wide range of steady state plasma-deferasirox concentrations, consistent with prior reports. The means for the 4 samples collected per patient were calculated and found to have a median of 36.3 ug/ml with a range of 13.4 - 56.0 ug/ml. For the individual sample collections, the range of plasma deferasirox concentrations was even greater (0.18 - 99.9 ug/ml). These results need to be analyzed further to account for the dosing regimen, iron burden and other individual patient characteristics. In this study, we also collected genomic DNA from the buffy coat to evaluate the impact of single nucleotide polymorphisms in enzymes involved in drug metabolism and distribution. Once all data is collected, we will evaluate whether patient age, weight, laboratory values, fed/fasted state, concomitant chelators or pharmacogenomics impact deferasirox serum concentrations and can inform individualized deferasirox dosing. This study is unique, unlike prior deferasirox PK studies which collected intensive PK, we are using sparse sampling to collect real world data on deferasirox at steady state in TDT patients. Our hope is that this study will enable safer more effective dosing of deferasirox in patients with TDT.

Genetic Correlation of miRNA Polymorphisms and STAT3 Signaling Pathway with Recurrent Implantation Failure in the Korean Population

The growing prevalence of in vitro fertilization-embryo transfer procedures has resulted in an increased incidence of recurrent implantation failure (RIF), necessitating focused research in this area. STAT3, a key factor in maternal endometrial remodeling and stromal proliferation, is crucial for successful embryo implantation. While the relationship between STAT3 and RIF has been studied, the impact of single nucleotide polymorphisms (SNPs) in miRNAs, well-characterized gene expression modulators, on STAT3 in RIF cases remains uncharacterized. Here, we investigated 161 RIF patients and 268 healthy control subjects in the Korean population, analyzing the statistical association between miRNA genetic variants and RIF risk. We aimed to determine whether SNPs in specific miRNAs, namely miR-218-2 rs11134527 G&gt;A, miR-34a rs2666433 G&gt;A, miR-34a rs6577555 C&gt;A, and miR-130a rs731384 G&gt;A, were significantly associated with RIF risk. We identified a significant association between miR-34a rs6577555 C&gt;A and RIF prevalence (implantation failure [IF] ≥ 2: adjusted odds ratio [AOR] = 2.264, 95% CI = 1.007–5.092, p = 0.048). These findings suggest that miR-34a rs6577555 C&gt;A may contribute to an increased susceptibility to RIF. However, further investigations are necessary to elucidate the precise mechanisms underlying the role of miR-34a rs6577555 C&gt;A in RIF. This study sheds light on the genetic and molecular factors underlying RIF, offering new avenues for research and potential advancements in the diagnosis and treatment of this complex condition.

CYP450 and drug efflux transporters polymorphism influence clinical outcomes of Thai osimertinib-treated non-small cell lung cancer patients.

Background: Osimertinib has shown greater efficacy than standard epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and fewer grade 3 or higher adverse drug reactions (ADRs) in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. However, the clinical outcomes of osimertinib treatment vary depending on the patient's ethnicity. Therefore, further research is necessary to evaluate the impact of single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP450) and drug transporters on the therapeutic outcomes and ADRs to osimertinib in Thai patients, to provide improved pharmacological treatments for cancer patients. Methods: This retrospective and prospective cohort study enrolled 63 Thai patients with NSCLC treated with 80mg of osimertinib once daily as monotherapy. Seventeen SNPs in candidate genes related to drug metabolism and transport pathways were analyzed in each patient. Chi-square or Fisher's exact tests were used to evaluate the associations between SNPs and clinical outcomes, including ADR incidence and objective response rate (ORR). In addition, the correlation between the genotype and median time to treatment failure (TTF) or progression-free survival (PFS) was assessed using Kaplan-Meier analysis and a log-rank test. Results: We identified six SNPs (rs2231142 and rs2622604 in ABCG2, rs762551 in CYP1A2, rs1057910 in CYP2C9, rs28371759 in CYP3A4, and CYP2A6 deletion polymorphism (CYP2A6*4)) that significantly increased the incidence of ADRs. In addition, we found two SNPs (rs2069514 in CYP1A2 and rs1057910 in CYP2C9) that significantly decreased the median TTF, and two SNPs (rs28399433 in CYP2A6 and rs1057910 in CYP2C9) that significantly decreased the median progression-free survival (PFS). Specifically, we found that one of these SNPs (rs1057910 in CYP2C9) influenced ADRs, TTF, and PFS. Additionally, SNPs in the CYP2A6 heterozygous variant (non4/*4) significantly increased ADR incidence, leading to a high frequency of dose reduction (27.0%). Conclusion: Our study demonstrated significant SNPs associated with increased ADR incidence, decreased PFS, and decreased TTF in Thai patients with NSCLC treated with osimertinib. The CYP2C9 (*3) and CYP2A6 (*4) allele frequencies differed between ethnicities and were associated with an increased incidence of ADRs. These findings highlight the importance of considering genetic factors in NSCLC treatment and may facilitate personalized medicine approaches. Moreover, our study showed a higher incidence of ADRs than the previous trials, including FLAURA and AURA2, and a higher frequency of dose reduction than reported in the AURA 3 trial, possibly due to genetic differences among the study populations.

Impact of Single Nucleotide Polymorphisms of the Promoter of the TNF Gene on Adalimumab Treatment Responses in Hidradenitis Suppurativa

Background: Results of randomized clinical trials show great variation in response to treatment with adalimumab (ADA) in hidradenitis suppurativa (HS). This varied response may be associated with genetic polymorphisms. Objectives: The aim of the study was to study the association between carriage of single nucleotide polymorphisms (SNPs) in the promoter of the tumor necrosis factor (TNF) gene and their response to ADA. Methods: Patients with moderate to severe HS who received ADA treatment for at least 12 weeks were enrolled. SNPs were analyzed with PCR-restriction fragment length polymorphism. Hidradenitis Suppurativa Clinical Response (HiSCR) score, International Hidradenitis Suppurativa Severity Scoring System 4 (IHS4) score, inflammatory lesion (AN) count, and draining tunnel (dT) count were collected at weeks 0, 12, 24, 36, and 48. Results: HiSCR response after 12 weeks of ADA treatment was 71.8% among carriers of the common GGG haplotype and 50.0% among carriers of minor frequency SNP haplotypes (p: 0.031; odds ratio: 0.39). This significant difference persisted until week 36. Carriers of minor frequency SNP haplotypes also had a lower relative decrease of the AN count at weeks 12 and 24; the dT count and IHS4 were not statistically different between the two groups. Conclusions: Carriage of at least one minor frequency SNP haplotype of the promoter of the TNF gene is associated with a decreased response to ADA. This association may have an impact on treatment decision-making.

3DVizSNP: a tool for rapidly visualizing missense mutations identified in high throughput experiments in iCn3D

BackgroundHigh throughput experiments in cancer and other areas of genomic research identify large numbers of sequence variants that need to be evaluated for phenotypic impact. While many tools exist to score the likely impact of single nucleotide polymorphisms (SNPs) based on sequence alone, the three-dimensional structural environment is essential for understanding the biological impact of a nonsynonymous mutation.ResultsWe present a program, 3DVizSNP, that enables the rapid visualization of nonsynonymous missense mutations extracted from a variant caller format file using the web-based iCn3D visualization platform. The program, written in Python, leverages REST APIs and can be run locally without installing any other software or databases, or from a webserver hosted by the National Cancer Institute. It automatically selects the appropriate experimental structure from the Protein Data Bank, if available, or the predicted structure from the AlphaFold database, enabling users to rapidly screen SNPs based on their local structural environment. 3DVizSNP leverages iCn3D annotations and its structural analysis functions to assess changes in structural contacts associated with mutations.ConclusionsThis tool enables researchers to efficiently make use of 3D structural information to prioritize mutations for further computational and experimental impact assessment. The program is available as a webserver at https://analysistools.cancer.gov/3dvizsnp or as a standalone python program at https://github.com/CBIIT-CGBB/3DVizSNP.

In Silico Prediction and Molecular Docking of SNPs in NRP1 Gene Associated with SARS-COV-2.

Neuropilin-1 (NRP1) which is a main transmembrane cell surface receptor acts as a host cell mediator resulting in increasing the SARS-Cov-2 infectivity and also plays a role in neuronal development, angiogenesis and axonal outgrowth. The goal of this study is to estimate the impact of single nucleotide polymorphisms (SNPs) in the NRP1 gene on the function, structure and stabilization of protein as well as on the miRNA-mRNA binding regions using bioinformatical tools. It is also aimed to investigate the changes caused by SNPs in NRP1 on interactions with drug molecule and spike protein. The missense type of SNPs was analyzed using SIFT, PolyPhen-2, SNAP2, PROVEAN, Mutation Assessor, SNPs&GO, PhD-SNP, I-Mutant 3.0, MUpro, STRING, Project HOPE, ConSurf, and PolymiRTS. Docking analyses were conducted by AutoDock Vina program. As a result, a total of 733 missense SNPs were determined within the NRP1 gene and nine SNPs were specified as damaging to the protein. The modelling results showed that wild and mutant type amino acids had some different properties such as size, charge, and hydrophobicity. Additionally, their three-dimensional structures of protein were utilized for confirmation of these differences. After evaluating the results, nine polymorphisms rs141633354, rs142121081, rs145954532, rs200028992, rs200660300, rs369312020, rs370117610, rs370551432, rs370641686 were determined to be damaging on the structure and function of NRP1 protein and located in conserved regions. The results of molecular docking showed that the binding affinity values are nearly the same for wild-type and mutant structures support that the mutations carried out are not in the focus of the binding site, therefore the ligand does not affect the binding energy. It is expected that the results will be useful for future studies.

Clinical Impact of Single Nucleotide Polymorphism in CD-19 on Treatment Outcome in FMC63-CAR-T Cell Therapy.

Chimeric antigen receptor (CAR)-T cell therapy is effective in patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) with response rates of 63-84% and complete response observed in 43-54%. Common germline variants of the target antigen CD19 may elicit different responses to CAR-T cell therapy. The CD19 gene single nucleotide polymorphism rs2904880 encoding leucine or valine at amino acid position 174 of the CD19 antigen was prevalent in 51% of the studied DLBCL patients. In a retrospective comparative analysis of clinical outcome, there were significant differences in CD19 L174 versus V174 carriers: the median time of progression-free survival was 22 vs. 6 months (p = 0.06), overall survival was 37 vs. 8 months (p = 0.11), complete response rates were 51% vs. 30% (p = 0.05), and refractory disease rates were 14% vs. 32% (p = 0.04). The single nucleotide polymorphism in CD19 was shown to influence the treatment outcome in FMC63-anti-CD19-CAR-T cell therapy, and the CD19 minor allele L174 predicted a favorable treatment outcome.

Associations among Plasma Concentrations of Edoxaban and M-4, Prothrombin Time, and the SLCO1B1*15 Haplotype in Patients With Nonvalvular Atrial Fibrillation.

The authors aimed to examine the impact of single nucleotide polymorphisms in P-glycoprotein, the hepatic uptake transporter organic anion transporter protein 1B1, cytochrome P450 ( CYP ) 3A5, and carboxylesterase-1 ( CES1 ) on the steady-state dose-adjusted trough concentrations of edoxaban (C Edo /D) and M-4 (C M-4 /D). They also investigated whether C M-4 and C Edo affect prothrombin time (PT). The analyses included 152 patients with nonvalvular atrial fibrillation (NVAF) undergoing AF catheter ablation. The CYP3A5*3 ; CES1 c.1168-33A>C, c.257+885T>C; SLCO1B1 c.388A>G, c.521T>C; and ABCB1 c.3435C>T, c.2677G>A/T, c.1236C>T genotypes were determined. Stepwise selection multiple linear regression analyses demonstrated that creatinine clearance (Ccr), concomitant use of amiodarone, and SLCO1B1*15 haplotype status were independent factors influencing C M-4 /D (partial R2 = 0.189, 0.098, 0.067, respectively, all P values < 0.005). Ccr and concomitant use of amiodarone were independent factors influencing C Edo /D (partial R2 = 0.260, 0.117, respectively, both P value < 0.001). C Edo and C M-4 showed a weak correlation with PT (ρ = 0.369 and 0.315, both P values < 0.001). Although information concerning Ccr, concomitant use of amiodarone, and SLCO1B1*15 haplotype may be useful in assessing the pharmacokinetics of edoxaban, further studies are needed to clarify the requirement of PT monitoring at the trough level for dose adjustment of edoxaban in patients with NVAF.