The most promising treatment options for severe uncontrolled asthma (SUA) have emerged in recent years with the development of monoclonal antibodies for blocking selective targets responsible for the underlying inflammation, such as mepolizumab and benralizumab. However, there is variability in treatment response that is not fully controlled. The variability of the response to mepolizumab and benralizumab could be influenced by single-nucleotide polymorphisms (SNPs), and it would be useful to detect these and use them as predictive biomarkers of response. We conducted a retrospective observational cohort study of 72 Caucasian patients recruited from a tertiary hospital with severe uncontrolled eosinophilic asthma treated with mepolizumab and benralizumab. Polymorphisms in the IL5 (rs4143832, rs17690122), RAD50 (rs11739623, rs4705959), IL1RL1 (rs1420101, rs17026974, rs1921622), GATA2 (rs4857855), IKZF2 (rs12619285), FCGR2A (rs1801274), FCGR2B (rs3219018, rs1050501), FCGR3A (rs10127939, rs396991), FCER1A (rs2251746, rs2427837), FCER1B (rs1441586, rs573790, rs569108), and ZNF415 (rs1054485) genes were analyzed by real-time polymerase chain reaction (PCR) using Taqman probes. The response was analyzed after 12 months of treatment. In patients under mepolizumab treatment, a treatment response defined as a reduction in exacerbations was associated with ZNF415 rs1054485-T (p = 0.042; OR = 5.33; 95% CI = 1.06-30.02), treatment response defined as a reduction in oral corticosteroids use was associated with the number of exacerbations in the previous year (p = 0.029; OR = 3.89; 95% CI = 1.24-14.92), and treatment response defined as improvement in lung function was associated with the age at the beginning of biological therapy (p = 0.002; OR = 1.10; 95% CI = 1.04-1.18), FCER1B rs569108-AA (p < 0.001; OR = 171.06; 95% CI = 12.94-6264.11), and FCER1A rs2427837-A (p = 0.021; OR = 8.61; 95% CI = 1.71-76.62). On the other hand, in patients under benralizumab treatment, treatment response, defined as a reduction in exacerbations, was associated with ZNF415 rs1054485-T (p = 0.073; OR = 1.3 × 108; 95% CI = 1.8 × 10-19-NA), FCER1B rs569108-AA (p = 0.050; OR = 11.51; 95% CI = 1.19-269.78), allergies (p = 0.045; OR = 4.02; 95% CI = 1.05-16.74), and sex (p = 0.028; OR = 4.78; 95% CI = 1.22-20.63); and treatment response defined as improvement in lung function was associated with polyposis (p = 0.027; OR = 9.16; 95% CI = 1.58-91.4), IKZF2 rs12619285-AA (p = 0.019; OR = 9.1; 95% CI = 1.7-75.78), IL5 rs4143832-T (p = 0.017; OR = 11.1; 95% CI = 1.9-112.17), and FCER1B rs1441586-C (p = 0.045; OR = 7.81; 95% CI = 1.16-73.45). The results of this study show the potential influence of the studied polymorphisms on the response to mepolizumab and benralizumab and the clinical benefit that could be obtained by defining predictive biomarkers of treatment response.

Genetic features of alcohol dependence have been extensively investigated in recent years. A large body of studies has underlined the important role of genetic variants not only in metabolic pathways but also in the neurobiology of alcohol dependence, mediated by the neuronal circuits regulating reward and craving. Serotonin transporter (5-HTT), encoded by the SLC6A4 gene (Solute carrier family 6-neurotransmitter transporter-member 4), is targeted by antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) and plays a pivotal role in serotoninergic transmission; it has been associated with psychiatric diseases and alcohol dependence. Transcriptional regulation and expression of 5-HTT depend not only on epigenetic modifications, among which DNA methylation (CpG and non-CpG) is primarily involved, but also on sequence variations occurring in intron/exon regions and in untranslated regions in 5\' and 3\', being the first sequences important for the splicing machinery and the last for the binding of transcription factors and micro RNAs. This work intends to shed light on the role of sequence variations known to affect the expression or function of 5-HTT in alcohol-dependent individuals. We found a statistically significant difference in the allelic (p = 0.0083) and genotypic (p = 0.0151) frequencies of the tri-allelic polymorphism, with higher function alleles and genotypes more represented in the control population. Furthermore, we identified three haplotypes more frequent in subjects with AUD (p < 0.0001) and one more frequent in the control population (p < 0.0001). The results obtained for the tri-allelic polymorphism in alcohol dependence confirm what is already present in part of the literature. The role of haplotypes requires further studies to be clarified.

UNASSIGNED: The influence of genetic variants on the glucose-lowering effects of dapagliflozin remains unclear. This study aims to investigate the impact of polymorphisms in solute carrier family 5 member 2 (SLC5A2), uridine diphosphate glucuronosyltransferase 1A9 (UGT1A9), solute carrier family 2 member 2 (SLC2A2) and member 4 (SLC2A4) on the anti-hyperglycemic effect of dapagliflozin in patients with type-2 diabetes mellitus (T2DM).
UNASSIGNED: A total of 141 patients with T2DM were included in this prospective cohort study. Twenty-nine single nucleotide polymorphisms (SNPs) were selected and genotyped using the Sequenom MassArray platform or Sanger sequencing. Glycated hemoglobin (HbA1c) and fasting blood glucose (FBG) levels were compared before and after the treatment with dapagliflozin.
UNASSIGNED: Among the 29 SNPs selected, 27 were successfully analyzed. After three months of dapagliflozin treatment, FBG levels were significantly reduced (8.00 mmol/L (5.45-10.71) mmol/L vs 6.40 mmol/L (5.45-9.20) mmol/L, p = 0.003) in patients with T2DM. However, there was no significant change in HbA1c levels (8.10% (6.88-10.00)% vs 8.10% (6.83-10.00)%, p = 0.452). Analysis of covariance showed that patients with the minor allele homozygote or heterozygote of rs12471030 (CT/TT), rs12988520 (AC/CC) or rs2602381 (TC/CC) had higher FBG levels compared to those with the major allele homozygote (p = 0.014, p = 0.024, and p = 0.044, respectively). After adjusting for baseline FBG level, age, gender, body mass index, use of insulin and use of metformin, three SNPs-rs12471030, rs12988520 and rs2602381-were associated with the anti-hyperglycemic effect of dapagliflozin. However, using a stringent significance threshold (p < 0.002 with Bonferroni correction), none of these selected SNPs were significantly associated with FBG and HbA1c levels after dapagliflozin treatment.
UNASSIGNED: After adjusting for confounding variables, polymorphisms in SLC5A2, UGT1A9, SLC2A2 and SLC2A4 genes were not associated with the anti-hyperglycemic effect of dapagliflozin in the Chinese population.
UNASSIGNED: ChiCTR2200059645.

Schizophrenia (SZ) is a multifactorial and neurodegenerative disorder that results from the interaction between genetic and environmental factors. Notably, hundreds of single nucleotide polymorphisms (SNPs) are associated with the susceptibility to SZ. Vitamin D (VD) plays an essential role in regulating several genes important for maintaining brain function and health. To the best of the authors\' knowledge, no studies have yet been conducted on the association between the VD pathway and patients with SZ. Therefore, the present study aimed to assess the potential association between eight SNPs in genes related to the VD pathway, including CYP2R1, CYP27B1, CYP24A1 and VDR among patients with SZ. A case-control study was conducted, involving a total of 400 blood samples drawn from 200 patients and 200 healthy controls. Genomic DNA was extracted and variants were genotyped using the tetra-amplification refractory mutation system-polymerase chain reaction method. The present study revealed statistically significant differences between patients with SZ and controls regarding the genotypes and allele distributions of three SNPs [CYP2R1 (rs10741657), CYP27B1 (rs10877012) and CYP24A1 (rs6013897) (P<0.0001)]. The AA genotype of rs10741657 was identified to be associated with SZ (P<0.0001) and the frequency of the A allele was higher in patients with SZ (P<0.0001) compared with the control group. Similarly, the TT genotype of rs10877012 was revealed to be associated with SZ (P<0.0001) and the T allele was more frequent in patients with SZ (P<0.0001) than in the control group. Moreover, the AA genotype of rs6013897 was revealed to be associated with SZ (P<0.0001), although no significant difference was detected between the two groups regarding the A allele (P=0.055). VDR (rs2228570, rs1544410, rs731236 and rs7975232) and CYP27B1 (rs4646536) gene polymorphisms did not exhibit a significant association with SZ. While the studied SNPs revealed promising discriminatory capacity between patients with SZ and controls, the rs10741657 SNP exhibited the most optimal area under the curve value at 0.615. A logistic model was applied considering only the significant SNPs and VD levels, which revealed that rs6013897 (T/A) and VD may have protective effects (0.267, P<0.001; 0.888, P<0.001, respectively). Moreover, a low serum VD level was highly prevalent in patients with SZ compared with the controls. Based on this finding, an association between serum 25(OH)D and SZ could be demonstrated. The present study revealed that CYP2R1 (rs10741657), CYP27B1 (rs10877012) and CYP24A1 (rs6013897) gene SNPs may be associated with SZ susceptibility.

UNASSIGNED: Single Amino Acid Polymorphisms (SAPs) or nonsynonymous Single Nucleotide Variants (nsSNVs) are the most common genetic variations. They result from missense mutations where a single base pair substitution changes the genetic code in such a way that the triplet of bases (codon) at a given position is coding a different amino acid. Since genetic mutations sometimes cause genetic diseases, it is important to comprehend and foresee which variations are harmful and which ones are neutral (not causing changes in the phenotype). This can be posed as a classification problem.
UNASSIGNED: Computational methods using machine intelligence are gradually replacing repetitive and exceedingly overpriced mutagenic tests. By and large, uneven quality, deficiencies, and irregularities of nsSNVs datasets debase the convenience of artificial intelligence-based methods. Subsequently, strong and more exact approaches are needed to address these problems. In the present work paper, we show a consensus classifier built on the holdout sampler, which appears strong and precise and outflanks all other popular methods.
UNASSIGNED: We produced 100 holdouts to test the structures and diverse classification variables of diverse classifiers during the training phase. The finest performing holdouts were chosen to develop a consensus classifier and tested using a k-fold (1 ≤ k ≤5) cross-validation method. We also examined which protein properties have the biggest impact on the precise prediction of the effects of nsSNVs.
UNASSIGNED: Our Consensus Holdout Sampler outflanks other popular algorithms, and gives excellent results, highly accurate with low standard deviation. The advantage of our method emerges from using a tree of holdouts, where diverse LM/AI-based programs are sampled in diverse ways.

Asthma is a chronic inflammatory respiratory condition, characterized by variable airflow limitation, leading to clinical symptoms such as dyspnea and chest tightness. These symptoms result from an underlying inflammatory process. The β2 agonists are bronchodilators prescribed for the relief of the disease. Nevertheless, their efficacy exhibits substantial interindividual variability. Currently, there is widespread recognition of the association between specific genetic variants, predominantly located within the ADRB2 and ADCY9 genes and their efficacy. This association, usually represented by the presence of non-synonymous single nucleotide polymorphisms (SNPs) have a strong impact in the protein functionality. The prevalence of these mutations varies based on the ethnic composition of the population and thus understanding the profiles of variability in different populations would contribute significantly to standardizing the use of these medications. In this study, we conducted a sequence-based genotyping of the relevant SNPs within the ADRB2 and ADCY9 genes in patients undergoing treatment with bronchodilators and/or corticosteroids at two healthcare facilities in the state of Rio de Janeiro, Brazil. We investigated the presence of c.46A>G, c.79C>G, c.252G>A, and c.491C>T SNPs within the ADRB2, and c.1320018 A>G within the ADCY9. Our results were in line with existing literature data with both for individuals in Brazil and Latin American.

UNASSIGNED: Otosclerosis (OTSC) is one of the most common causes of progressive adult-onset hearing loss in the Caucasian population, with a female preponderance. The etiology of OTSC is complex and there are a number of genetic variants reported to be associated with OTSC susceptibility, but no data on the genetic background of OTSC in patients originating from the central-eastern part of Europe have been available. The purpose of our study was to investigate in Polish patients the frequency of genetic variants previously reported to be most strongly associated with OTSC.
UNASSIGNED: Genomic DNA was isolated from blood samples or buccal swabs. Variants in TGFB1 (rs1800472) and RELN (rs39335, rs39350, rs39374) were genotyped in surgically confirmed OTSC patients (n = 94) and a control group (n = 198) using custom TaqMan SNP genotyping assays and real-time PCR. Allele and genotype frequencies were compared between the groups in statistical analysis and the odds ratios with 95% confidence intervals were calculated to estimate the risk.
UNASSIGNED: For all of the tested variants the distributions of alleles and genotypes were not statistically significantly different between OTCS patients and the control group. There were also no statistically significant differences in relation to gender of the tested subjects.
UNASSIGNED: Despite multiple confirmatory studies on TGFB1 and RELN association with OTSC development in some populations, no significant association between the studied variants and OTSC was found in Polish patients. Our results indicate the presence of inter-population differences in OTSC susceptibility factors and confirm the large genetic heterogeneity of this disorder.

BACKGROUND: The cancer burden is rising every year. Lung cancer is one of the most common cancers and non-small cell lung cancer is the most common type. Chemotherapy based on platinum drugs and third-generation nucleoside anti-metabolites such as gemcitabine are used widely. Gemcitabine has a complex metabolic pathway, with many mechanisms contributing to its cytotoxicity. Derangements in the metabolic pathway genes contribute to drug resistance and toxicity with this drug. Association studies including these genetic polymorphisms in the metabolic pathway, clinical outcomes, and cancer risk reported inter-individual differences. Thus, the aim of this study was to ascertain the role of these genetic variants in South Indian cancer patients treated with gemcitabine-based therapy.
METHODS: The study was done with 184 healthy volunteers for frequency establishment and 123 cancer patients were treated with gemcitabine-based chemotherapy for response and toxicity assessment. The participants were aged 18-65 years and resided in the southern states of India. DNA extraction was done from the leukocyte fraction of the blood by phenol-chloroform extraction procedures and genotyping was done by reverse transcription-polymerase chain reaction (RT-PCR) techniques to identify DNA repair gene polymorphisms. Tumor response was determined using Response evaluation criteria in solid tumors (RECIST) guidelines and toxicity using Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. The patients were followed up for survival analysis.
RESULTS: The minor allele frequency of the single nucleotide polymorphism (SNP) NRF2-617 C>A (rs6721961) in the healthy population was 12.8%. SNPs were in Hardy-Weinberg equilibrium (p>0.05). Gender-based differences were not observed with the studied SNP in the healthy population and the lung cancer patients. These frequencies of NRF2 were found to be similar when compared to EUR (European) and all the South Asian subpopulations. They are significantly divergent compared to AFR (African), AMR (American), and EAS (East Asian) populations. The minor allele frequency in cancer patients was found to be 14.2% and the lung cancer risk with the SNP studied could not be detected. There was no association found with the response, toxicity, and survival among lung cancer patients.
CONCLUSIONS: NRF2, being a multifaced molecule, did not show a significant association with lung cancer risk, response, and toxicity in patients with gemcitabine-based chemotherapy.

The major histocompatibility (MHC) locus, also known as the Human Leukocyte Antigen (HLA) genes, is located on the short arm of chromosome 6, and contains three regions (Class I, Class II and Class III). This 5 Mbp locus is one of the most variable regions of the human genome, yet it also encodes a set of highly conserved and important proteins related to immunological response. Genetic variations in this region are responsible for more diseases than in the entire rest of the human genome. However, information on local structural features of the DNA is largely ignored. With recent advances in long-read sequencing technology, it is now becoming possible to sequence the entire 5 Mbp MHC locus, producing complete diploid haplotypes of the whole region. Here, we describe structural maps based on the complete sequences from six different homozygous HLA cell lines. We find long-range structural variability in the different sequences for DNA stacking energy, position preference and curvature, variation in repeats, as well as more local changes in regions forming open chromatin structures, likely to influence gene expression levels. These structural maps can be useful in visualizing large scale structural variation across HLA types, in particular when this can be complemented with epigenetic signals.

UNASSIGNED: Nucleotide excision repair (NER) plays a vital role in maintaining genome stability, and the effect of NER gene polymorphisms on hepatoblastoma susceptibility is still under investigation. This study aimed to evaluate the relationship between NER gene polymorphisms and the risk of hepatoblastoma in Eastern Chinese Han children.
UNASSIGNED: In this five-center case-control study, we enrolled 966 subjects from East China (193 hepatoblastoma patients and 773 healthy controls). The TaqMan method was used to genotype 19 single nucleotide polymorphisms (SNPs) in NER pathway genes, including ERCC1, XPA, XPC, XPD, XPF, and XPG. Then, multivariate logistic regression analysis was performed, and odds ratios (ORs) and 95% confidence intervals (95% CIs) were utilized to assess the strength of associations.
UNASSIGNED: Three SNPs were related to hepatoblastoma risk. XPC rs2229090 and XPD rs3810366 significantly contributed to hepatoblastoma risk according to the dominant model (adjusted OR=1.49, 95% CI=1.07-2.08, P=0.019; adjusted OR=1.66, 95% CI=1.12-2.45, P=0.012, respectively). However, XPD rs238406 conferred a significantly decreased risk of hepatoblastoma under the dominant model (adjusted OR=0.68, 95% CI=0.49-0.95; P=0.024). Stratified analysis demonstrated that these significant associations were more prominent in certain subgroups. Moreover, there was evidence of functional implications of these significant SNPs suggested by online expression quantitative trait loci (eQTLs) and splicing quantitative trait loci (sQTLs) analysis.
UNASSIGNED: In summary, NER pathway gene polymorphisms (XPC rs2229090, XPD rs3810366, and XPD rs238406) are significantly associated with hepatoblastoma risk, and further research is required to verify these findings.