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Background: Human leukocyte antigen-G (HLA-G) is a pivotal protein involved in immune regulation and tolerance, while systemic lupus erythematosus (SLE) is a multifaceted autoimmune condition influenced by genetic and environmental factors. Research indicates that variations and mutations in HLA-G may impact SLE development. Objective: This study aimed to explore the relationship between polymorphisms in the 3'-untranslated region (UTR) of the HLA-G gene and SLE. Methods: DNA from 100 SLE patients and 100 controls was analyzed using polymerase chain reaction to amplify the target sequence. Allele and genotype frequencies were determined, and haplotypes were assessed using Haploview v.4.2 software, with linkage disequilibrium calculated. Results: Findings revealed that the +2960 Ins allele was significantly linked to SLE as a risk factor, with the Del allele showing a protective effect. In addition, the +3010C allele and +3187A allele were significantly associated with SLE at both allele and genotype levels. The +3142 GG homozygote was notably linked to SLE at the genotype level. Haplotype analysis identified UTR-2 haplotypes as risk factors for SLE, whereas the UTR-1 haplotype was protective, shedding light on genetic factors influencing SLE risk. Conclusion: This study underscores the importance of HLA-G gene 3'-UTR polymorphisms in SLE susceptibility, suggesting their potential as diagnostic or therapeutic targets.
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Regiones no Traducidas 3' , Alelos , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Antígenos HLA-G , Haplotipos , Desequilibrio de Ligamiento , Lupus Eritematoso Sistémico , Polimorfismo de Nucleótido Simple , Humanos , Lupus Eritematoso Sistémico/genética , Antígenos HLA-G/genética , Haplotipos/genética , Regiones no Traducidas 3'/genética , Femenino , Masculino , Adulto , Frecuencia de los Genes/genética , Estudios de Casos y Controles , Polimorfismo de Nucleótido Simple/genética , Persona de Mediana Edad , Genotipo , Estudios de Asociación Genética , Factores de RiesgoRESUMEN
BACKGROUND: Bovine leukocyte adhesion deficiency (BLAD), bovine citrullinemia (BC), and deficiency of Uridine monophosphate synthetase (DUMPS) are the common autosomal recessive disorders affecting the global dairy industry. BLAD leads to poor wound healing and recurrent infections. In BC, ammonia builds up leading to neurological disorders and death. DUMPS results in developmental abnormalities. METHODOLOGY: In this study, tetra-primer amplification refractory mutation system polymerase chain reaction (ARMS PCR) based diagnostic tests were optimized for BLAD, BC, and DUMPS. A total of 250 animals (58 indigenous and 192 Holstein Friesian (HF)) were screened from all across Pakistan. In addition to validation of ARMS-PCR results through Sanger sequencing, the protein modeling provided structural insights of the disease-associated reported SNPs. Pathway analysis illustrated gene functions under normal and mutated conditions. Furthermore, haplotype and phylogenetic analysis of ASS1 (Argininosuccinate synthetase) gene were performed on study samples and NCBI retrieved sequences. RESULTS: The study's focus was to screen the herds for prevalence of carriers of genetic disorders, as they are the main source of disease dissemination. One animal was found carrier for BC, whereas no carriers were found for BLAD and DUMPS. The protein models corroborated the reported amino acid change in BLAD, and protein truncation in both BC and DUMPS proteins. SNPs found in NCBI retrieved sequences were either silent or missense and had no effect on protein structure. DNA network presented graphical illustration of haplotype interactions and phylogenetic analysis conferred evolutionary landscape of ASS1 gene. The combination of these approaches produced an in-depth genetic picture of BC in Pakistani cattle. CONCLUSION: The development of diagnostic tests and identification of the heterozygous BC sample underscores the significance of constant monitoring to avoid the unwanted dissemination of mutant alleles among Pakistani cattle, thereby promoting the general well-being and sustainability of the dairy sector.
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Enfermedades de los Bovinos , Polimorfismo de Nucleótido Simple , Animales , Bovinos , Pakistán , Enfermedades de los Bovinos/genética , Enfermedades de los Bovinos/diagnóstico , Polimorfismo de Nucleótido Simple/genética , Síndrome de Deficiencia de Adhesión del Leucocito/genética , Síndrome de Deficiencia de Adhesión del Leucocito/diagnóstico , Síndrome de Deficiencia de Adhesión del Leucocito/veterinaria , Filogenia , Reacción en Cadena de la Polimerasa/métodos , Haplotipos/genética , Argininosuccinato Sintasa/genética , Argininosuccinato Sintasa/metabolismo , Variación Genética/genética , Mutación/genéticaRESUMEN
BACKGROUND: Polygenic risk scores (PRS) derived from European individuals have reduced portability across global populations, limiting their clinical implementation at worldwide scale. Here, we investigate the performance of a wide range of PRS models across four ancestry groups (Africans, Europeans, East Asians, and South Asians) for 14 conditions of high-medical interest. METHODS: To select the best-performing model per trait, we first compared PRS performances for publicly available scores, and constructed new models using different methods (LDpred2, PRS-CSx and SNPnet). We used 285 K European individuals from the UK Biobank (UKBB) for training and 18 K, including diverse ancestries, for testing. We then evaluated PRS portability for the best models in Europeans and compared their accuracies with respect to the best PRS per ancestry. Finally, we validated the selected PRS models using an independent set of 8,417 individuals from Biobank of the Americas-Genomelink (BbofA-GL); and performed a PRS-Phewas. RESULTS: We confirmed a decay in PRS performances relative to Europeans when the evaluation was conducted using the best-PRS model for Europeans (51.3% for South Asians, 46.6% for East Asians and 39.4% for Africans). We observed an improvement in the PRS performances when specifically selecting ancestry specific PRS models (phenotype variance increase: 1.62 for Africans, 1.40 for South Asians and 0.96 for East Asians). Additionally, when we selected the optimal model conditional on ancestry for CAD, HDL-C and LDL-C, hypertension, hypothyroidism and T2D, PRS performance for studied populations was more comparable to what was observed in Europeans. Finally, we were able to independently validate tested models for Europeans, and conducted a PRS-Phewas, identifying cross-trait interplay between cardiometabolic conditions, and between immune-mediated components. CONCLUSION: Our work comprehensively evaluated PRS accuracy across a wide range of phenotypes, reducing the uncertainty with respect to which PRS model to choose and in which ancestry group. This evaluation has let us identify specific conditions where implementing risk-prioritization strategies could have practical utility across diverse ancestral groups, contributing to democratizing the implementation of PRS.
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Predisposición Genética a la Enfermedad , Herencia Multifactorial , Humanos , Herencia Multifactorial/genética , Población Blanca/genética , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo , Pueblo Asiatico/genética , Femenino , Modelos Genéticos , Puntuación de Riesgo GenéticoRESUMEN
Psoriasis is a chronic, immune-mediated inflammatory skin disease associated with a polygenic mode of inheritance. There are few studies that explore the association of a psoriasis Polygenic Risk Score (PRS) with patient clinical characteristics, and to our knowledge there are no studies examining psoriasis PRS associations across different ethnicities. In this study, we used a multi-racial psoriasis cohort to investigate PRS associations with clinical phenotypes including age of onset, psoriatic arthritis, other comorbidities, psoriasis body location, psoriasis subtype, environmental triggers, and response to therapies. We collected patient data and Affymetrix genome-wide SNP data from a cohort of 607 psoriasis patients and calculated an 88-loci PRS (PRS-ALL), also partitioned between genetic loci within the HLA region (PRS-HLA; 11 SNPS) and loci outside the HLA region (PRS-NoHLA; 77 SNPS). We used t-test and logistic regression to analyze the association of PRS with clinical phenotypes. We found that PRS-HLA and PRS-noHLA had differing effects on psoriasis age of onset, psoriatic arthritis, psoriasis located on the ears, genitals, nails, soles of feet, skin folds, and palms, skin injury as an environmental trigger, cardiovascular comorbidities, and response to phototherapy. In some cases these PRS associations were ethnicity specific. Overall, these results show that the genetic basis for clinical manifestations of psoriasis are driven by distinct HLA and non-HLA effects, and that these PRS associations can be dependent on ethnicity.
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Etnicidad , Predisposición Genética a la Enfermedad , Herencia Multifactorial , Fenotipo , Psoriasis , Humanos , Psoriasis/genética , Herencia Multifactorial/genética , Estudios de Cohortes , Masculino , Femenino , Factores de Riesgo , Etnicidad/genética , Polimorfismo de Nucleótido Simple/genética , Persona de Mediana Edad , Adulto , Puntuación de Riesgo GenéticoRESUMEN
Aspen (Populus tremula L.) is a keystone species and a model system for forest tree genomics. We present an updated resource comprising a chromosome-scale assembly, population genetics and genomics data. Using the resource, we explore the genetic basis of natural variation in leaf size and shape, traits with complex genetic architecture. We generated the genome assembly using long-read sequencing, optical and high-density genetic maps. We conducted whole-genome resequencing of the Umeå Aspen (UmAsp) collection. Using the assembly and re-sequencing data from the UmAsp, Swedish Aspen (SwAsp) and Scottish Aspen (ScotAsp) collections we performed genome-wide association analyses (GWAS) using Single Nucleotide Polymorphisms (SNPs) for 26 leaf physiognomy phenotypes. We conducted Assay of Transposase Accessible Chromatin sequencing (ATAC-Seq), identified genomic regions of accessible chromatin, and subset SNPs to these regions, improving the GWAS detection rate. We identified candidate long non-coding RNAs in leaf samples, quantified their expression in an updated co-expression network, and used this to explore the functions of candidate genes identified from the GWAS. A GWAS found SNP associations for seven traits. The associated SNPs were in or near genes annotated with developmental functions, which represent candidates for further study. Of particular interest was a ~177-kbp region harbouring associations with several leaf phenotypes in ScotAsp. We have incorporated the assembly, population genetics, genomics, and GWAS data into the PlantGenIE.org web resource, including updating existing genomics data to the new genome version, to enable easy exploration and visualisation. We provide all raw and processed data to facilitate reuse in future studies.
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Genética de Población , Genoma de Planta , Estudio de Asociación del Genoma Completo , Polimorfismo de Nucleótido Simple , Populus , Populus/genética , Genoma de Planta/genética , Polimorfismo de Nucleótido Simple/genética , Cromosomas de las Plantas/genética , Fenotipo , Hojas de la Planta/genética , Genómica/métodos , Mapeo CromosómicoRESUMEN
BACKGROUND: Our previous genomewide association studies (GWAS) have suggested rs912304 in 14q12 as a suggestive risk variant for type 1 diabetes (T1D). However, the association between this risk region and T1D subgroups and related clinical risk features, the underlying causal functional variant(s), putative candidate gene(s), and related mechanisms are yet to be elucidated. METHODS: We assessed the association between variant rs912304 and T1D, as well as islet autoimmunity and islet function, stratified by the diagnosed age of 12. We used epigenome bioinformatics analyses, dual luciferase reporter assays, and expression quantitative trait loci (eQTL) analyses to prioritize the most likely functional variant and potential causal gene. We also performed functional experiments to evaluate the role of the causal gene on islet function and its related mechanisms. RESULTS: We identified rs912304 as a risk variant for T1D subgroups with diagnosed age ≥ 12 but not < 12. This variant is associated with residual islet function but not islet-specific autoantibody positivity in T1D individuals. Bioinformatics analysis indicated that rs912304 is a functional variant exhibiting spatial overlaps with enhancer active histone marks (H3K27ac and H3K4me1) and open chromatin status (ATAC-seq) in the human pancreas and islet tissues. Luciferase reporter gene assays and eQTL analyses demonstrated that the biallelic sites of rs912304 had differential allele-specific enhancer activity in beta cell lines and regulated STXBP6 expression, which was defined as the most putative causal gene based on Open Targets Genetics, GTEx v8 and Tiger database. Moreover, Stxbp6 was upregulated by T1D-related proinflammatory cytokines but not high glucose/fat. Notably, Stxbp6 over-expressed INS-1E cells exhibited decreasing insulin secretion and increasing cell apoptosis through Glut1 and Gadd45ß, respectively. CONCLUSIONS: This study expanded the genomic landscape regarding late-onset T1D risk and supported islet function mechanistically connected to T1D pathogenesis.
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Diabetes Mellitus Tipo 1 , Islotes Pancreáticos , Humanos , Diabetes Mellitus Tipo 1/genética , Islotes Pancreáticos/metabolismo , Femenino , Masculino , Polimorfismo de Nucleótido Simple/genética , Predisposición Genética a la Enfermedad , Citocinas/genética , Citocinas/metabolismo , Niño , Adolescente , Sitios de Carácter Cuantitativo , Animales , Edad de Inicio , Regulación de la Expresión Génica , Estudio de Asociación del Genoma CompletoRESUMEN
Background: Bridging integrator 1 (BIN1) gene polymorphism has been reported to play a role in the pathological processes of Alzheimer's disease (AD). Objective: To explore the association of BIN1 loci with neuroinflammation and AD pathology. Methods: Alzheimer's Disease Neuroimaging Initiative (ADNI, Nâ=â495) was the discovery cohort, and Chinese Alzheimer's Biomarker and LifestylE (CABLE, Nâ=â619) study was used to replicate the results. Two BIN1 gene polymorphism (rs7561528 and rs744373) were included in the analysis. Multiple linear regression model and causal mediation analysis conducted through 10,000 bootstrapped iterations were used to examine the BIN1 loci relationship with cerebrospinal fluid (CSF) AD biomarkers and alternative biomarker of microglial activation microglia-soluble triggering receptor expressed on myeloid cells 2 (sTREM2). Results: In ADNI database, we found a significant association between BIN1 loci (rs7561528 and rs744373) and levels of CSF phosphorylated-tau (P-tau) (pcâ=â0.017; 0.010, respectively) and total-tau (T-tau) (pcâ=â0.011; 0.013, respectively). The BIN1 loci were also correlated with CSF sTREM2 levels (pcâ=â0.010; 0.008, respectively). Mediation analysis demonstrated that CSF sTREM2 partially mediated the association of BIN1 loci with P-tau (Proportion of rs7561528â:â20.8%; Proportion of rs744373â:â24.8%) and T-tau (Proportion of rs7561528â:â36.5%; Proportion of rs744373â:â43.9%). The analysis in CABLE study replicated the mediation role of rs7561528. Conclusions: This study demonstrated the correlation between BIN1 loci and CSF AD biomarkers as well as microglia biomarkers. Additionally, the link between BIN1 loci and tau pathology was partially mediated by CSF sTREM2.
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Proteínas Adaptadoras Transductoras de Señales , Enfermedad de Alzheimer , Biomarcadores , Glicoproteínas de Membrana , Receptores Inmunológicos , Proteínas Supresoras de Tumor , Proteínas tau , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/patología , Proteínas tau/líquido cefalorraquídeo , Proteínas tau/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Femenino , Proteínas Supresoras de Tumor/genética , Masculino , Anciano , Receptores Inmunológicos/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Polimorfismo de Nucleótido Simple/genética , Anciano de 80 o más Años , Proteínas NuclearesRESUMEN
This study aims to assess the effect of familial structures on the still-missing heritability estimate and prediction accuracy of Type 2 Diabetes (T2D) using pedigree estimated risk values (ERV) and genomic ERV. We used 11,818 individuals (T2D cases: 2,210) with genotype (649,932 SNPs) and pedigree information from the ongoing periodic cohort study of the Iranian population project. We considered three different familial structure scenarios, including (i) all families, (ii) all families with ≥ 1 generation, and (iii) families with ≥ 1 generation in which both case and control individuals are presented. Comprehensive simulation strategies were implemented to quantify the difference between estimates of [Formula: see text] and [Formula: see text]. A proportion of still-missing heritability in T2D could be explained by overestimation of pedigree-based heritability due to the presence of families with individuals having only one of the two disease statuses. Our research findings underscore the significance of including families with only case/control individuals in cohort studies. The presence of such family structures (as observed in scenarios i and ii) contributes to a more accurate estimation of disease heritability, addressing the underestimation that was previously overlooked in prior research. However, when predicting disease risk, the absence of these families (as seen in scenario iii) can yield the highest prediction accuracy and the strongest correlation with Polygenic Risk Scores. Our findings represent the first evidence of the important contribution of familial structure for heritability estimations and genomic prediction studies in T2D.
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Diabetes Mellitus Tipo 2 , Predisposición Genética a la Enfermedad , Linaje , Polimorfismo de Nucleótido Simple , Humanos , Diabetes Mellitus Tipo 2/genética , Femenino , Polimorfismo de Nucleótido Simple/genética , Masculino , Genómica/métodos , Irán , Modelos Genéticos , Estudios de Cohortes , Estudio de Asociación del Genoma Completo , Genotipo , Estudios de Casos y Controles , Persona de Mediana Edad , Familia , Estructura FamiliarRESUMEN
Single nucleotide variants (SNVs) can exert substantial and extremely variable impacts on various cellular functions, making accurate predictions of their consequences challenging, albeit crucial especially in clinical settings such as in oncology. Laboratory-based experimental methods for assessing these effects are time-consuming and often impractical, highlighting the importance of in-silico tools for variant impact prediction. However, the performance metrics of currently available tools on breast cancer missense variants from benchmarking databases have not been thoroughly investigated, creating a knowledge gap in the accurate prediction of pathogenicity. In this study, the benchmarking datasets ClinVar and HGMD were used to evaluate 21 Artificial Intelligence (AI)-derived in-silico tools. Missense variants in breast cancer genes were extracted from ClinVar and HGMD professional v2023.1. The HGMD dataset focused on pathogenic variants only, to ensure balance, benign variants for the same genes were included from the ClinVar database. Interestingly, our analysis of both datasets revealed variants across genes with varying penetrance levels like low and moderate in addition to high, reinforcing the value of disease-specific tools. The top-performing tools on ClinVar dataset identified were MutPred (Accuracy = 0.73), Meta-RNN (Accuracy = 0.72), ClinPred (Accuracy = 0.71), Meta-SVM, REVEL, and Fathmm-XF (Accuracy = 0.70). While on HGMD dataset they were ClinPred (Accuracy = 0.72), MetaRNN (Accuracy = 0.71), CADD (Accuracy = 0.69), Fathmm-MKL (Accuracy = 0.68), and Fathmm-XF (Accuracy = 0.67). These findings offer clinicians and researchers valuable insights for selecting, improving, and developing effective in-silico tools for breast cancer pathogenicity prediction. Bridging this knowledge gap contributes to advancing precision medicine and enhancing diagnostic and therapeutic approaches for breast cancer patients with potential implications for other conditions.
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Inteligencia Artificial , Neoplasias de la Mama , Bases de Datos Genéticas , Mutación Missense , Polimorfismo de Nucleótido Simple , Humanos , Neoplasias de la Mama/genética , Mutación Missense/genética , Femenino , Polimorfismo de Nucleótido Simple/genética , Biología Computacional/métodos , Predisposición Genética a la Enfermedad , Programas InformáticosRESUMEN
OBJECTIVE: We studied gene-environment, as well as gene-gene interaction to elucidate their effects on symptom severity and predict clinical outcomes in functional neurological disorders (FND). METHODS: Eighty-five patients with mixed FND were genotyped for ten single-nucleotide polymorphisms (SNP) from seven different stress-related genes. We tested cross-sectionally the association between genotype and the symptomatology of FND (symptom severity assessed with the examiner-based clinical global impression score [CGI] and age of onset). Clinical outcome was assessed in 52 patients who participated in a follow-up clinical visit after eight months (following their individual therapies as usual). We tested longitudinally the association between genotype and clinical outcome in FND. We examined the contribution of each SNP and their interaction between them to FND symptomatology and outcome. RESULTS: We identified a nominal association between tryptophan hydroxylase 1 (TPH1) rs1800532 and symptom severity (CGI1) in FND under a codominant model (T/T: ßT/T = 2.31, seT/T = 0.57; G/T: ßG/T = -0.18, seG/T = 0.29, P = 0.035), with minor allele (T) carriers presenting more severe symptoms. An association was identified between TPH1 and clinical outcome, suggesting that major allele (G) carriers were more likely to have an improved outcome under a codominant model (G/T: ORG/T = 0.18, CIG/T = [0.02-1.34]; T/T: ORT/T = 2.08, CIT/T = [0.30-14.53], P = 0.041). Our analyses suggested a significant gene-gene interaction for TPH2 (rs4570625) and OXTR (rs2254298) on symptom severity, and a significant gene-gene interaction for TPH1, TPH2 and BDNF (rs1491850) on clinical outcome. CONCLUSION: FND might arise from a complex interplay between individual predisposing risk genes involved in the serotonergic pathway and their gene-gene interactions.
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Enfermedades del Sistema Nervioso , Polimorfismo de Nucleótido Simple , Índice de Severidad de la Enfermedad , Triptófano Hidroxilasa , Humanos , Femenino , Masculino , Triptófano Hidroxilasa/genética , Adulto , Polimorfismo de Nucleótido Simple/genética , Persona de Mediana Edad , Enfermedades del Sistema Nervioso/genética , Interacción Gen-Ambiente , Estudios Transversales , Genotipo , AncianoRESUMEN
Garlic bulbs generally possess several swelling cloves, and the swelling degree of the bulbs determines its yield and appearance quality. However, the genetic basis underlying bulb traits remains poorly known. To address this issue, we performed a genome-wide association analysis for three bulb traits: bulb weight, diameter, and height. It resulted in the identification of 51 significant associated signals from 38 genomic regions. Twelve genes from the associated regions, whose transcript abundances in the developmental bulb showed significant correlations with the investigated traits in 81 garlic accessions, were considered the candidates of the corresponding locus. We focused on five of these candidates and their variations and revealed that the promoter variations of fructose-bisphosphate aldolase-encoding Asa8G05696.1 and beta-fructofuranosidase-encoding Asa6G01167.1 are responsible for the functional diversity of these two genes in garlic population. Interestingly, our results revealed that all candidates we focused on experienced a degree of selection during garlic evolutionary history, and different genotypes of them were retained in two China-cultivated garlic groups. Taken together, these results suggest a potential involvement of those candidates in the parallel evolution of garlic bulb organs in two China-cultivated garlic groups. This study provides important insights into the genetic basis of garlic bulb traits and their evolution.
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Ajo , Estudio de Asociación del Genoma Completo , Ajo/genética , Ajo/crecimiento & desarrollo , Raíces de Plantas/genética , Raíces de Plantas/crecimiento & desarrollo , Fenotipo , Genotipo , Polimorfismo de Nucleótido Simple/genética , Genoma de Planta/genéticaRESUMEN
INTRODUCTION: Personality disorders (PD) are characterized by socially dysfunctional behavioral patterns that affect patients and show higher incidence rates within families. Substance abuse disorders (SAD) are exemplified by extensive and prolonged use of substances, including alcohol, nicotine, or illegal drugs. Genetic predisposition for both PD and SAD has been reported to involve gene variants regulating dopaminergic pathways. Yet, discrepancy among reported results necessitates further elucidation of potential hereditary-related risk factors. Because both disorders impose a societal burden, knowledge on the impact of certain genetic backgrounds on these diseases could help develop evidence-based strategies for efficacious treatment approaches. MATERIALS AND METHODS: In the present study a systematic review was performed, and the association between dopamine transporter gene polymorphism (SLC6A3), particularly rs28363170 entailing a 40-bp variable number tandem repeat, and PD as well as SAD was investigated recruiting meta-analysis approach. RESULTS: Initial literature search for PD yielded 1577, from which nine fulfilled eligibility criteria to be used in a meta-analysis including 729 cases and 2113 controls. From the 934 studies retrieved for SAD, only 29 articles with 5221 cases and 4822 controls were used for meta-analysis. A statistically significant association was seen between rs28363170 (for the 9-repeat allele) and PD in European populations according to the co-dominant mode of inheritance. For SAD no statistically significant correlation under any mode of inheritance was observed. There was no indication of time-trend phenomena. CONCLUSION: Our findings demonstrate the association of SLC6A3 gene polymorphism with PD, thus underling the need to understand neurobiological mechanisms inherent to the above disorders to guide treatment strategies under the perspective of personalized medicine.
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Proteínas de Transporte de Dopamina a través de la Membrana Plasmática , Predisposición Genética a la Enfermedad , Trastornos de la Personalidad , Trastornos Relacionados con Sustancias , Humanos , Proteínas de Transporte de Dopamina a través de la Membrana Plasmática/genética , Trastornos Relacionados con Sustancias/genética , Trastornos de la Personalidad/genética , Polimorfismo de Nucleótido Simple/genética , Estudios de Asociación Genética/métodosRESUMEN
A reply to the correspondence by Deora et al.- Critical insights on "Association of the C allele of rs479200 in the EGLN1 gene with COVID19 severity in Indian population: a novel finding". The reply contains point-wise rebuttal to the concerns, particularly addressing the epidemiological, statistical, and mathematical issues raised by Deora et al.
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Alelos , COVID-19 , Prolina Dioxigenasas del Factor Inducible por Hipoxia , SARS-CoV-2 , Humanos , COVID-19/genética , COVID-19/epidemiología , COVID-19/virología , India/epidemiología , SARS-CoV-2/genética , SARS-CoV-2/patogenicidad , Prolina Dioxigenasas del Factor Inducible por Hipoxia/genética , Polimorfismo de Nucleótido Simple/genética , Índice de Severidad de la Enfermedad , Predisposición Genética a la EnfermedadRESUMEN
This study offers insights into the genetic and biological connections between nine common metabolic diseases using data from genome-wide association studies. Our goal is to unravel the genetic interactions and biological pathways of these complex diseases, enhancing our understanding of their genetic architecture. We employed a range of advanced analytical techniques to explore the genetic correlations and shared genetic variants of these diseases. These methods include Linked Disequilibrium Score Regression, High-Definition Likelihood (HDL), genetic analysis combining multiplicity and annotation (GPA), two-sample Mendelian randomization analyses, analysis under the multiplicity-complex null hypothesis (PLACO), and Functional mapping and annotation of genetic associations (FUMA). Additionally, Bayesian co-localization analyses were used to examine associations of specific loci across traits. Our study discovered significant genomic correlations and shared loci, indicating complex genetic interactions among these metabolic diseases. We found several shared single nucleotide variants and risk loci, notably highlighting the role of the immune system and endocrine pathways in these diseases. Particularly, rs2476601 and its associated gene PTPN22 appear to play a crucial role in the connection between type 2 diabetes mellitus, hypothyroidism/mucous oedema and hypoglycaemia. These findings enhance our understanding of the genetic underpinnings of these diseases and open new potential avenues for targeted therapeutic and preventive strategies. The results underscore the importance of considering pleiotropic effects in deciphering the genetic architecture of complex diseases, especially metabolic ones.
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Pleiotropía Genética , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Desequilibrio de Ligamiento , Enfermedades Metabólicas , Polimorfismo de Nucleótido Simple , Humanos , Enfermedades Metabólicas/genética , Polimorfismo de Nucleótido Simple/genética , Desequilibrio de Ligamiento/genética , Teorema de Bayes , Análisis de la Aleatorización Mendeliana , Diabetes Mellitus Tipo 2/genética , Epistasis GenéticaRESUMEN
BACKGROUND: In light of several epidemiological studies, the etiology of recurrent pregnancy loss is complex. One of the most frequent causes of women experiencing inexplicable recurrent pregnancy loss is maternal thrombophilia. Hence, the association between genetic polymorphisms causing thrombophilia and recurrent pregnancy loss needs to be explored. AIM: Is to study the relation of polymorphisms affecting folate pathway mainly, 5-Methytetrahydrofolate-Homocysteine Methyltransferase (MTR A2756G) and 5-Methytetrahydrofolate-Homocysteine MethyltransferaseReductase (MTRR A66G) with recurrent pregnancy loss. METHODS: It is a case-control study. Four hundred participants were enrolled. Two hundred participants with unexplained recurrent pregnancy loss (case group) and two hundred healthy fertile participants (control group). All participants were screened for (MTR A2756G) and (MTRR A66G). DNA was extracted using salting out method followed by genotyping via Real-time PCR. RESULTS: Mutant homozygous genotype (GG) in MTRR A66G was statistically significantly among RPL group in comparison to controls. (GG vs. AA) had odds ratio and confidence interval of 1.22(1.12-2.23), P = 0.012. (GG) increased the liability 1.2 folds for recurrent pregnancy loss. Mutant homozygous genotype (GG) in MTR A2756G was not correlated with the risk of recurrent pregnancy loss. (GG vs.AA) = (1.13(0.56-2.29)), P = 0.7 CONCLUSION: MTRR A66G increases susceptibly for recurrent pregnancy loss among Egyptian women.
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5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa , Aborto Habitual , Ferredoxina-NADP Reductasa , Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Humanos , Femenino , Aborto Habitual/genética , Estudios de Casos y Controles , Ferredoxina-NADP Reductasa/genética , Adulto , Embarazo , 5-Metiltetrahidrofolato-Homocisteína S-Metiltransferasa/genética , Polimorfismo de Nucleótido Simple/genética , Genotipo , Frecuencia de los Genes/genética , Estudios de Asociación Genética , Alelos , Oportunidad RelativaRESUMEN
Background: Next-generation sequencing of Mycobacterium tuberculosis, the infectious agent causing tuberculosis, is improving the understanding of genomic diversity of circulating lineages and strain-types, and informing knowledge of drug resistance mutations. An increasingly popular approach to characterizing M. tuberculosis genomes (size: 4.4 Mbp) and variants (e.g., single nucleotide polymorphisms (SNPs)) involves the de novo assembly of sequence data. Methods: We compared the performance of genome assembly tools (Unicycler, RagOut, and RagTag) on sequence data from nine drug resistant M. tuberculosis isolates (multi-drug (MDR) n = 1; pre-extensively-drug (pre-XDR) n = 8) generated using Illumina HiSeq, Oxford Nanopore Technology (ONT) PromethION, and PacBio platforms. Results: Our investigation found that Unicycler-based assemblies had significantly higher genome completeness (~98.7%; p values = 0.01) compared to other assembler tools (RagOut = 98.6%, and RagTag = 98.6%). The genome assembly sizes (bp) across isolates and sequencers based on RagOut was significantly longer (p values < 0.001) (4,418,574 ± 8,824 bp) than Unicycler and RagTag assemblies (Unicycler = 4,377,642 ± 55,257 bp, and RagTag = 4,380,711 ± 51,164 bp). RagOut-based assemblies had the fewest contigs (~32) and the longest genome size (4,418,574 bp; vs. H37Rv reference size 4,411,532 bp) and therefore were chosen for downstream analysis. Pan-genome analysis of Illumina and PacBio hybrid assemblies revealed the greatest number of detected genes (4,639 genes; H37Rv reference contains 3,976 genes), while Illumina and ONT hybrid assemblies produced the highest number of SNPs. The number of genes from hybrid assemblies with ONT and PacBio long-reads (mean: 4,620 genes) was greater than short-read assembly alone (4,478 genes). All nine RagOut hybrid genome assemblies detected known mutations in genes associated with MDR-TB and pre-XDR-TB. Conclusions: Unicycler software performed the best in terms of achieving contiguous genomes, whereas RagOut improved the quality of Unicycler's genome assemblies by providing a longer genome size. Overall, our approach has demonstrated that short-read and long-read hybrid assembly can provide a more complete genome assembly than short-read assembly alone by detecting pan-genomes and more genes, including IS6110, and SNPs.
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Genoma Bacteriano , Secuenciación de Nucleótidos de Alto Rendimiento , Mycobacterium tuberculosis , Mycobacterium tuberculosis/genética , Genoma Bacteriano/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Polimorfismo de Nucleótido Simple/genética , Análisis de Secuencia de ADN/métodosRESUMEN
Objective: Mediator complex subunit 12 (MED12) is among the most frequently mutated genes in various types of human cancers. However, there is still a lack of understanding regarding the role of MED12 in breast cancer patient. Therefore, the aim of this study is to explore the roles of MED12 in breast cancer. Materials and Methods: We utilized the UALCAN platform (http://ualcan.path.uab.edu/) for analyzing the transcriptional expression, protein expression, and protein phosphorylation data of MED12. Our study involved 35 breast cancer patients. From these samples, we extracted proteins and RNA. To obtain the sequence of MED12 3'-UTR, we performed reverse transcription-polymerase chain reaction and sequencing. We then used TargetScan to predict the miRNA targets of MED12 3'-UTR and confirmed the interactions between miRNAs and MED12 3'-UTR through dual luciferase assay. Results: The protein level of MED12 was upregulated in breast cancer, while the mRNA level did not show significant changes. Interestingly, higher levels of MED12 mRNA were associated with better prognosis, whereas patients with increased MED12 protein levels tended to have a poorer prognosis. Furthermore, through our analysis of the MED12 3'-UTR sequence, we identified a specific C->T variation that was unique to breast tumors. We also identified four miRNAs (miR-204, -211, -450 b, and -518a) that directly target MED12 3'-UTR. Most important, this C->T variation disrupts the interaction between MED12 3'-UTR and miR-450b, ultimately leading to the upregulation of MED12 in breast cancer. Conclusion: Our study revealed a significant finding regarding a mutation site in the MED12 3'-UTR that contributes to the upregulation of MED12 in breast cancer. This mutation disrupts the interactions between specific miRNAs and MED12 mRNA, leading to increased expression of MED12. These findings have important implications for breast cancer diagnosis, as this mutation site can serve as a potent biomarker.
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Regiones no Traducidas 3' , Neoplasias de la Mama , Regulación Neoplásica de la Expresión Génica , Complejo Mediador , MicroARNs , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Femenino , Complejo Mediador/genética , Complejo Mediador/metabolismo , Pronóstico , Regiones no Traducidas 3'/genética , MicroARNs/genética , MicroARNs/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Persona de Mediana Edad , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Adulto , Línea Celular Tumoral , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
BACKGROUND: Variant interpretation is essential for identifying patients' disease-causing genetic variants amongst the millions detected in their genomes. Hundreds of Variant Impact Predictors (VIPs), also known as Variant Effect Predictors (VEPs), have been developed for this purpose, with a variety of methodologies and goals. To facilitate the exploration of available VIP options, we have created the Variant Impact Predictor database (VIPdb). RESULTS: The Variant Impact Predictor database (VIPdb) version 2 presents a collection of VIPs developed over the past three decades, summarizing their characteristics, ClinGen calibrated scores, CAGI assessment results, publication details, access information, and citation patterns. We previously summarized 217 VIPs and their features in VIPdb in 2019. Building upon this foundation, we identified and categorized an additional 190 VIPs, resulting in a total of 407 VIPs in VIPdb version 2. The majority of the VIPs have the capacity to predict the impacts of single nucleotide variants and nonsynonymous variants. More VIPs tailored to predict the impacts of insertions and deletions have been developed since the 2010s. In contrast, relatively few VIPs are dedicated to the prediction of splicing, structural, synonymous, and regulatory variants. The increasing rate of citations to VIPs reflects the ongoing growth in their use, and the evolving trends in citations reveal development in the field and individual methods. CONCLUSIONS: VIPdb version 2 summarizes 407 VIPs and their features, potentially facilitating VIP exploration for various variant interpretation applications. VIPdb is available at https://genomeinterpretation.org/vipdb.
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Bases de Datos Genéticas , Variación Genética , Humanos , Bases de Datos Genéticas/tendencias , Variación Genética/genética , Genoma Humano/genética , Programas Informáticos , Biología Computacional/métodos , Genómica/métodos , Polimorfismo de Nucleótido Simple/genéticaRESUMEN
Allergic respiratory diseases such as asthma might be considered multifactorial diseases, having a complex pathogenesis that involves environmental factors and the activation of a large set of immune response pathways and mechanisms. In addition, variations in genetic background seem to play a central role. The method developed for the analysis of the complexities, as association rule mining, nowadays may be applied to different research areas including genetic and biological complexities such as atopic airway diseases to identify complex genetic or biological markers and enlighten new diagnostic and therapeutic targets. A total of 308 allergic patients and 205 controls were typed for 13 single nucleotide polymorphisms (SNPs) of cytokine and receptors genes involved in type 1 and type 2 inflammatory response (IL-4 rs2243250 C/T, IL-4R rs1801275A/G, IL-6 rs1800795 G/C, IL-10 rs1800872 A/C and rs1800896 A/G, IL-10RB rs2834167A/G, IL-13 rs1800925 C/T, IL-18 rs187238G/C, IFNγ rs 24030561A/T and IFNγR2 rs2834213G/A), the rs2228137C/T of CD23 receptor gene and rs577912C/T and rs564481C/T of Klotho genes, using KASPar SNP genotyping method. Clinical and laboratory data of patients were analyzed by formal statistic tools and by a data-mining technique-market basket analysis-selecting a minimum threshold of 90% of rule confidence. Formal statistical analyses show that IL-6 rs1800795GG, IL-10RB rs2834167G positive genotypes, IL-13 rs1800925CC, CD23 rs2228137TT Klotho rs564481TT, might be risk factors for allergy. Applying the association rule methodology, we identify 10 genotype combination patterns associated with susceptibility to allergies. Together these data necessitate being confirmed in further studies, indicating that the heuristic approach might be a straightforward and useful tool to find predictive and diagnostic molecular patterns that might be also considered potential therapeutic targets in allergy.
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Predisposición Genética a la Enfermedad , Polimorfismo de Nucleótido Simple , Humanos , Polimorfismo de Nucleótido Simple/genética , Masculino , Femenino , Adulto , Asma/genética , Estudios de Casos y Controles , Subunidad beta del Receptor de Interleucina-10/genética , Receptores de IgE/genética , Persona de Mediana Edad , Adolescente , Hipersensibilidad/genética , NiñoRESUMEN
BACKGROUND: Honey bees are the principal commercial pollinators. Along with other arthropods, they are increasingly under threat from anthropogenic factors such as the incursion of invasive honey bee subspecies, pathogens and parasites. Better tools are needed to identify bee subspecies. Genomic data for economic and ecologically important organisms is increasing, but in its basic form its practical application to address ecological problems is limited. RESULTS: We introduce HBeeID a means to identify honey bees. The tool utilizes a knowledge-based network and diagnostic SNPs identified by discriminant analysis of principle components and hierarchical agglomerative clustering. Tests of HBeeID showed that it identifies African, Americas-Africanized, Asian, and European honey bees with a high degree of certainty even when samples lack the full 272 SNPs of HBeeID. Its prediction capacity decreases with highly admixed samples. CONCLUSION: HBeeID is a high-resolution genomic, SNP based tool, that can be used to identify honey bees and screen species that are invasive. Its flexible design allows for future improvements via sample data additions from other localities.