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1.
Nat Commun ; 12(1): 1046, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33594051

RESUMEN

Three-dimensional chromatin looping interactions play an important role in constraining enhancer-promoter interactions and mediating transcriptional gene regulation. CTCF is thought to play a critical role in the formation of these loops, but the specificity of which CTCF binding events form loops and which do not is difficult to predict. Loops often have convergent CTCF binding site motif orientation, but this constraint alone is only weakly predictive of genome-wide interaction data. Here we present an easily interpretable and simple mathematical model of CTCF mediated loop formation which is consistent with Cohesin extrusion and can predict ChIA-PET CTCF looping interaction measurements with high accuracy. Competition between overlapping loops is a critical determinant of loop specificity. We show that this model is consistent with observed chromatin interaction frequency changes induced by CTCF binding site deletion, inversion, and mutation, and is also consistent with observed constraints on validated enhancer-promoter interactions.


Asunto(s)
Factor de Unión a CCCTC/metabolismo , Cromatina/metabolismo , Modelos Biológicos , Proteínas Portadoras/metabolismo , Elementos de Facilitación Genéticos/genética , Técnicas de Inactivación de Genes , Células HeLa , Humanos , Proteínas Nucleares/metabolismo , Polimorfismo de Nucleótido Simple/genética , Regiones Promotoras Genéticas , Unión Proteica , Proteínas Proto-Oncogénicas/metabolismo
2.
Nat Commun ; 12(1): 1050, 2021 02 16.
Artículo en Inglés | MEDLINE | ID: mdl-33594080

RESUMEN

Attributing the similarity between individuals to genetic and non-genetic factors is central to genetic analyses. In this paper we use the genomic relationship ([Formula: see text]) among 417,060 individuals to investigate the phenotypic covariance between pairs of individuals for 32 traits across the spectrum of relatedness, from unrelated pairs through to identical twins. We find linear relationships between phenotypic covariance and [Formula: see text] that agree with the SNP-based heritability ([Formula: see text]) in unrelated pairs ([Formula: see text]), and with pedigree-estimated heritability in close relatives ([Formula: see text]). The covariance increases faster than [Formula: see text] in distant relatives ([Formula: see text]), and we attribute this to imperfect linkage disequilibrium between causal variants and the common variants used to construct [Formula: see text]. We also examine the effect of assortative mating on heritability estimates from different experimental designs. We find that full-sib identity-by-descent regression estimates for height (0.66 s.e. 0.07) are consistent with estimates from close relatives (0.82 s.e. 0.04) after accounting for the effect of assortative mating.


Asunto(s)
Genoma Humano , Filogenia , Adulto , Anciano , Bancos de Muestras Biológicas , Índice de Masa Corporal , Escolaridad , Humanos , Patrón de Herencia/genética , Desequilibrio de Ligamiento , Persona de Mediana Edad , Modelos Genéticos , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Carácter Cuantitativo Heredable , Análisis de Regresión , Reino Unido
3.
Medicine (Baltimore) ; 100(6): e24355, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578531

RESUMEN

BACKGROUND: Genetic polymorphisms in the 15q25 region have been associated with the risk of lung cancer (LC). However, studies have yielded conflicting results. METHODS: Searches were conducted in databases, including PubMed, EMbase, Web of Science, CNKI, and Wanfang, for case-control studies up to August 1, 2019. After retrieving eligible studies and data extraction, we calculated pooled odds ratios with 95% confidence intervals. In the meta-analysis, we included 32 publications with a total of 52,795 patients with LC and 97,493 control cases to evaluate the polymorphisms in the CHRNA5/A3/B4 gene cluster in the 15q25 region. RESULTS: Data of the meta-analysis showed a significantly increased risk of LC in the presence of genetic polymorphisms (rs1051730, rs16969968, rs8034191). In the smoking subgroup, the CHRNA3 rs1051730 polymorphism was found to contribute to LC risk using following 5 models: the allelic model, the homozygous model, the heterozygous model, the dominant model, and the recessive model. Thus, the rs1051730 polymorphism may modify LC susceptibility under the condition of smoking. Stratification studies for CHRNA5-rs8034191 showed that Caucasian groups with the wild-type genotype (C/C) may be susceptible to LC in all 5 models. No significant relationship between CHRNA3 rs6495309 or rs3743073 and LC susceptibility was found. However, Asians with the rs3743037 B-allele showed an obviously higher risk of LC susceptibility than the Caucasian population, observed via allelic, heterozygous, and dominant models. CONCLUSIONS: The 3 polymorphisms of rs1051730, rs16969968 and rs8034191 in the CHRNA5/A3/B4 gene cluster in the 15q25 region were associated with LC risk, which might be influenced by ethnicity and smoking status.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Neoplasias Pulmonares/genética , Proteínas del Tejido Nervioso/genética , Polimorfismo de Nucleótido Simple/genética , Receptores Nicotínicos/genética , Humanos , Neoplasias Pulmonares/etiología , Familia de Multigenes/genética , Factores de Riesgo
4.
Medicine (Baltimore) ; 100(6): e24464, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578539

RESUMEN

BACKGROUND: Recently, the relationships between uncoupling protein-2 (UCP2) -866G/A (rs659366) and Ala55Val (rs660339) polymorphisms and the risk of type 2 diabetes mellitus (T2DM) have been explored considerably, but the results are greatly inconsistent. This meta-analysis was performed to further identify the association of UCP2 rs659366 and rs660339 with the risk of T2DM. METHODS: Eligible studies were searched from PubMed, Embase, Cochrane Library, VIP database, Chinese National Knowledge Infrastructure, and Chinese WanFang database until March 8, 2020. The odds ratios with corresponding 95% confidence intervals (CIs), and P-values were used to assess the strength of the association. RESULTS: A total of 26 studies were included in this study. UCP2 rs659366 was associated with the risk of T2DM in allele model (OR: 1.112, 95%CI: 1.009-1.224, P = 0.032), dominant model (OR: 1.189, 95%CI: 1.035-1.366, P = 0.014), and heterozygous model (OR: 1.177, 95%CI: 1.032-1.342, P = .015). A significantly increased risk of T2DM was detected in Asians by UCP2 rs659366 allele (OR: 1.132, 95%CI: 1.016-1.262, P = .025), dominant (OR: 1.218, 95%CI: 1.046-1.418, P = .011), homozygous (OR: 1.254, 95%CI: 1.022-1.540, P = .031) or heterozygous (OR: 1.198, 95%CI: 1.047-1.371, P = .009) models. There was no significant correlation between UCP2 rs660339 and the risk of T2DM (P>.05). CONCLUSIONS: The UCP2 rs65366 is significantly associated with the risk of T2DM, especially in Asian population, while no evidence is found between the UCP2 rs660339 and the susceptibility to T2DM.


Asunto(s)
Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Proteína Desacopladora 2/genética , Humanos
5.
Commun Biol ; 4(1): 228, 2021 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-33589648

RESUMEN

SARS-CoV-2 has been mutating since it was first sequenced in early January 2020. Here, we analyze 45,494 complete SARS-CoV-2 geneome sequences in the world to understand their mutations. Among them, 12,754 sequences are from the United States. Our analysis suggests the presence of four substrains and eleven top mutations in the United States. These eleven top mutations belong to 3 disconnected groups. The first and second groups consisting of 5 and 8 concurrent mutations are prevailing, while the other group with three concurrent mutations gradually fades out. Moreover, we reveal that female immune systems are more active than those of males in responding to SARS-CoV-2 infections. One of the top mutations, 27964C > T-(S24L) on ORF8, has an unusually strong gender dependence. Based on the analysis of all mutations on the spike protein, we uncover that two of four SASR-CoV-2 substrains in the United States become potentially more infectious.


Asunto(s)
/virología , Mutación/genética , /genética , Regiones no Traducidas 5'/genética , Secuencia de Aminoácidos , /metabolismo , Evolución Molecular , Femenino , Humanos , Masculino , Modelos Moleculares , Nucleocápside/metabolismo , Sistemas de Lectura Abierta/genética , Polimorfismo de Nucleótido Simple/genética , Unión Proteica , Dominios Proteicos , Pliegue de Proteína , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Termodinámica , Estados Unidos
6.
Medicine (Baltimore) ; 100(6): e23305, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578508

RESUMEN

BACKGROUND: Brain-derived neurotrophic factor (BDNF) rs6265 polymorphism has been previously suggested to be associated with the susceptibility of type 2 diabetes mellitus (T2DM), but results remained controversial. We aim to provide a more reliable conclusion about the association between BDNF rs6265 polymorphism and T2DM risk by using a meta-analysis. METHODS: Electronic databases such as Pubmed, Embase, CNKI, and Wanfang were searched for relevant articles published up to May 06, 2020. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the associations. Subgroup analysis was carried out according to source of controls and quality score of included studies. A trial sequential analysis was conducted to reduce the risk of type I error. RESULTS: A total of 8 case-control studies (7 conducted in China) with 1576 T2DM patients and 1866 controls were included. Overall, our results indicated no significant association between BDNF rs6265 polymorphism and T2DM risk with the random-effects model (allele model: pooled OR = 1.14, 95% CI = 0.79-1.65, homozygote model: pooled OR = 1.13, 95% CI = 0.57-2.21, heterozygote model: pooled OR = 1.07, 95% CI = 0.78-1.48, dominant model: pooled OR = 1.14, 95% CI = 0.74-1.75 and recessive model: pooled OR = 1.10, 95% CI = 0.67-1.80). Subgroup analysis by source of controls and quality score also showed no significant association between BDNF rs6265 polymorphism and T2DM risk. Trial sequential analysis results confirmed the null association and further studies were unnecessary. CONCLUSION: This meta-analysis study indicated that no significant association between BDNF rs6265 polymorphism and T2DM risk.


Asunto(s)
Factor Neurotrófico Derivado del Encéfalo/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Anciano , Alelos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Estudios de Casos y Controles , China/epidemiología , Ensayos Clínicos como Asunto , Dinamarca/epidemiología , Femenino , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Heterocigoto , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Factores de Riesgo
7.
Medicine (Baltimore) ; 100(6): e24647, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578591

RESUMEN

PURPOSE: Presently, whether interleukin-6 (IL-6) gene-174 G/C promoter polymorphism is correlated to the susceptibility of multiple myeloma (MM) remains controversial. For this reason, the method of meta-analysis was applied to exploring the association between IL-6 gene-174 G/C promoter polymorphism and MM. METHOD: Two independent researchers systematically searched PubMed, EMBASE, Google academic, Cochrane Library and Chinese literature databases to screen case-control studies on IL-6 gene-174 G/C promoter polymorphism and MM susceptibility. The retrieval period was limited from the formation of the database to January 2020, and data analysis was conducted by employing Stata 11.0 software. RESULT: Seven articles were ultimately included in the present study, including 594 MM patients and 681 controls. Integration analysis exhibited that compared with GC or CC genotype, GG genotype did not increase MM susceptibility (OR = 0.95, 95% CI 0.75-1.22; OR = 0.79, 95% CI 0.52-1.19, respectively). Further, in comparison with CC genotype, GC genotype also presented no effect on increasing MM susceptibility (OR = 0.79, 95% CI 0.53-1.16), while compared with GC+CC genotype, GG genotype had no significant relationship with MM susceptibility (OR = 0.94, 95% CI 0.75-1.19). In subsequent analysis, an observation was made that allele G or C was not related to MM susceptibility (OR = 0.92, 95% CI 0.76-1.12). Funnel chart and Begg test did not reveal publication bias in the included articles. CONCLUSION: The results of the present study advocate that there is no testimony to support the relationship between IL-6 gene-174 G/C promoter polymorphism and MM susceptibility.


Asunto(s)
Interleucina-6/genética , Mieloma Múltiple/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Alelos , Estudios de Casos y Controles , China/epidemiología , Manejo de Datos , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Factores de Riesgo
8.
Nat Genet ; 53(1): 86-99, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33414553

RESUMEN

Patient-derived xenografts (PDXs) are resected human tumors engrafted into mice for preclinical studies and therapeutic testing. It has been proposed that the mouse host affects tumor evolution during PDX engraftment and propagation, affecting the accuracy of PDX modeling of human cancer. Here, we exhaustively analyze copy number alterations (CNAs) in 1,451 PDX and matched patient tumor (PT) samples from 509 PDX models. CNA inferences based on DNA sequencing and microarray data displayed substantially higher resolution and dynamic range than gene expression-based inferences, and they also showed strong CNA conservation from PTs through late-passage PDXs. CNA recurrence analysis of 130 colorectal and breast PT/PDX-early/PDX-late trios confirmed high-resolution CNA retention. We observed no significant enrichment of cancer-related genes in PDX-specific CNAs across models. Moreover, CNA differences between patient and PDX tumors were comparable to variations in multiregion samples within patients. Our study demonstrates the lack of systematic copy number evolution driven by the PDX mouse host.


Asunto(s)
Variaciones en el Número de Copia de ADN/genética , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Bases de Datos Genéticas , Regulación Neoplásica de la Expresión Génica , Humanos , Ratones , Metástasis de la Neoplasia , Polimorfismo de Nucleótido Simple/genética , Secuenciación del Exoma Completo
9.
Nat Genet ; 53(1): 35-44, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33414549

RESUMEN

Little is known about the genetic architecture of traits affecting educational attainment other than cognitive ability. We used genomic structural equation modeling and prior genome-wide association studies (GWASs) of educational attainment (n = 1,131,881) and cognitive test performance (n = 257,841) to estimate SNP associations with educational attainment variation that is independent of cognitive ability. We identified 157 genome-wide-significant loci and a polygenic architecture accounting for 57% of genetic variance in educational attainment. Noncognitive genetics were enriched in the same brain tissues and cell types as cognitive performance, but showed different associations with gray-matter brain volumes. Noncognitive genetics were further distinguished by associations with personality traits, less risky behavior and increased risk for certain psychiatric disorders. For socioeconomic success and longevity, noncognitive and cognitive-performance genetics demonstrated associations of similar magnitude. By conducting a GWAS of a phenotype that was not directly measured, we offer a view of genetic architecture of noncognitive skills influencing educational success.


Asunto(s)
Cognición , Estudio de Asociación del Genoma Completo , Encéfalo/diagnóstico por imagen , Toma de Decisiones , Escolaridad , Fertilidad , Humanos , Inteligencia , Trastornos Mentales/genética , Modelos Genéticos , Anotación de Secuencia Molecular , Herencia Multifactorial/genética , Personalidad , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Asunción de Riesgos
10.
Nat Commun ; 12(1): 2, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397972

RESUMEN

Oxford Nanopore (ONT) is a leading long-read technology which has been revolutionizing transcriptome analysis through its capacity to sequence the majority of transcripts from end-to-end. This has greatly increased our ability to study the diversity of transcription mechanisms such as transcription initiation, termination, and alternative splicing. However, ONT still suffers from high error rates which have thus far limited its scope to reference-based analyses. When a reference is not available or is not a viable option due to reference-bias, error correction is a crucial step towards the reconstruction of the sequenced transcripts and downstream sequence analysis of transcripts. In this paper, we present a novel computational method to error correct ONT cDNA sequencing data, called isONcorrect. IsONcorrect is able to jointly use all isoforms from a gene during error correction, thereby allowing it to correct reads at low sequencing depths. We are able to obtain a median accuracy of 98.9-99.6%, demonstrating the feasibility of applying cost-effective cDNA full transcript length sequencing for reference-free transcriptome analysis.


Asunto(s)
Perfilación de la Expresión Génica , Nanoporos , Nanotecnología/métodos , Algoritmos , Alelos , Animales , Drosophila melanogaster/genética , Exones/genética , Regulación de la Expresión Génica , Heurística , Polimorfismo de Nucleótido Simple/genética , Isoformas de Proteínas/metabolismo , Sitios de Empalme de ARN/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo
11.
Nat Genet ; 53(1): 54-64, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33414548

RESUMEN

In cross-platform analyses of 174 metabolites, we identify 499 associations (P < 4.9 × 10-10) characterized by pleiotropy, allelic heterogeneity, large and nonlinear effects and enrichment for nonsynonymous variation. We identify a signal at GLP2R (p.Asp470Asn) shared among higher citrulline levels, body mass index, fasting glucose-dependent insulinotropic peptide and type 2 diabetes, with ß-arrestin signaling as the underlying mechanism. Genetically higher serine levels are shown to reduce the likelihood (by 95%) and predict development of macular telangiectasia type 2, a rare degenerative retinal disease. Integration of genomic and small molecule data across platforms enables the discovery of regulators of human metabolism and translation into clinical insights.


Asunto(s)
Salud , Metabolismo/genética , Diabetes Mellitus Tipo 2/genética , Oftalmopatías/genética , Frecuencia de los Genes/genética , Sitios Genéticos , Pleiotropía Genética , Genoma Humano , Receptor del Péptido 2 Similar al Glucagón/genética , Glicina/metabolismo , Humanos , Modelos Lineales , Análisis de la Aleatorización Mendeliana , Errores Innatos del Metabolismo/genética , Metaboloma/genética , Mutación Missense/genética , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Telangiectasia Retiniana/genética , Tamaño de la Muestra , Serina/metabolismo
12.
Nat Genet ; 53(1): 120-126, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33414550

RESUMEN

Low-coverage whole-genome sequencing followed by imputation has been proposed as a cost-effective genotyping approach for disease and population genetics studies. However, its competitiveness against SNP arrays is undermined because current imputation methods are computationally expensive and unable to leverage large reference panels. Here, we describe a method, GLIMPSE, for phasing and imputation of low-coverage sequencing datasets from modern reference panels. We demonstrate its remarkable performance across different coverages and human populations. GLIMPSE achieves imputation of a genome for less than US$1 in computational cost, considerably outperforming other methods and improving imputation accuracy over the full allele frequency range. As a proof of concept, we show that 1× coverage enables effective gene expression association studies and outperforms dense SNP arrays in rare variant burden tests. Overall, this study illustrates the promising potential of low-coverage imputation and suggests a paradigm shift in the design of future genomic studies.


Asunto(s)
Análisis de Secuencia de ADN , Genoma Humano , Genotipo , Humanos , Funciones de Verosimilitud , Polimorfismo de Nucleótido Simple/genética , Estándares de Referencia
13.
Nat Commun ; 12(1): 226, 2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33431880

RESUMEN

The complete human genome sequence is used as a reference for next-generation sequencing analyses. However, some ethnic ancestries are under-represented in the reference genome (e.g., GRCh37) due to its bias toward European and African ancestries. Here, we perform de novo assembly of three Japanese male genomes using > 100× Pacific Biosciences long reads and Bionano Genomics optical maps per sample. We integrate the genomes using the major allele for consensus and anchor the scaffolds using genetic and radiation hybrid maps to reconstruct each chromosome. The resulting genome sequence, JG1, is contiguous, accurate, and carries the Japanese major allele at most loci. We adopt JG1 as the reference for confirmatory exome re-analyses of seven rare-disease Japanese families and find that re-analysis using JG1 reduces total candidate variant calls versus GRCh37 while retaining disease-causing variants. These results suggest that integrating multiple genomes from a single population can aid genome analyses of that population.


Asunto(s)
Grupo de Ascendencia Continental Asiática/genética , Genoma Humano , Estudios de Cohortes , Exoma/genética , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Análisis de Componente Principal
14.
Respir Res ; 22(1): 23, 2021 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-33472618

RESUMEN

BACKGROUND: When infected with Mycobacterium tuberculosis, only a small proportion of the population will develop active TB, and the role of host genetic factors in different TB infection status was not fully understood. METHODS: Forty-three patients with active tuberculosis and 49 with latent tuberculosis were enrolled in the prospective cohort. Expressing levels of 27 candidate mRNAs, which were previously demonstrated to differentially expressed in latent and active TB, were measured by dual color reverse transcription multiplex ligation dependent probe amplification assay (dcRT-MLPA). Using expression levels of these mRNAs as quantitative traits, associations between expression abundance and genome-wild single nucleotide polymorphisms (SNPs) were calculated. Finally, identified candidate SNPs were further assessed for their associations with TB infection status in a validation cohort with 313 Chinese Han cases. RESULTS: We identified 9 differentially expressed mRNAs including il7r, il4, il8, tnfrsf1b, pgm5, ccl19, il2ra, marco and fpr1 in the prospective cohort. Through expression quantitative trait loci mapping, we screened out 8 SNPs associated with these mRNAs. Then, CG genotype of the SNP rs62292160 was finally verified to be significantly associated with higher transcription levels of IL4 in LTBI than in TB patients. CONCLUSION: We reported that the SNP rs62292160 in Chinese Han population may link to higher expression of il4 in latent tuberculosis. Our findings provided a new genetic variation locus for further exploration of the mechanisms of TB and a possible target for TB genetic susceptibility studies, which might aid the clinical decision to precision treatment of TB.


Asunto(s)
Grupo de Ascendencia Continental Asiática/genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Sitios de Carácter Cuantitativo/genética , ADN Polimerasa Dirigida por ARN/genética , Tuberculosis/genética , Adulto , China/epidemiología , Estudios de Cohortes , Femenino , Expresión Génica , Redes Reguladoras de Genes/genética , Predisposición Genética a la Enfermedad/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple/genética , Estudios Prospectivos , Tuberculosis/diagnóstico , Tuberculosis/epidemiología
15.
Nucleic Acids Res ; 49(1): 90-97, 2021 01 11.
Artículo en Inglés | MEDLINE | ID: mdl-33330918

RESUMEN

PIWI-interacting RNAs (piRNAs) are an emerging class of non-coding RNAs involved in tumorigenesis. Expression quantitative trait locus (eQTL) analysis has been demonstrated to help reveal the genetic mechanism of single nucleotide polymorphisms (SNPs) in cancer etiology. However, there are no databases that have been constructed to provide an eQTL analysis between SNPs and piRNA expression. In this study, we collected genotyping and piRNA expression data for 10 997 samples across 33 cancer types from The Cancer Genome Atlas (TCGA). Using linear regression cis-eQTL analysis with adjustment of appropriate covariates, we identified millions of SNP-piRNA pairs in tumor (76 924 831) and normal (24 431 061) tissues. Further, we performed differential expression and survival analyses, and linked the eQTLs to genome-wide association study (GWAS) data to comprehensively decipher the functional roles of identified cis-piRNA eQTLs. Finally, we developed a user-friendly database, piRNA-eQTL (http://njmu-edu.cn:3838/piRNA-eQTL/), to help users query, browse and download corresponding eQTL results. In summary, piRNA-eQTL could serve as an important resource to assist the research community in understanding the roles of genetic variants and piRNAs in the development of cancers.


Asunto(s)
Regulación Neoplásica de la Expresión Génica/genética , Polimorfismo de Nucleótido Simple/genética , Sitios de Carácter Cuantitativo/genética , ARN Neoplásico/genética , ARN Interferente Pequeño/biosíntesis , Bases de Datos Genéticas , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , Estimación de Kaplan-Meier , Neoplasias/genética , Neoplasias/mortalidad , ARN Interferente Pequeño/genética , Interfaz Usuario-Computador
16.
Gene ; 766: 145118, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32896588

RESUMEN

Insulin-like growth factor 1 (IGF1) is a multifunctional cell proliferation regulator that plays a critical role in regulating animal growth and development. In this study, the expression level of IGF1 gene in different tissues of Dezhou donkey in different periods was investigated by RT-qPCR. Meanwhile, two mutation sites were identified within the IGF1 gene and its effect on body size traits of Dezhou donkey was analysed. The results showed that the expression level of the adult donkey IGF1 gene in heart, liver, spleen, lung, renal and gastric tissues is higher than that of the young donkeys, but the young donkeys are significantly higher in muscle tissues than the adult donkeys. The IGF1-1 and IGF1-2 loci showed a trend that the GG mutant was larger than other genotypes in the growth traits of both male and female donkeys, among which the IGF1-1 loci had a significant association with the chest circumference and chest depth of male donkeys (P < 0.05), and the IGF1-2 loci had a significant association with the chest circumference of female donkeys. Haplotype combination Hap1Hap1 (GG-GG) showed a greater tendency than Hap2Hap2 (AA-GG) combination in terms of growth traits, reflecting that the results were consistent with the analysis results of genotypes, which also proved the analysis results of genotypes and growth traits had certain reliability. In summary, the IGF1 gene is a candidate gene for growth and development, and its polymorphisms can be used as the molecular markers for Dezhou donkey breeding.


Asunto(s)
Tamaño Corporal/genética , Equidae/genética , Factor I del Crecimiento Similar a la Insulina/genética , Transcriptoma/genética , Animales , Cruzamiento/métodos , Femenino , Genotipo , Haplotipos/genética , Masculino , Fenotipo , Polimorfismo de Nucleótido Simple/genética
17.
Gene ; 766: 145143, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32911028

RESUMEN

We aimed to test the hypothesis that apelin (APLN) and its receptor AGTRL1 (APLNR) genes may contribute to the pathogenesis of myocardial infarction in Han Chinese. This is a hospital-based, case-control association study, involving 1067 patients with myocardial infarction and 942 healthy controls. Myocardial infarction is diagnosed by electrocardiogram or anatomopathological examination. Eight polymorphisms in APLN gene and 5 in APLNR gene were genotyped using the TaqMan assay. Risk was summarized as odds ratio (OR) and 95% confidence interval (CI). In males, rs56204867-G allele (adjusted OR, 95% CI, p: 0.21, 0.08-0.55, 0.002) and rs2235309-T allele (0.60, 0.42-0.84, 0.004) was associated with a significantly reduced risk of myocardial infarction, and the mutations of rs2235310 was associated with an increased risk (1.41, 1.06-2.52, 0.021), as well as for rs948847-GG genotype (1.85, 1.23-2.91, 0.007). In females, the presence of rs56204867-AG and -GG genotypes was significantly associated with 44% and 50% reduced risk (0.56 and 0.50, 0.40-8.04 and 0.29-0.86, 0.007 and 0.036), respectively; for rs2235310, CC genotype was associated with 72% increased risk (1.72, 1.09-3.22, 0.016), and the odds of myocardial infarction was 3.47 for rs9943582-TT genotype (95% CI: 1.53-7.57, 0.009). The gender-specific association of APLN and APLNR genes with myocardial infarction was reinforced by further linkage and haplotype analyses. Finally, nomograms based on significant polymorphisms are satisfactory, with the C-indexes over 80% for both genders. Taken together, our findings indicate that APLN and APLNR genes are potential candidates in the pathogenesis of myocardial infarction in Han Chinese, and importantly their contribution is gender-dependent.


Asunto(s)
Receptores de Apelina/genética , Apelina/genética , Grupo de Ascendencia Continental Asiática/genética , Predisposición Genética a la Enfermedad/genética , Infarto del Miocardio/genética , Polimorfismo de Nucleótido Simple/genética , Anciano , Alelos , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes/genética , Genotipo , Haplotipos/genética , Humanos , Masculino , Persona de Mediana Edad
18.
Gene ; 766: 145132, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32911029

RESUMEN

Dysfunctions in mechanisms of gene regulation based on RNA interference are recognized as a common feature of the molecular basis of cancer pathogenesis. Therefore, as one of the crucial components of the machinery involved in the biogenesis of both siRNAs and microRNA molecules, DICER was recognized as one of the candidates for the research in the field of carcinogenesis. Due to their potential functional properties, several genetic variants located within DICER1 gene were analyzed for their possible association with the susceptibility to cancer through case-control studies. In order to elucidate their effect on the overall cancer risk, we conducted an updated meta-analysis of all eligible association studies. The publications were selected based on PubMed database search, while OpenMeta-analyst and MetaGenyo software were used for quantitative data synthesis. Statistically significant results were found for the association of rs1057035 with the overall cancer risk under multiple genetic models (PCT vs. TT < 0.001, ORCT vs. TT = 0.870, 95% CI = 0.812-0.933; Pallelic = 0.009, ORallelic = 0.896, 95% CI = 0.825-0.973; Pdom < 0.001, ORdom = 0.874, 95% CI = 0.817-0.934; Poverdom = 0.004, ORoverdom = 0.858, 95% CI = 0.773-0.953). Other selected genetic variants within DICER1, rs13078, rs1209904 and rs3742330, did not show the association with the overall susceptibility to malignant diseases. We conclude that rs1057035 may represent a potential biomarker associated with the risk of developing cancer, which requires a confirmation in a larger set of studies.


Asunto(s)
ARN Helicasas DEAD-box/genética , Predisposición Genética a la Enfermedad/genética , Neoplasias/genética , Polimorfismo de Nucleótido Simple/genética , Ribonucleasa III/genética , Alelos , Biomarcadores de Tumor/genética , Estudios de Casos y Controles , Estudios de Asociación Genética , Genotipo , Humanos , MicroARNs/genética , Riesgo
19.
Gene ; 766: 145092, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32916247

RESUMEN

Cigarette smoking is a major lifestyle factor leading to different human diseases. The DNA repair gene, thymine DNA glycosylase, is important to cell survival because it stops cells from becoming cancerous protecting/preventing DNA. Exposure to CS may induce genetic changes such as single nucleotide polymorphisms in DNA repair genes. Therefore, the purpose of this study was to investigate the genotype and allele distributions of four TDG SNPs with only smoking behavior in normal patients. Four TDG SNPs-rs4135066 (C/T), rs3751209 (A/G), rs1866074 (C/T), and rs1882018 (C/T) were analyzed by genotyping 235 and 239 blood samples collected from cigarette smokers and non-smokers, among the Saudi population. The results showed that TDG rs4135066 has a significant susceptibility effect observed in long-term smokers (>5 years; OR = 4.53; P = 0.0347) but not in short-term smokers (≤5 years) in contrast with non-smokers. Also, in smokers aged less than 29 years, the "CT," "TT," and "CT + TT" alleles of rs1882018 increased the risk of developing all diseases related to smoking by approximately 6, 4, and 5 times, respectively, in contrast with the ancestral "CC" homozygous allele. A comparison of the allele distributions of TDG SNPs in a Saudi population with those in other populations represented in the HapMap project showed that the genetic makeup of the Saudi Arabian population appears to differ from that of other ethnicities. Exceptions include the Yoruba people in Ibadan, Nigeria; those of Mexican ancestry in Los Angeles, California; the Luhya population in Webuye, Kenya; Gujarati Indians in Houston, Texas; and the Tuscan population in Italy, which showed similar allelic frequencies for rs3751209 compared to our Saudi population. In this ethnic, we have found a high variation in the distribution of the alleles and genotype frequencies on TDG gene. This variation on TDG SNP's with smoking could lead to increase the susceptibility to many diseases related to smoking habits in this population.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Fumar/genética , Timina ADN Glicosilasa/genética , Adulto , Alelos , Grupos Étnicos/genética , Femenino , Frecuencia de los Genes/genética , Genotipo , Humanos , Masculino
20.
Gene ; 766: 145127, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32937184

RESUMEN

Telomeres are duplex tandem repeats of DNA sequence 5'-TTAGGG-3' at chromosomal ends synthesized by telomerase enzyme (TE). Telomeres length (TL) shortening is associated with age and age-related disorders. Recently, we demonstrated marked leukocytes TL (LTL) shortening in T2DM. To set the relationship between the TE, LTL and T2DM, we analyzed samples from 212 Kuwaiti subjects, 112 patients withT2DM and 100 non-diabetic subjects. The plasma TE and fasting insulin were measured by ELISA, the LTL was estimated by qPCR and three SNPs of genes related to TL; TERC rs12696304 (C/G), TERT rs2736100 (C/A) and ACYP2 rs6713088 (C/G) were genotyped by rtPCR. Results revealed comparable TE levels and alleles/genotypes between the cases and controls with no influence of either on the LTL. Interestingly, although the plasma concentration of the TE was generally low, it was significantly influenced by the TERT and ACYP2 but not TERC polymorphisms. The CC genotype carriers of rs2736100 (C/A) had significantly higher plasma TE levels compared to CA and AA carriers, p 0.009 and p 0.047, respectively, and the A-allele was associated with low TE, p 0.018. Similarly, significantly higher TE levels were detected in CC carriers of ACYP2 rs6713088 (C/G) compared with GC carriers, p 0.002, and the G-allele was associated with low TE, p 0.009. Finally, the TERT and ACYP2 polymorphisms had an influence on blood glucose levels. In conclusion, the telomeres shortening in T2DM was not due to TE deficiency or gene polymorphisms, while the TE levels were significantly associated with the TERT and ACYP2 but not TERC polymorphisms.


Asunto(s)
Ácido Anhídrido Hidrolasas/genética , Diabetes Mellitus Tipo 2/genética , Polimorfismo de Nucleótido Simple/genética , ARN/genética , Telomerasa/genética , Acortamiento del Telómero/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Telomerasa/sangre
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