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1.
Plant Genome ; 13(1): e20005, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-33016626

RESUMEN

A genome-wide association study (GWAS) needs to have a suitable population. The factors that affect a GWAS (e.g. population structure, sample size, and sequence analysis and field testing costs) need to be considered. Mixed populations containing subpopulations of different genetic backgrounds may be suitable populations. We conducted simulation experiments to see if a population with high genetic diversity, such as a diversity panel, should be added to a target population, especially when the target population harbors small genetic diversity. The target population was 112 accessions of Oryza sativa L. subsp. japonica, mainly developed in Japan. We combined the target population with three populations that had higher genetic diversity. These were 100 indica accessions, 100 japonica accessions, and 100 accessions with various genetic backgrounds. The results showed that the GWAS's power with a mixed population was generally higher than with a separate population. Also, the optimal GWAS populations varied depending on the fixation index (FST ) of the quantitative trait nucleotides (QTNs) and the polymorphism of QTNs in each population. When a QTN was polymorphic in a target population, a target population combined with a higher diversity population improved the QTN's detection power. By investigating FST and the expected heterozygosity (He ) as factors influencing the detection power, we showed that single nucleotide polymorphisms with high FST or low He are less likely to be detected by GWAS with mixed populations. Sequenced or genotyped germplasm collections can improve the GWAS's detection power by using a subset of the collections with a target population.


Asunto(s)
Oryza , Estudio de Asociación del Genoma Completo , Genotipo , Japón , Oryza/genética , Polimorfismo de Nucleótido Simple
2.
Euro Surveill ; 25(39)2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33006300

RESUMEN

We found that a single nucleotide polymorphism (SNP) in the nucleoprotein gene of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from a patient interfered with detection in a widely used commercial assay. Some 0.2% of the isolates in the EpiCoV database contain this SNP. Although SARS-CoV-2 was still detected by the other probe in the assay, this underlines the necessity of targeting two independent essential regions of a pathogen for reliable detection.


Asunto(s)
Betacoronavirus/genética , Técnicas de Laboratorio Clínico , Infecciones por Coronavirus/diagnóstico , Nucleoproteínas/genética , Pandemias , Neumonía Viral/diagnóstico , Mutación Puntual , Polimorfismo de Nucleótido Simple , ARN Viral/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Proteínas Virales/genética , Secuencia de Bases , Betacoronavirus/aislamiento & purificación , Técnicas de Laboratorio Clínico/métodos , Trazado de Contacto , Infecciones por Coronavirus/virología , Cartilla de ADN , Errores Diagnósticos , Reacciones Falso Negativas , Femenino , Genes Virales , Humanos , Persona de Mediana Edad , Nasofaringe/virología , Nucleoproteínas/análisis , Filogenia , Neumonía Viral/virología , Reacción en Cadena en Tiempo Real de la Polimerasa/métodos , Rumanía , Enfermedad Relacionada con los Viajes , Proteínas Virales/análisis
3.
Medicine (Baltimore) ; 99(40): e22614, 2020 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-33019481

RESUMEN

BACKGROUND: The relationship between MTHFR (5, 10-methylene tetrahydrofolate reductase) gene polymorphisms and Systemic Lupus Erythematosus (SLE) has been wildly studied, but the results are still conflicting. Therefore, the purpose of this meta and pooled analysis was to identify the role of the MTHFR SNP (single nucleotide polymorphism, rs1801133) in SLE in a large sample of subjects and to assess the risk of SLE. METHODS: Data were collected from EMBASE, PubMed and China National Knowledge Infrastructure from inception to August, 2019. Summary odds ratio (OR) with 95% confidence interval (CI) was applied to assess the association. Subgroup and sensitivity analysis were performed to assess the potential sources of heterogeneity of the pooled estimation. RESULTS: We identified seven eligible studies involving 882 cases and 991 controls. MTHFR rs1801133 T carrier was significantly associated with increased risk of SLE when comparing to C allele [ORs were 1.766 (1.014-3.075) for T carrier vs CC, P = .04]. Furthermore, the results of the subgroup analysis by genotyping methods suggested that T allele significantly contributed to the risk of SLE for both by polymerase chain reaction-TaqMan (PCR-TaqMan) [10.111 (2.634-38.813) for TT vs CC, 3.467 (1.324-9.078) for CT vs CC and 3.744 (1.143-12.264) for TT vs C carrier]. Also the results of the subgroup analysis by ethnicity suggested that T allele significantly contributed to the risk of SLE for Asians [9.679 (4.444-21.082) for TT vs CC, 5.866 (3.021-11.389) for T carrier vs CC and 8.052 (3.861-16.795) for TT vs C carrier]. CONCLUSION: This cumulative meta-analysis showed that the MTHFR SNP (rs1801133) contributed to susceptibility of SLE. However, more multicentre well-designed case-control studies and larger sample sizes are exceedingly required to validate our findings in the future.


Asunto(s)
Lupus Eritematoso Sistémico/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Nucleótido Simple/genética , Alelos , Grupo de Ascendencia Continental Asiática/genética , Portador Sano , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Lupus Eritematoso Sistémico/etnología , Masculino , Medición de Riesgo , Sensibilidad y Especificidad
4.
Vestn Oftalmol ; 136(5): 129-135, 2020.
Artículo en Ruso | MEDLINE | ID: mdl-33056974

RESUMEN

The article reviews literature on developmental stages of genome-wide association studies (GWAS) of primary open-angle glaucoma (POAG). This problem is currently developing and one of the most complex in ophthalmology. The article considers main GWAS of POAG and established GWAS-significant polymorphisms associated with the disease. The topic of genome-wide studies of primary open-angle glaucoma will be of certain interest to ophthalmologists, materials on GWAS-significant loci can be used both in the selection of polymorphisms in replicative studies of POAG in various populations of Russia, and to expand ideas about the molecular genetic mechanisms of the development of the disease.


Asunto(s)
Estudio de Asociación del Genoma Completo , Glaucoma de Ángulo Abierto , Predisposición Genética a la Enfermedad , Glaucoma de Ángulo Abierto/diagnóstico , Glaucoma de Ángulo Abierto/genética , Humanos , Polimorfismo de Nucleótido Simple , Federación de Rusia
5.
Nat Commun ; 11(1): 4912, 2020 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-32999275

RESUMEN

Most signals detected by genome-wide association studies map to non-coding sequence and their tissue-specific effects influence transcriptional regulation. However, key tissues and cell-types required for functional inference are absent from large-scale resources. Here we explore the relationship between genetic variants influencing predisposition to type 2 diabetes (T2D) and related glycemic traits, and human pancreatic islet transcription using data from 420 donors. We find: (a) 7741 cis-eQTLs in islets with a replication rate across 44 GTEx tissues between 40% and 73%; (b) marked overlap between islet cis-eQTL signals and active regulatory sequences in islets, with reduced eQTL effect size observed in the stretch enhancers most strongly implicated in GWAS signal location; (c) enrichment of islet cis-eQTL signals with T2D risk variants identified in genome-wide association studies; and (d) colocalization between 47 islet cis-eQTLs and variants influencing T2D or glycemic traits, including DGKB and TCF7L2. Our findings illustrate the advantages of performing functional and regulatory studies in disease relevant tissues.


Asunto(s)
Glucemia/genética , Diabetes Mellitus Tipo 2/genética , Predisposición Genética a la Enfermedad , Islotes Pancreáticos/metabolismo , Sitios de Carácter Cuantitativo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Animales , Glucemia/metabolismo , Línea Celular Tumoral , Estudios de Cohortes , Diabetes Mellitus Tipo 2/sangre , Diacilglicerol Quinasa/genética , Diacilglicerol Quinasa/metabolismo , Elementos de Facilitación Genéticos , Femenino , Regulación de la Expresión Génica , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Ratones , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , RNA-Seq , Análisis de Secuencia de ADN , Proteína 2 Similar al Factor de Transcripción 7/genética , Proteína 2 Similar al Factor de Transcripción 7/metabolismo , Adulto Joven
6.
Lancet Oncol ; 21(10): 1378-1386, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33002439

RESUMEN

BACKGROUND: Genetic variants and lifestyle factors have been associated with gastric cancer risk, but the extent to which an increased genetic risk can be offset by a healthy lifestyle remains unknown. We aimed to establish a genetic risk model for gastric cancer and assess the benefits of adhering to a healthy lifestyle in individuals with a high genetic risk. METHODS: In this meta-analysis and prospective cohort study, we first did a fixed-effects meta-analysis of the association between genetic variants and gastric cancer in six independent genome-wide association studies (GWAS) with a case-control study design. These GWAS comprised 21 168 Han Chinese individuals, of whom 10 254 had gastric cancer and 10 914 geographically matched controls did not. Using summary statistics from the meta-analysis, we constructed five polygenic risk scores in a range of thresholds (p=5 × 10-4 p=5 × 10-5 p=5 × 10-6 p=5 × 10-7, and p=5 × 10-8) for gastric cancer. We then applied these scores to an independent, prospective, nationwide cohort of 100 220 individuals from the China Kadoorie Biobank (CKB), with more than 10 years of follow-up. The relative and absolute risk of incident gastric cancer associated with healthy lifestyle factors (defined as not smoking, never consuming alcohol, the low consumption of preserved foods, and the frequent intake of fresh fruits and vegetables), was assessed and stratified by genetic risk (low [quintile 1 of the polygenic risk score], intermediate [quintile 2-4 of the polygenic risk score], and high [quintile 5 of the polygenic risk score]). Individuals with a favourable lifestyle were considered as those who adopted all four healthy lifestyle factors, those with an intermediate lifestyle adopted two or three factors, and those with an unfavourable lifestyle adopted none or one factor. FINDINGS: The polygenic risk score derived from 112 single-nucleotide polymorphisms (p<5 × 10-5) showed the strongest association with gastric cancer risk (p=7·56 × 10-10). When this polygenic risk score was applied to the CKB cohort, we found that there was a significant increase in the relative risk of incident gastric cancer across the quintiles of the polygenic risk score (ptrend<0·0001). Compared with individuals who had a low genetic risk, those with an intermediate genetic risk (hazard ratio [HR] 1·54 [95% CI 1·22-1·94], p=2·67 × 10-4) and a high genetic risk (2·08 [1·61-2·69], p<0·0001) had a greater risk of gastric cancer. A similar increase in the relative risk of incident gastric cancer was observed across the lifestyle categories (ptrend<0·0001), with a higher risk of gastric cancer in those with an unfavourable lifestyle than those with a favourable lifestyle (2·03 [1·46-2·83], p<0·0001). Participants with a high genetic risk and a favourable lifestyle had a lower risk of gastric cancer than those with a high genetic risk and an unfavourable lifestyle (0·53 [0·29-0·99], p=0·048), with an absolute risk reduction of 1·12% (95% CI 0·62-1·56). INTERPRETATION: Chinese individuals at an increased risk of incident gastric cancer could be identified by use of our newly developed polygenic risk score. Compared with individuals at a high genetic risk who adopt an unhealthy lifestyle, those who adopt a healthy lifestyle could substantially reduce their risk of incident gastric cancer. FUNDING: National Key R&D Program of China, National Natural Science Foundation of China, 333 High-Level Talents Cultivation Project of Jiangsu Province, and China Postdoctoral Science Foundation.


Asunto(s)
Predisposición Genética a la Enfermedad/genética , Estilo de Vida Saludable , Neoplasias Gástricas/genética , Adulto , Anciano , Grupo de Ascendencia Continental Asiática , China/epidemiología , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad/epidemiología , Predisposición Genética a la Enfermedad/psicología , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Herencia Multifactorial , Polimorfismo de Nucleótido Simple , Estudios Prospectivos , Factores de Riesgo , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/psicología
7.
Medicine (Baltimore) ; 99(40): e21962, 2020 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-33019388

RESUMEN

To evaluate the association between gene polymorphisms of MTHFR (C677T, A1298C) and MTRR (A66G), and the recurrent spontaneous abortion (RSA) risk in Asia.Related case-control studies were collected, selected, and screened. A meta-analysis was conducted by Stata 12.0 software to assess the association between polymorphisms of target genes and RSA.Altogether 30 studies examining the relationship between genetic polymorphism of folate metabolism and RSA risk were included, among which 20 studies were related to MTHFR C677T, 11 to MTHFR A1298C and 6 to MTRR A66G. The studies suggested that MTHFR C677T polymorphism was closely connected with RSA risk under all models (P < .05). Furthermore according to the subgroup analysis of ethnicity, the correlation between C677T polymorphism and RSA was stronger in north of China when compared with south of China and other Asian countries (P > . 05). For MTHFR A1298C, it was closely related to RSA risk in all gene models except for (AC vs AA) (P < .05). However, when it comes to MTRR A66G, there was no significant correlation between gene A66G polymorphism and RSA risk except for the additive gene model (G vs A) (P < .05).The present evidence shows that the correlation between gene polymorphisms and RSA risk can be found in MTHFR C677T, A1298C (except for heterozygote model) and MTRR A66G (only in additive genotypes), and the detection of the correlated gene polymorphisms mentioned above is of certain guiding significance for preventing RSA and screening high-risk groups.


Asunto(s)
Aborto Habitual/genética , Ferredoxina-NADP Reductasa/metabolismo , Ácido Fólico/metabolismo , Metilenotetrahidrofolato Reductasa (NADPH2)/metabolismo , China , Femenino , Humanos , Estudios Observacionales como Asunto , Polimorfismo de Nucleótido Simple , Embarazo , Medición de Riesgo
8.
Medicine (Baltimore) ; 99(40): e22436, 2020 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-33019425

RESUMEN

In addition to governing key functions in bone metabolism and the immune system, the RANK/RANKL/OPG system plays a role in the vascular system, particularly in vascular calcification and atherosclerosis.Given that these 2 phenotypes are considered a major cause of high blood pressure (BP), in this study we analyzed the association of SNPs in RANK and OPG genes with blood pressure. An observational study was conducted of 2 SNPs in the RANK gene (rs884205 and rs78326403) and 1 in the OPG gene (rs4876869) with systolic (SBP) and diastolic blood pressure (DBP) in a cohort of 695 women.Data analysis revealed a statistically significant association between the SNP rs884205 and BP pressure (SBP and DBP). Analyzing this relationship by the dominant inheritance model for this SNP (allele risk: A), women of the AA/AC genotype showed higher BP than women of the CC genotype, both for SBP (P = .001) and for DBP (P = .003), and these associations both surpassed the Bonferroni threshold for multiple comparisons. Multivariate regression analysis including known predictors of BP as independent variables was performed to evaluate the strength of this association, which in the case of the SNP rs884205 of the RANK gene remained statistically significant after adjustment for both SBP (P = .0006) and DBP (P = .005), demonstrating the key role of this SNP in BP.We report a robust association between the SNP rs884205 in RANK gene and BP in women, and this SNP is validated as a candidate in cardiovascular risk studies.


Asunto(s)
Presión Sanguínea/genética , Receptor Activador del Factor Nuclear kappa-B/sangre , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Persona de Mediana Edad , Osteoprotegerina/sangre , Polimorfismo de Nucleótido Simple , España
9.
Yi Chuan ; 42(9): 832-846, 2020 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-32952118

RESUMEN

Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction and chronic airway inflammation, caused by a combination of environmental and genetic factors. It is the third leading cause of death worldwide. In recent years, researchers have applied the genome-wide association study (GWAS) and identified a large number of genetic variants associated with lung functions and potential drug targets for treating COPD. In this review, we summarize the results of GWAS studies and perform a review of the literature since 2007 to highlight the progress of GWAS on COPD. We discuss the challenges, the underlying mechanisms, and the possible drug targets, thereby providing insights on the pathogenesis and potential treatment strategies for COPD.


Asunto(s)
Estudio de Asociación del Genoma Completo , Enfermedad Pulmonar Obstructiva Crónica , Predisposición Genética a la Enfermedad , Humanos , Pulmón , Polimorfismo de Nucleótido Simple
10.
Yi Chuan ; 42(9): 882-888, 2020 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-32952122

RESUMEN

Recent epidemiological studies suggest an association between shorter telomere length and higher risk for type 2 diabetes (T2D). However, results from observational studies are susceptible to confounding and reverse causation, and it is not clear whether there is a causal association between telomere length and T2D. Using Mendelian randomization (MR) and polygenic risk score (PRS) approaches, we had evaluated the causal effect of telomere length on T2D in the Chinese Han population. Using 8 telomere-length associated genetic variants as instrumental variables, an analysis of genetically predicted telomere length and T2D risk was performed in the MR study based on data from a T2D genome-wide association study (GWAS) in 2632 individuals (1318 cases and 1314 controls). We also applied a PRS approach to investigate the causal relationship using Chinese GWAS data. The inverse-variance weighted, MR-Egger regression, simple median, and weighted median methods yielded no evidence of association between genetically predicted longer telomere length and risk of T2D (OR = 0.78, 95% CI: 0.36 ~ 1.68, P = 0.522; OR = 0.23, 95% CI: 0.01 ~ 7.64, P = 0.412; OR = 0.60, 95% CI: 0.28 ~ 1.28, P = 0.185; OR = 0.64, 95% CI: 0.31 ~ 1.33,P = 0.233; respectively). Further, PRS analysis did not produce consistent genetic overlap between telomere length and T2D. Accordingly, this study found no evidence supporting a causal association between telomere length and T2D. Further studies with larger cohorts could yield more reliable results and conclusions.


Asunto(s)
Diabetes Mellitus Tipo 2 , Estudio de Asociación del Genoma Completo , Humanos , Análisis de la Aleatorización Mendeliana , Polimorfismo de Nucleótido Simple , Telómero
11.
Yi Chuan ; 42(9): 889-897, 2020 Sep 20.
Artículo en Inglés | MEDLINE | ID: mdl-32952123

RESUMEN

Osteoporosis is a typical polygenic disease, and its heritability is as high as 85%. The incidence of osteoporosis has jumped to the fifth among the common diseases. Although a large number of osteoporosis-susceptible SNPs have been identified, most of them are in the non-coding regions of the genome and the functional mechanisms are unknown. The purpose of this study was to explore the function of non-coding osteoporosis-susceptible SNP rs4325274 and dissect the molecular regulatory mechanisms through integrating bioinformatics analysis and functional experiments. Firstly, we found the SNP rs4325274 resided in a putative enhancer element through functional annotation. eQTL and Hi-C analysis found that the SOX6 gene might be a potential distal target of rs4325274. We conducted the motif prediction using multiple databases and verified the result using ChIP-seq data from GEO database. The result showed that the transcription factor HNF1A could preferentially bind to SNP rs4325274-G allele. We further demonstrated that SNP rs4325274 acted as an enhancer regulating SOX6 gene expression by using dual-luciferase reporter assays. Knockdown of HNF1A decreased the SOX6 gene expression. Taken together, our results uncovered a new mechanism of a non-coding functional SNP rs4325274 as a distal enhancer to modulate SOX6 expression, which provides new insights into deciphering molecular regulatory mechanisms underlying non-coding susceptibility SNPs on complex diseases.


Asunto(s)
Osteoporosis , Polimorfismo de Nucleótido Simple , Factores de Transcripción SOXD/genética , Alelos , Predisposición Genética a la Enfermedad , Humanos , Osteoporosis/genética , Sitios de Carácter Cuantitativo
12.
PLoS One ; 15(8): e0230404, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32866150

RESUMEN

High-throughput SNP genotyping has become a precondition to move to higher precision and wider genome coverage genetic analysis of natural and breeding populations of non-model species. We developed a 44,318 annotated SNP catalog for Araucaria angustifolia, a grandiose subtropical conifer tree, one of the only two native Brazilian gymnosperms, critically endangered due to its valuable wood and seeds. Following transcriptome assembly and annotation, SNPs were discovered from RNA-seq and pooled RAD-seq data. From the SNP catalog, an Axiom® SNP array with 3,038 validated SNPs was developed and used to provide a comprehensive look at the genetic diversity and structure of 15 populations across the natural range of the species. RNA-seq was a far superior source of SNPs when compared to RAD-seq in terms of conversion rate to polymorphic markers on the array, likely due to the more efficient complexity reduction of the huge conifer genome. By matching microsatellite and SNP data on the same set of A. angustifolia individuals, we show that SNPs reflect more precisely the actual genome-wide patterns of genetic diversity and structure, challenging previous microsatellite-based assessments. Moreover, SNPs corroborated the known major north-south genetic cline, but allowed a more accurate attribution to regional versus among-population differentiation, indicating the potential to select ancestry-informative markers. The availability of a public, user-friendly 3K SNP array for A. angustifolia and a catalog of 44,318 SNPs predicted to provide ~29,000 informative SNPs across ~20,000 loci across the genome, will allow tackling still unsettled questions on its evolutionary history, toward a more comprehensive picture of the origin, past dynamics and future trend of the species' genetic resources. Additionally, but not less importantly, the SNP array described, unlocks the potential to adopt genomic prediction methods to accelerate the still very timid efforts of systematic tree breeding of A. angustifolia.


Asunto(s)
Araucaria/genética , Brasil , Genoma de Planta/genética , Genómica/métodos , Genotipo , Repeticiones de Microsatélite/genética , Polimorfismo de Nucleótido Simple/genética , Tracheophyta/genética , Transcriptoma/genética , Árboles/genética
13.
Gene ; 762: 145102, 2020 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-32882331

RESUMEN

The Angiotensin system is implicated in the pathogenesis of COVID-19. First, ACE2 is the cellular receptor for SARS-CoV-2, and expression of the ACE2 gene could regulate the individuals susceptibility to infection. In addition, the balance between ACE1 and ACE2 activity has been implicated in the pathogenesis of respiratory diseases and could play a role in the severity of COVID-19. Functional ACE1/ACE2 gene polymorphisms have been associated with the risk of cardiovascular and pulmonary diseases, and could thus also contribute to the outcome of COVID-19. We studied 204 COVID-19 patients (137 non-severe and 67 severe-ICU cases) and 536 age-matched controls. The ACE1 insertion/deletion and ACE2 rs2285666 polymorphism were determined. Variables frequencies were compared between the groups by logistic regression. We also sequenced the ACE2 coding nucleotides in a group of patients. Severe COVID-19 was associated with hypertension male gender (p < 0.001), hypertension (p = 0.006), hypercholesterolaemia (p = 0.046), and the ACE1-DD genotype (p = 0.049). In the multiple logistic regression hypertension (p = 0.02, OR = 2.26, 95%CI = 1.12-4.63) and male gender (p = 0.002; OR = 3.15, 95%CI = 1.56-6.66) remained as independent significant predictors of severity. The ACE2 polymorphism was not associated with the disease outcome. The ACE2 sequencing showed no coding sequence variants that could explain an increased risk of developing COVID-19. In conclusion, an adverse outcome of COVID-19 was associated with male gender, hypertension, hypercholesterolemia and the ACE1 genotype. Our work suggested that the ACE1-I/D might influence COVID-19 severity, but the effect was dependent on the hypertensive status. This result requires further validation in other large cohorts.


Asunto(s)
Infecciones por Coronavirus/genética , Peptidil-Dipeptidasa A/genética , Neumonía Viral/genética , Adulto , Anciano , Anciano de 80 o más Años , Betacoronavirus , Estudios de Casos y Controles , Femenino , Técnicas de Genotipaje , Humanos , Hipercolesterolemia/complicaciones , Hipertensión/complicaciones , Mutación INDEL , Masculino , Persona de Mediana Edad , Pandemias , Polimorfismo de Nucleótido Simple , Factores de Riesgo , España , Adulto Joven
14.
Genes (Basel) ; 11(9)2020 08 27.
Artículo en Inglés | MEDLINE | ID: mdl-32867305

RESUMEN

The recent global COVID-19 public health emergency is caused by SARS-CoV-2 infections and can manifest extremely variable clinical symptoms. Host human genetic variability could influence susceptibility and response to infection. It is known that ACE2 acts as a receptor for this pathogen, but the viral entry into the target cell also depends on other proteins. The aim of this study was to investigate the variability of genes coding for these proteins involved in the SARS-CoV-2 entry into the cells. We analyzed 131 COVID-19 patients by exome sequencing and examined the genetic variants of TMPRSS2, PCSK3, DPP4, and BSG genes. In total we identified seventeen variants. In PCSK3 gene, we observed a missense variant (c.893G>A) statistically more frequent compared to the EUR GnomAD reference population and a missense mutation (c.1906A>G) not found in the GnomAD database. In TMPRSS2 gene, we observed a significant difference in the frequency of c.331G>A, c.23G>T, and c.589G>A variant alleles in COVID-19 patients, compared to the corresponding allelic frequency in GnomAD. Genetic variants in these genes could influence the entry of the SARS-CoV-2. These data also support the hypothesis that host genetic variability may contribute to the variability in infection susceptibility and severity.


Asunto(s)
Basigina/genética , Infecciones por Coronavirus/genética , Furina/genética , Mutación , Neumonía Viral/genética , Serina Endopeptidasas/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Preescolar , Infecciones por Coronavirus/patología , Dipeptidil Peptidasa 4/genética , Exoma , Femenino , Humanos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/patología , Polimorfismo de Nucleótido Simple
15.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 38(4): 364-370, 2020 Aug 01.
Artículo en Chino | MEDLINE | ID: mdl-32865352

RESUMEN

OBJECTIVE: To explore the association between two single nucleotide polymorphisms (SNPs), namely, rs4691383 and rs7667857, in the platelet-derived growth factor-C (PDGF-C) gene, the genotypes, environmental exposure factors, and nonsyndromic cleft lip with or without cleft palate (NSCL/P) in Western Chinese population. METHODS: A total of 268 case-parent trios were selected, and two SNPs (rs4691383 andrs7667857) were genotyped by using polymerase chain reaction and restriction enzyme fragment length polymorphic method and direct sequencing method. Hardy-Weinberg equilibrium, linkage disequilibrium test, transmission disequilibrium test, and haplotype analysis were conducted to analyze the data. Meanwhile, the questionnaires on the epidemiology of cleft lip and palate filled by the included samples were collected, and the interaction between the genotypes of the two SNPs and environmental exposure factors was assessed by conditional logistic regression. RESULTS: The A allele at rs4691383 and the G allele at rs7667857 of PDGF-C gene were over-transmitted for NSCL/P (P<0.05). No interaction effect was observed between the three environmental exposure factors (history of smoking/passive smoking, folic acid supplementation, and long-term inhalation of harmful environmental gases) and the PDGF-C genotypes among NSCL/P (P>0.05). CONCLUSIONS: The rs4691383 and rs7667857 at PDGF-C gene are closely related to the occurrence of NSCL/P in Western Chinese population. However, the interaction between environmental exposure factors and PDGF-C genotypes is not obvious in the occurrence of NSCL/P.


Asunto(s)
Labio Leporino , Fisura del Paladar , Estudios de Casos y Controles , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Linfocinas , Factor de Crecimiento Derivado de Plaquetas , Polimorfismo de Nucleótido Simple
16.
Lancet Oncol ; 21(9): e431-e443, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32888472

RESUMEN

Peptide receptor radionuclide therapy (PRRT) is a type of radiotherapy that targets peptide receptors and is typically used for neuroendocrine tumours (NETs). Some of the key challenges in its use are the prediction of efficacy and toxicity, patient selection, and response optimisation. In this Review, we assess current knowledge on the molecular profile of NETs and the strategies and tools used to predict, monitor, and assess the toxicity of PRRT. The few mutations in tumour genes that can be evaluated (eg, ATM and DAXX) are limited to pancreatic NETs and are most likely not informative. Assays that are transcriptomic or based on genes are effective in the prediction of radiotherapy response in other cancers. A blood-based assay for eight genes (the PRRT prediction quotient [PPQ]) has an overall accuracy of 95% for predicting responses to PRRT in NETs. No molecular markers exist that can predict the toxicity of PRRT. Candidate molecular targets include seven single nucleotide polymorphisms (SNPs) that are susceptible to radiation. Transcriptomic evaluations of blood and a combination of gene expression and specific SNPs, assessed by machine learning with algorithms that are tumour-specific, might yield molecular tools to enhance the efficacy and safety of PRRT.


Asunto(s)
Proteínas de Neoplasias/genética , Tumores Neuroendocrinos/radioterapia , Neoplasias Pancreáticas/radioterapia , Receptores de Formil Péptido/uso terapéutico , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Humanos , Masculino , Tumores Neuroendocrinos/genética , Tumores Neuroendocrinos/patología , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patología , Polimorfismo de Nucleótido Simple/genética , Radioisótopos/uso terapéutico , Transcriptoma/efectos de la radiación
17.
Nat Commun ; 11(1): 4301, 2020 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-32879317

RESUMEN

Copy-number aberrations (CNAs) and whole-genome duplications (WGDs) are frequent somatic mutations in cancer but their quantification from DNA sequencing of bulk tumor samples is challenging. Standard methods for CNA inference analyze tumor samples individually; however, DNA sequencing of multiple samples from a cancer patient has recently become more common. We introduce HATCHet (Holistic Allele-specific Tumor Copy-number Heterogeneity), an algorithm that infers allele- and clone-specific CNAs and WGDs jointly across multiple tumor samples from the same patient. We show that HATCHet outperforms current state-of-the-art methods on multi-sample DNA sequencing data that we simulate using MASCoTE (Multiple Allele-specific Simulation of Copy-number Tumor Evolution). Applying HATCHet to 84 tumor samples from 14 prostate and pancreas cancer patients, we identify subclonal CNAs and WGDs that are more plausible than previously published analyses and more consistent with somatic single-nucleotide variants (SNVs) and small indels in the same samples.


Asunto(s)
Neoplasias de la Mama/genética , Variaciones en el Número de Copia de ADN , Duplicación de Gen , Neoplasias Pancreáticas/genética , Neoplasias de la Próstata/genética , Neoplasias de la Mama/patología , Conjuntos de Datos como Asunto , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Mutación INDEL , Masculino , Tasa de Mutación , Metástasis de la Neoplasia/genética , Neoplasias Pancreáticas/patología , Polimorfismo de Nucleótido Simple , Neoplasias de la Próstata/patología , Análisis de la Célula Individual , Secuenciación del Exoma Completo
19.
Tumour Biol ; 42(9): 1010428320958955, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32921281

RESUMEN

Colorectal cancer is the fourth most common type of malignancy worldwide that may develop due to the accumulation of several genetic variations. Different single nucleotide polymorphisms of SMAD1 gene are assumed to be linked with increased colorectal cancer risk. The current case-control study was conducted to verify the association of genetic polymorphisms of SMAD1 (rs11100883 and rs7661162) with colorectal cancer in the Bangladeshi population. This study was performed on 275 colorectal cancer patients and 300 healthy volunteers using polymerase chain reaction-restriction fragment length polymorphism method. The odds ratios were adjusted for age and sex with logistic regression analysis. In case of SMAD1 rs11100883 polymorphism, GA heterozygous genotype, GA + AA (dominant model), and minor allele "A" were significantly associated with colorectal cancer (adjusted odds ratio = 1.55, 95% confidence interval = 1.09-2.20, p = 0.014; adjusted odds ratio = 1.59, 95% confidence interval = 1.13-2.23, p = 0.008; and odds ratio = 1.35, 95% confidence interval = 1.06-1.73, p = 0.015, respectively) and the significance exists after the Bonferroni correction. Again, single nucleotide polymorphism rs7661162 showed significant association with an elevated colorectal cancer risk for AG heterozygous genotype, AG + GG (dominant model), AG versus AA + GG (overdominant model), and minor allele "G" (adjusted odds ratio = 1.78, 95% confidence interval = 1.24-2.56, p = 0.002; adjusted odds ratio = 1.68, 95% confidence interval = 1.18-2.39, p = 0.004; adjusted odds ratio = 1.76, 95% confidence interval = 1.23-2.53, p = 0.002; and odds ratio = 1.47, 95% confidence interval = 1.08-2.00, p = 0.014, respectively) and significance withstands after the Bonferroni correction. No significant age and gender differences between cases and controls were observed. In silico, gene expression analysis showed that the SMAD1 mRNA level was downregulated in the colon and rectal cancer tissues compared to healthy tissues. In conclusion, our findings indicate that SMAD1 rs11100883 and rs7661162 polymorphisms are responsible for increasing the susceptibility of colorectal cancer development in the Bangladeshi population.


Asunto(s)
Neoplasias Colorrectales/genética , Predisposición Genética a la Enfermedad/genética , Proteína Smad1/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Bangladesh , Estudios de Casos y Controles , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Adulto Joven
20.
Nat Commun ; 11(1): 4662, 2020 09 16.
Artículo en Inglés | MEDLINE | ID: mdl-32938926

RESUMEN

Haplotype reconstruction of distant genetic variants remains an unsolved problem due to the short-read length of common sequencing data. Here, we introduce HapTree-X, a probabilistic framework that utilizes latent long-range information to reconstruct unspecified haplotypes in diploid and polyploid organisms. It introduces the observation that differential allele-specific expression can link genetic variants from the same physical chromosome, thus even enabling using reads that cover only individual variants. We demonstrate HapTree-X's feasibility on in-house sequenced Genome in a Bottle RNA-seq and various whole exome, genome, and 10X Genomics datasets. HapTree-X produces more complete phases (up to 25%), even in clinically important genes, and phases more variants than other methods while maintaining similar or higher accuracy and being up to 10×  faster than other tools. The advantage of HapTree-X's ability to use multiple lines of evidence, as well as to phase polyploid genomes in a single integrative framework, substantially grows as the amount of diverse data increases.


Asunto(s)
Desequilibrio Alélico , Haplotipos , Análisis de Secuencia de ARN , Algoritmos , Bases de Datos Genéticas , Diploidia , Humanos , Células K562 , Modelos Genéticos , Modelos Estadísticos , Polimorfismo de Nucleótido Simple , Poliploidía , RNA-Seq , Análisis de Secuencia de ARN/métodos , Análisis de Secuencia de ARN/estadística & datos numéricos
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