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1.
Gene ; 747: 144700, 2020 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-32330537

RESUMEN

OBJECTIVE: Survival rate of laryngeal squamous cell carcinoma (LSCC) patients is not improving. To understand more complete biology of LSCC, studies focused on identification of new specific and prognostic markers are performed. The aim of current study was to evaluate the impact of five different single nucleotide polymorphisms (SNP) (IL6 rs1800795, BLK rs13277113, TIMP3 rs9621532, IL1RL1 rs1041973 and IL1RAP rs4624606) on LSCC development. MATERIAL AND METHODS: A total of 891 subjects (353 histologically verified LSCC patients and 538 healthy controls) were involved in this study. The genotyping was carried out using the real-time-PCR. RESULTS: Statistical analysis revealed statistically significant associations between TIMP3 rs96215332 variants and LSCC in the codominant (OR = 0.600; 95% CI: 0.390-0.922; p = 0.020), overdominant (OR = 0.599; 95% CI: 0.390-0.922; p = 0.020) and additive (OR = 0.675; 95% CI: 0.459-0.991; p = 0.045) models. Also, significant variants of IL1RAP rs4624606 were determined in the codominant (OR = 1.372; 95% CI: 1.031-1.827; p = 0.030), overdominant (OR = 1.353; 95% CI: 1.018-1.798; p = 0.037) and additive (OR = 1.337; 95% CI: 1.038-1.724; p = 0.025) models. CONCLUSION: Results of the current study indicate significant associations between TIMP3 rs9621532 and IL1RAP rs4624606 gene polymorphisms and LSCC development.


Asunto(s)
Carcinoma de Células Escamosas/genética , Proteína Accesoria del Receptor de Interleucina-1/genética , Proteína 1 Similar al Receptor de Interleucina-1/genética , Interleucina-6/genética , Neoplasias Laríngeas/genética , Polimorfismo de Nucleótido Simple/genética , Inhibidor Tisular de Metaloproteinasa-3/genética , Familia-src Quinasas/genética , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Mapas de Interacción de Proteínas/genética
2.
Gene ; 747: 144673, 2020 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-32304783

RESUMEN

Krabbe disease is one of the rarest autosomal recessive disorders in human, caused by mutation in the GALC (ß-galactosylceramidase) gene, resulting in several mental and physical health issues. Due to its rarity and phenotypic heterogeneity, diagnosis rate of this disease is very low. This study generated information on the recessive allele frequency dynamics of GALC gene across 15 global populations, with the highest frequency detected in Druze (Israel) population and the lowest frequency in Turkey and the United States. The recessive allele would take more time period (about 24,975 years) to be completely removed from the population having the lowest frequency and vice versa. The codon usage patterns of four isoforms of GALC gene revealed that a few synonymous codons were used more frequently than others in the isoforms. The codon AGA (arginine) was found to be overrepresented in GALC gene, except for galactocerebrosidase isoform a precursor. Further, GALC gene showed low codon usage bias (CUB) as evident from high ENC values (55.7-58.2), with A/T ending codons more preferred to G/C ending codons. CUB analysis elucidated the dual role of mutational pressure (major role) and natural selection (minor role) in GALC gene evolution.


Asunto(s)
Uso de Codones/genética , Galactosilceramidasa/genética , Frecuencia de los Genes/genética , Leucodistrofia de Células Globoides/enzimología , Leucodistrofia de Células Globoides/genética , Aminoácidos/genética , Composición de Base/genética , Codón/genética , Evolución Molecular , Galactosilceramidasa/metabolismo , Humanos , Filogenia , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo
3.
Biol Res ; 53(1): 15, 2020 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-32299502

RESUMEN

BACKGROUND: Current South American populations trace their origins mainly to three continental ancestries, i.e. European, Amerindian and African. Individual variation in relative proportions of each of these ancestries may be confounded with socio-economic factors due to population stratification. Therefore, ancestry is a potential confounder variable that should be considered in epidemiologic studies and in public health plans. However, there are few studies that have assessed the ancestry of the current admixed Chilean population. This is partly due to the high cost of genome-scale technologies commonly used to estimate ancestry. In this study we have designed a small panel of SNPs to accurately assess ancestry in the largest sampling to date of the Chilean mestizo population (n = 3349) from eight cities. Our panel is also able to distinguish between the two main Amerindian components of Chileans: Aymara from the north and Mapuche from the south. RESULTS: A panel of 150 ancestry-informative markers (AIMs) of SNP type was selected to maximize ancestry informativeness and genome coverage. Of these, 147 were successfully genotyped by KASPar assays in 2843 samples, with an average missing rate of 0.012, and a 0.95 concordance with microarray data. The ancestries estimated with the panel of AIMs had relative high correlations (0.88 for European, 0.91 for Amerindian, 0.70 for Aymara, and 0.68 for Mapuche components) with those obtained with AXIOM LAT1 array. The country's average ancestry was 0.53 ± 0.14 European, 0.04 ± 0.04 African, and 0.42 ± 0.14 Amerindian, disaggregated into 0.18 ± 0.15 Aymara and 0.25 ± 0.13 Mapuche. However, Mapuche ancestry was highest in the south (40.03%) and Aymara in the north (35.61%) as expected from the historical location of these ethnic groups. We make our results available through an online app and demonstrate how it can be used to adjust for ancestry when testing association between incidence of a disease and nongenetic risk factors. CONCLUSIONS: We have conducted the most extensive sampling, across many different cities, of current Chilean population. Ancestry varied significantly by latitude and human development. The panel of AIMs is available to the community for estimating ancestry at low cost in Chileans and other populations with similar ancestry.


Asunto(s)
Grupos Étnicos/genética , Genética de Población/organización & administración , Indios Sudamericanos/genética , Polimorfismo de Nucleótido Simple/genética , Grupos de Población/genética , Chile , Femenino , Frecuencia de los Genes/genética , Marcadores Genéticos/genética , Genotipo , Técnicas de Genotipaje , Humanos , Masculino , Filogeografía , Saliva
4.
Am J Hum Genet ; 106(4): 453-466, 2020 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-32197076

RESUMEN

Identity-by-descent (IBD) segments are a useful tool for applications ranging from demographic inference to relationship classification, but most detection methods rely on phasing information and therefore require substantial computation time. As genetic datasets grow, methods for inferring IBD segments that scale well will be critical. We developed IBIS, an IBD detector that locates long regions of allele sharing between unphased individuals, and benchmarked it with Refined IBD, GERMLINE, and TRUFFLE on 3,000 simulated individuals. Phasing these with Beagle 5 takes 4.3 CPU days, followed by either Refined IBD or GERMLINE segment detection in 2.9 or 1.1 h, respectively. By comparison, IBIS finishes in 6.8 min or 7.8 min with IBD2 functionality enabled: speedups of 805-946× including phasing time. TRUFFLE takes 2.6 h, corresponding to IBIS speedups of 20.2-23.3×. IBIS is also accurate, inferring ≥7 cM IBD segments at quality comparable to Refined IBD and GERMLINE. With these segments, IBIS classifies first through third degree relatives in real Mexican American samples at rates meeting or exceeding other methods tested and identifies fourth through sixth degree pairs at rates within 0.0%-2.0% of the top method. While allele frequency-based approaches that do not detect segments can infer relationship degrees faster than IBIS, the fastest are biased in admixed samples, with KING inferring 30.8% fewer fifth degree Mexican American relatives correctly compared with IBIS. Finally, we ran IBIS on chromosome 2 of the UK Biobank dataset and estimate its runtime on the autosomes to be 3.3 days parallelized across 128 cores.


Asunto(s)
Análisis de Secuencia/métodos , Alelos , Cromosomas Humanos Par 2/genética , Frecuencia de los Genes/genética , Genoma Humano/genética , Humanos , Modelos Genéticos , Polimorfismo de Nucleótido Simple/genética
5.
PLoS One ; 15(2): e0227997, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32023277

RESUMEN

BACKGROUND: Behçet's disease (BD) is a chronic multi-systemic vasculitis with a considerable prevalence in Asian countries. There are many genes associated with a higher risk of developing BD, one of which is endoplasmic reticulum aminopeptidase-1 (ERAP1). In this study, we aimed to investigate the interactions of ERAP1 single nucleotide polymorphisms (SNPs) using a novel data mining method called Model-based multifactor dimensionality reduction (MB-MDR). METHODS: We have included 748 BD patients and 776 healthy controls. A peripheral blood sample was collected, and eleven SNPs were assessed. Furthermore, we have applied the MB-MDR method to evaluate the interactions of ERAP1 gene polymorphisms. RESULTS: The TT genotype of rs1065407 had a synergistic effect on BD susceptibility, considering the significant main effect. In the second order of interactions, CC genotype of rs2287987 and GG genotype of rs1065407 had the most prominent synergistic effect (ß = 12.74). The mentioned genotypes also had significant interactions with CC genotype of rs26653 and TT genotype of rs30187 in the third-order (ß = 12.74 and ß = 12.73, respectively). CONCLUSION: To the best of our knowledge, this is the first study investigating the interaction of a particular gene's SNPs in BD patients by applying a novel data mining method. However, future studies investigating the interactions of various genes could clarify this issue.


Asunto(s)
Algoritmos , Aminopeptidasas/genética , Síndrome de Behçet/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Antígenos de Histocompatibilidad Menor/genética , Modelos Genéticos , Reducción de Dimensionalidad Multifactorial , Polimorfismo de Nucleótido Simple/genética , Adulto , Entropía , Femenino , Frecuencia de los Genes/genética , Redes Reguladoras de Genes , Humanos , Irán , Masculino
6.
Gene ; 736: 144406, 2020 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-32007580

RESUMEN

Estrogen receptor (ER) signaling is key regulator for maintaining successful pregnancy. Several research suggested that genetic variation in ER genes (ESR)1 and ESR2 is associated with the susceptibility to unexplained recurrent pregnancy loss (RPL), often with inconclusive results. In this study, we investigate the relationship between ESR1 and ESR2 polymorphisms and idiopathic RPL. A total of 444 patients with RPL, defined as three or more consecutive pregnancy losses of unknown etiology, and 446 control women were recruited to the study and their genotypes for ESR1-rs2234693, ESR1-rs3020314, and ESR2-rs928554 variants were determined using allelic exclusion method on real-time polymerase chain reaction. Minor allele frequencies (MAF) of tagging SNPs ESR1 rs2234693 and rs3020314, and ESR2 rs928554 were not significantly different between RPL cases and control women. Considerable higher frequencies of homozygous (2/2) ESR1 rs2234693 genotype carriers were seen between patients vs. control women, which maintained after controlling for age, body mass index (BMI), and menarche. ESR1 haplotype analysis demonstrated two common haplotype (rs2234693-rs3020314) with no linkage disequilibrium between both polymorphisms, and no 2-locus haplotype linked with RPL risk was revealed. The present study confirmed a significant association of specific ESR1 variant (rs2234693) with an increased risk of RPL, further supporting a role for ESR1 as an important candidate locus inducing RPL.


Asunto(s)
Aborto Habitual/genética , Aborto Espontáneo/genética , Receptor alfa de Estrógeno/genética , Receptor beta de Estrógeno/genética , Predisposición Genética a la Enfermedad/genética , Polimorfismo de Nucleótido Simple/genética , Adulto , Estudios de Casos y Controles , Estrógenos/genética , Femenino , Frecuencia de los Genes/genética , Genotipo , Humanos , Desequilibrio de Ligamiento/genética , Embarazo , Estudios Retrospectivos , Túnez
7.
Gene ; 736: 144419, 2020 Apr 30.
Artículo en Inglés | MEDLINE | ID: mdl-32018016

RESUMEN

OBJECTIVES: To evaluate the relationship between two common single nucleotide polymorphisms (SNPs) of CD40 gene (rs1883832 C/T and rs4810485 G/T) and the risk of immune thrombocytopenia (ITP) in the Egyptian population. METHODS: A case-control study was conducted retrospectively on 101 cases with ITP and 97 healthy subjects. Two SNPs of CD40 gene (rs1883832 C/T and rs4810485 G/T) were genotyped via Taqman allele discrimination real-time PCR. The frequencies of different genetic models of both SNPs were calculated and compared between ITP cases and controls. Linkage analysis was performed between the studied SNPs. Odds ratio (OR) and 95% confidence interval (CI) were assessed using multinomial logistic regression analysis to determine the association of CD40 gene SNPs genotypes, alleles, and haplotypes with the risk of ITP. The odds ratio was further adjusted to the confounders for risk stratification. RESULTS: CD40 (rs1883832) TT genotype carriers have a significantly higher risk of ITP when compared to CC genotype carriers (adjusted OR: 3.792, 95%CI: 1.252-11.49, P = 0.018). T allele also represents 1.711-fold increased risk of ITP which is more evident in males (P = 0.016). No significant difference was observed in the frequency of CD40 (rs4810485 G/T) genetic models between cases and controls. Linkage disequilibrium was found between the two SNPs and revealed four main haplotypes (C-G; C-T; T-G; T-T) with a significantly higher frequency of T-G haplotype in ITP cases than in healthy controls which confers an increased risk of ITP development (OR: 2.349, 95%CI: 1.271-4.339, P = 0.006). CONCLUSIONS: CD40 gene SNP rs1883832 is associated with an increased risk of ITP development in the Egyptian population, while the SNP rs4810485 has no association. Moreover, T-G haplotype is a risk genetic model for ITP.


Asunto(s)
Antígenos CD40/genética , Polimorfismo de Nucleótido Simple/genética , Púrpura Trombocitopénica Idiopática/genética , Adulto , Alelos , Estudios de Casos y Controles , Egipto , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Haplotipos/genética , Humanos , Desequilibrio de Ligamiento/genética , Masculino , Estudios Retrospectivos
8.
Nucleic Acids Res ; 48(6): e36, 2020 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-32067044

RESUMEN

Alu retrotransposons account for more than 10% of the human genome, and insertions of these elements create structural variants segregating in human populations. Such polymorphic Alus are powerful markers to understand population structure, and they represent variants that can greatly impact genome function, including gene expression. Accurate genotyping of Alus and other mobile elements has been challenging. Indeed, we found that Alu genotypes previously called for the 1000 Genomes Project are sometimes erroneous, which poses significant problems for phasing these insertions with other variants that comprise the haplotype. To ameliorate this issue, we introduce a new pipeline - TypeTE - which genotypes Alu insertions from whole-genome sequencing data. Starting from a list of polymorphic Alus, TypeTE identifies the hallmarks (poly-A tail and target site duplication) and orientation of Alu insertions using local re-assembly to reconstruct presence and absence alleles. Genotype likelihoods are then computed after re-mapping sequencing reads to the reconstructed alleles. Using a high-quality set of PCR-based genotyping of >200 loci, we show that TypeTE improves genotype accuracy from 83% to 92% in the 1000 Genomes dataset. TypeTE can be readily adapted to other retrotransposon families and brings a valuable toolbox addition for population genomics.


Asunto(s)
Secuencias Repetitivas Esparcidas/genética , Mutagénesis Insercional/genética , Programas Informáticos , Secuenciación Completa del Genoma/métodos , Bases de Datos Genéticas , Frecuencia de los Genes/genética , Sitios Genéticos , Genética de Población , Genoma Humano , Genotipo , Humanos
9.
PLoS One ; 15(1): e0228000, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31971968

RESUMEN

Interethnic variability in drug response arises from genetic differences associated with drug metabolism, action and transport. These genetic variations can affect drug efficacy as well as cause adverse drug reactions (ADRs). We retrieved drug-response related single nucleotide polymorphism (SNP) associated data from databases and analyzed to elucidate population specific distribution of 159 drug-response related SNPs in twenty six populations belonging to five super-populations (African, Admixed Americans, East Asian, European and South Asian). Significant interpopulation differences exist in the minor (variant) allele frequencies (MAFs), linkage disequilibrium (LD) and haplotype distributions among these populations. 65 of the drug-response related alleles, which are considered as minor (variant) in global population, are present as the major alleles (frequency ≥0.5) in at least one or more populations. Populations that belong to the same super-population have similar distribution pattern for majority of the variant alleles. These drug response related variant allele frequencies and their pairwise LD measure (r2) can clearly distinguish the populations in a way that correspond to the known evolutionary history of human and current geographic distributions, while D' cannot. The data presented here may aid in identifying drugs that are more appropriate and/or require pharmacogenetic testing in these populations. Our findings emphasize on the importance of distinct, ethnicity-specific clinical guidelines, especially for the African populations, to avoid ADRs and ensure effective drug treatment.


Asunto(s)
Heterogeneidad Genética , Genética de Población , Preparaciones Farmacéuticas/metabolismo , Filogenia , Polimorfismo de Nucleótido Simple/genética , Alelos , Análisis por Conglomerados , Frecuencia de los Genes/genética , Geografía , Haplotipos/genética , Humanos , Desequilibrio de Ligamiento/genética , Análisis Multivariante
10.
Int J Occup Environ Med ; 11(1): 53-58, 2020 01.
Artículo en Inglés | MEDLINE | ID: mdl-31905195

RESUMEN

BACKGROUND: Exposure to numerous chemicals, including industrial ones, may result in liver damage. The body susceptibility to the environmental hazards largely depends on the activity of the enzymes in the xenobiotic detoxification system. Function abnormalities of such enzymes due to genetic variations would increase the risk of developing various diseases. OBJECTIVE: To elucidate the relationship between polymorphism in glutathione S-transferase genes (GSTM1, GSTT1 and GSTP1) and the risk of toxic liver damage in a group of petrochemical workers. METHODS: This study was conducted on 72 workers with toxic liver injury, 156 healthy workers, and 322 healthy individuals without history of occupational exposure to chemicals. Genotyping of the GSTP1 rs1695 gene polymorphism was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Polymerase chain reaction (PCR) was used to perform genotyping of the GSTM1 and GSTT1 genes polymorphism. RESULTS: There was a significant difference in genotype frequencies of the GSTP1 rs1695 gene polymorphism among the groups studied. The distribution of Val/Val genotype of the GSTP1 rs1695 gene polymorphism had a higher incidence in healthy workers compared with patients with toxic liver damage (p=0.036). No significant association was found between the GSTM1 and GSTT1 polymorphisms and toxic liver damage. CONCLUSION: The GSTP1 rs1695 gene polymorphism can play a protective role in the development of toxic liver damage in petrochemical workers.


Asunto(s)
Gutatión-S-Transferasa pi/genética , Glutatión Transferasa/genética , Hígado/patología , Exposición Profesional/efectos adversos , Adulto , Estudios de Casos y Controles , Frecuencia de los Genes/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa , Polimorfismo Genético , Polimorfismo de Longitud del Fragmento de Restricción
11.
PLoS One ; 15(1): e0227148, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31968001

RESUMEN

We used genotyping-by-sequencing (GBS) to investigate the evolutionary history of domesticated tetraploid wheats. With a panel of 189 wild and domesticated wheats, we identified 1,172,469 single nucleotide polymorphisms (SNPs) with a read depth ≥3. Principal component analyses (PCAs) separated the Triticum turgidum and Triticum timopheevii accessions, as well as wild T. turgidum from the domesticated emmers and the naked wheats, showing that SNP typing by GBS is capable of providing robust information on the genetic relationships between wheat species and subspecies. The PCAs and a neighbour-joining analysis suggested that domesticated tetraploid wheats have closest affinity with wild emmers from the northern Fertile Crescent, consistent with the results of previous genetic studies on the origins of domesticated wheat. However, a more detailed examination of admixture and allele sharing between domesticates and different wild populations, along with genome-wide association studies (GWAS), showed that the domesticated tetraploid wheats have also received a substantial genetic input from wild emmers from the southern Levant. Taking account of archaeological evidence that tetraploid wheats were first cultivated in the southern Levant, we suggest that a pre-domesticated crop spread from this region to southeast Turkey and became mixed with a wild emmer population from the northern Fertile Crescent. Fixation of the domestication traits in this mixed population would account for the allele sharing and GWAS results that we report. We also propose that feralization of the component of the pre-domesticated population that did not acquire domestication traits has resulted in the modern wild population from southeast Turkey displaying features of both the domesticates and wild emmer from the southern Levant, and hence appearing to be the sole progenitor of domesticated tetraploids when the phylogenetic relationships are studied by methods that assume a treelike pattern of evolution.


Asunto(s)
Evolución Biológica , Domesticación , Tetraploidía , Triticum/genética , Alelos , Secuencia de Bases , Frecuencia de los Genes/genética , Sitios Genéticos/genética , Genoma de Planta/genética , Estudio de Asociación del Genoma Completo , Genotipo , Fenotipo , Filogenia , Polimorfismo de Nucleótido Simple , Triticum/clasificación , Turquia
12.
Gene ; 733: 144358, 2020 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-31935507

RESUMEN

PURPOSE: Identification the genetic factors in preeclampsia (PE) are useful to increase the current knowledge of the pathophysiology of the disorder. The genetic factors implicated for all cases of PE remain to be determined. This study was aimed to investigate association between ADD1 1378G > T, AGTR2 1675G > A, AGTR1 1166A > C, NOS3 894 G > T and CYP11B2 -344C > T gene polymorphisms in Iranian women with PE. MATERIAL AND METHODS: 117 pregnant women with PE and 103 healthy women without affected previous pregnancy by PE were selected. Genomic DNA was extracted from peripheral blood and real-time PCR was performed to investigate the polymorphisms using a commercial kit. RESULTS: There was a significant difference in CYP11B2 -344C > T gene polymorphism between case and control groups (P = 0.025). The odds ratio was 0.71 (CI 95% = 0.28-1.79). There were no statistical significant differences between other genetic polymorphisms. CONCLUSION: Our results showed a significant association between CYP11B2 -344C > T gene polymorphism with PE. This finding suggests that mentioned polymorphism may be associated with susceptibility to PE at least in IRAN.


Asunto(s)
Citocromo P-450 CYP11B2/genética , Preeclampsia/genética , Adulto , Alelos , Estudios de Casos y Controles , Citocromo P-450 CYP11B2/metabolismo , Femenino , Frecuencia de los Genes/genética , Estudios de Asociación Genética/métodos , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Irán/epidemiología , Oportunidad Relativa , Polimorfismo Genético/genética , Preeclampsia/fisiopatología , Embarazo
13.
Gene ; 733: 144372, 2020 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-31954858

RESUMEN

BACKGROUND: Obesity is a huge burden of the world. It is commonly recognized that dietary structure and physical inactivity is essential in the progress of obesity. However, some individuals still face the trouble of obese even though they live a healthy life. Except for the combination of diseases, the operation of both lifestyle and genetic features contributes to obesity. Melanocortin-4-receptor (MC4R) gene is one of the known hereditary factors of obesity. rs17782313, a single nucleotide variant in MC4R gene, has been reported unclear results in whether it plays a role in obesity. This meta-analysis is to estimate the association between MC4R rs17782313 genotype and obesity. METHOD: A systematic literature retrieval was conducted in four databases: PubMed, Embase, Web of Science and Cochrane Library with specific search strategy. Select qualified studies to identify relevant studies. Odds ratios (ORs) with 95% confidence intervals (CI), P value and I2 value were used to assess the strength of the association in meta-analysis and adjusted with ethnicity, quality and single nucleotide polymorphism (SNP) testing method. RESULT: 6 eligible studies involving 3133 obese cases and 3123 normal-weight participants were selected from 378 articles. Allele B of MC4R rs17782313 present a statistically significant association with obesity under allele contrast model (OR = 1.325, 95%CI: 1.219-1.439), dominant model (OR = 1.320, 95%CI: 1.184-1.472), recessive model (OR = 1.690, 95%CI: 1.420-2.011) and homozygous type of co-dominant model (OR = 1.925, 95%CI: 1.590-2.330), respectively, and P < 0.05. CONCLUSION: Mutated MC4R rs17782313 is associated with higher risk of obesity. People with homozygous mutant genotype of MC4R rs17782313 would be more likely to suffer from obesity, while heterozygous mutant genotype needs further studies to clarify.


Asunto(s)
Obesidad/genética , Receptor de Melanocortina Tipo 4/genética , Alelos , Índice de Masa Corporal , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/genética , Receptor de Melanocortina Tipo 4/metabolismo
14.
BMC Infect Dis ; 20(1): 59, 2020 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-31959123

RESUMEN

BACKGROUND: Tuberculosis (TB) and AIDS are the leading causes of infectious disease death worldwide. In some TB-HIV co-infected individuals treated for both diseases simultaneously, a pathological inflammatory reaction termed immune reconstitution inflammatory syndrome (IRIS) may occur. The risk factors for IRIS are not fully defined. We investigated the association of HLA-B, HLA-C, and KIR genotypes with TB, HIV-1 infection, and IRIS onset. METHODS: Patients were divided into four groups: Group 1- TB+/HIV+ (n = 88; 11 of them with IRIS), Group 2- HIV+ (n = 24), Group 3- TB+ (n = 24) and Group 4- healthy volunteers (n = 26). Patients were followed up at INI/FIOCRUZ and HGNI (Rio de Janeiro/Brazil) from 2006 to 2016. The HLA-B and HLA-C loci were typed using SBT, NGS, and KIR genes by PCR-SSP. Unconditional logistic regression models were performed for Protection/risk estimation. RESULTS: Among the individuals with TB as the outcome, KIR2DS2 was associated with increased risk for TB onset (aOR = 2.39, P = 0.04), whereas HLA-B*08 and female gender were associated with protection against TB onset (aOR = 0.23, P = 0.03, and aOR = 0.33, P = 0.01, respectively). Not carrying KIR2DL3 (aOR = 0.18, P = 0.03) and carrying HLA-C*07 (aOR = 0.32, P = 0.04) were associated with protection against TB onset among HIV-infected patients. An increased risk for IRIS onset was associated with having a CD8 count ≤500 cells/mm3 (aOR = 18.23, P = 0.016); carrying the KIR2DS2 gene (aOR = 27.22, P = 0.032), the HLA-B*41 allele (aOR = 68.84, P = 0.033), the KIR2DS1 + HLA-C2 pair (aOR = 28.58, P = 0.024); and not carrying the KIR2DL3 + HLA-C1/C2 pair (aOR = 43.04, P = 0.034), and the KIR2DL1 + HLA-C1/C2 pair (aOR = 43.04, P = 0.034), CONCLUSIONS: These results suggest the participation of these genes in the immunopathogenic mechanisms related to the conditions studied. This is the first study demonstrating an association of HLA-B*41, KIR2DS2, and KIR + HLA-C pairs with IRIS onset among TB-HIV co-infected individuals.


Asunto(s)
Infecciones por VIH/complicaciones , Infecciones por VIH/genética , VIH-1 , Síndrome Inflamatorio de Reconstitución Inmune/etiología , Síndrome Inflamatorio de Reconstitución Inmune/genética , Tuberculosis/complicaciones , Tuberculosis/genética , Brasil , Coinfección/tratamiento farmacológico , Coinfección/genética , Coinfección/patología , Femenino , Estudios de Seguimiento , Frecuencia de los Genes/genética , Marcadores Genéticos , Genotipo , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/patología , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Humanos , Síndrome Inflamatorio de Reconstitución Inmune/patología , Masculino , Receptores KIR/genética , Factores Sexuales , Tuberculosis/tratamiento farmacológico , Tuberculosis/patología
15.
Mol Genet Genomics ; 295(1): 23-30, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31410611

RESUMEN

P2RX7 (purinergic receptor P2X 7) is an important membrane ion channel and involved in multiple physiological processes. One non-synonymous SNP on P2RX7, rs3751143, had been proven to reduce ion channel function and further associated with multiple diseases. However, it was still unclear whether there were other cis-regulatory elements for P2RX7, which might further contribute to related diseases. Allele-specific expression (ASE) is a robust and sensitive approach to identify the potential functional region in human genome. In the current study, we measured ASE on rs3751143 in lung tissues and observed a consistent excess of A allele over C (P = 0.001), which indicated that SNP(s) in linkage disequilibrium (LD) could regulate P2RX7 expression. By analyzing the 1000 genomes project data for Chinese, one SNP locating ~ 5 kb away and downstream of P2RX7, rs11615992, was disclosed to be in strong LD with rs3751143. The dual-luciferase assay confirmed that rs11615992 could alter target gene expression in lung cell line. Through chromosome conformation capture, it was verified that the region surrounding rs11615992 could interact with P2RX7 promoter and effect as an enhancer. By chromatin immunoprecipitation, the related transcription factor POU2F1 (POU class 2 homeobox 1) was recognized to bind the region spanning rs11615992. Our work identified a novel long-distance cis-regulatory SNP for P2RX7, which might contribute to multiple diseases.


Asunto(s)
Polimorfismo de Nucleótido Simple/genética , Receptores Purinérgicos P2X7/genética , Alelos , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Genoma Humano/genética , Haplotipos/genética , Humanos , Desequilibrio de Ligamiento/genética , Regiones Promotoras Genéticas/genética
16.
Gene ; 729: 144263, 2020 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-31759985

RESUMEN

The HOTAIR gene encodes a long noncoding RNA (lncRNA), which functions in development and tumorigenesis. A single nucleotide polymorphism (SNP) rs920778 in the HOTAIR gene, has been recurrently studied for susceptibility to many cancers including oesophageal cancer, gastric cancer, lung cancer, and hepatocellular carcinoma. Most of these studies were conducted in Chinese populations, and a few in Turkish, Iranian, and Portuguese populations. They mostly give rise to controversial results. It still remains largely unknown whether the cancer risk is conferred in a Japanese population. Here, we established an association study on the representative SNP rs920778, to examine its contribution to the presence of cancer in consecutive autopsy cases in the JG-SNP database. A total of 1373 subjects (mean age 80) including 827 cancer positive and 546 cancer negative subjects were analyzed. As a result, the occurrence of overall cancer was not associated with the rs920778 polymorphism (p > 0.05). For each cancer type, we did not find association except for lung cancer (p = 0.04) which was more likely a by-chance association after multiple testing. Our findings imply that rs920778 polymorphism does not affect total cancer presence and the effect on specific cancer types is also weak in the Japanese population.


Asunto(s)
Neoplasias/genética , ARN Largo no Codificante/genética , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , Bases de Datos Genéticas , Femenino , Frecuencia de los Genes/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Japón , Masculino , Polimorfismo de Nucleótido Simple/genética , ARN Largo no Codificante/metabolismo , Factores de Riesgo
17.
Gene ; 727: 144262, 2020 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-31759987

RESUMEN

Neuroblastoma is an extracranial solid tumor that mainly occurs in childhood. Mutations of NRAS gene have been described in several cancers. However, whether NRAS gene polymorphisms can predict the risk of neuroblastoma have not been investigated. We hypothesized that variations of NRAS gene contribute to neuroblastoma predisposition. Therefore, we conducted a multi-center case-control study using 263 cases and 715 controls to examine the association of NRAS gene rs2273267 A>T polymorphism and neuroblastoma risk. We calculated odds ratios (ORs) and corresponding 95% confidence intervals (CIs) to assess the strength of the associations. Relative to those with AA genotype, subjects with AT/TT genotype had reduced neuroblastoma risk (adjusted OR = 0.72, 95% CI = 0.54-0.96, P = 0.024). Stratified analysis revealed that rs2273267 AT/TT carriers were less likely to develop neuroblastoma for patients with tumor originating from the adrenal gland (adjusted OR = 0.67, 95% CI = 0.45-0.99, P = 0.047) and clinical stages III + IV (adjusted OR = 0.57, 95% CI = 0.36-0.90, P = 0.015). Our findings underline the likely importance of NRAS gene rs2273267 A>T in the risk of neuroblastoma. Further independent case-control studies with functional analysis are needed to verify the role of NRAS gene rs2273267 A>T polymorphism in the risk of neuroblastoma.


Asunto(s)
GTP Fosfohidrolasas/genética , Proteínas de la Membrana/genética , Neuroblastoma/genética , Alelos , Grupo de Ascendencia Continental Asiática/genética , Estudios de Casos y Controles , Niño , Preescolar , China , Femenino , GTP Fosfohidrolasas/metabolismo , Frecuencia de los Genes/genética , Genes ras/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Lactante , Masculino , Proteínas de la Membrana/metabolismo , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo
18.
Mol Genet Genomics ; 295(1): 221-231, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31641857

RESUMEN

The Xinjiang Uyghur Autonomous Region of China (XUARC) with 47 ethnic groups is a very colorful ethnic region of China, harboring abundant genetic and cultural diversity. The Kazakhs are the third largest ethnic group (7.02%) after Uyghur (46.42%) and Han (38.99%) in Xinjiang, but their genetic diversity and forensic characterization are poorly understood. In the current study, we genotyped 15 autosomal short tandem repeat (STR) loci and ten Y-STRs in 889 individuals (659 male and 230 female) collected from Kazak population of the Ili Kazak Autonomous Prefecture using AGCU Expressmarker 16 and 10Y-STR Kit (EX16 + 10Y). For autosomal STRs, we observed a total of 174 different alleles ranging from 6 to 34.2 repeat units and FGA showed the greatest power of discrimination (20 alleles) in Ili Kazakh population. We have not observed departures from Hardy-Weinberg equilibrium (HWE) after sequential Bonferroni correction and only found a minimal departure from linkage equilibrium (LE) for a very small number of pairwise combinations of loci. The combined power of exclusion (CPE) was 0.99999998395 and combined power of discrimination (CPD) was 99.999999999999999798%. For Y-STRs, we observed a total of 496 different haplotypes in these ten Y-STR loci. The gene diversities ranged from 0.5023 (DYS391) to 0.8357 (DYS385a/b). The overall haplotype diversity (GD) was 0.9985 with random matching probability (RMP) of 0.0015. The results of population genetic analysis based on both autosomal and Y-chromosome STRs demonstrated that the genetic affinity among populations is generally consistent with ethnic, linguistic, and continental geographical classifications.


Asunto(s)
Grupo de Ascendencia Continental Asiática/genética , Cromosomas/genética , Polimorfismo Genético/genética , Alelos , Femenino , Frecuencia de los Genes/genética , Pruebas Genéticas/métodos , Genética de Población/métodos , Haplotipos/genética , Humanos , Masculino , Repeticiones de Microsatélite/genética , Filogenia
19.
Cancer Sci ; 111(1): 266-278, 2020 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-31746520

RESUMEN

According to cancer genome sequences, more than 90% of cases of pancreatic ductal adenocarcinoma (PDAC) harbor active KRAS mutations. Digital PCR (dPCR) enables accurate detection and quantification of rare mutations. We assessed the dynamics of circulating tumor DNA (ct-DNA) in patients with advanced PDAC undergoing chemotherapy using dPCR. KRAS G12/13 mutation was assayed by dPCR in 47 paired tissue- and ct-DNA samples. The 21 patients were subjected to quantitative ct-DNA monitoring at 4 to 8-week intervals during chemotherapy. KRAS mutation was detected in 45 of those 47 patients using tissue DNA. In the KRAS mutation-negative cases, next-generation sequencing revealed KRAS Q61K and NRAS Q61R mutations. KRAS mutation was detected in 23/45 cases using ct-DNA (liver or lung metastasis, 18/19; mutation allele frequency [MAF], 0.1%-31.7%; peritoneal metastasis, 3/9 [0.1%], locally advanced, 2/17 [0.1%-0.2%]). In the ct-DNA monitoring, the MAF value changed in concordance with the disease state. In the 6 locally advanced cases, KRAS mutation appeared concurrently with liver metastasis. Among the 6 cases with liver metastasis, KRAS mutation disappeared during the duration of stable disease or a partial response, and reappeared at the time of progressive disease. The median progression-free survival was longer in cases in which KRAS mutation disappeared after an initial course of chemotherapy than in those in which it was continuously detected (248.5 vs 50 days, P < .001). Therefore, ct-DNA monitoring enables continuous assessment of disease state and could have prognostic utility during chemotherapy.


Asunto(s)
ADN Tumoral Circulante/genética , ADN/sangre , Neoplasias Pancreáticas/sangre , Neoplasias Pancreáticas/genética , Adulto , Anciano , Biomarcadores de Tumor/sangre , Carcinoma Ductal Pancreático/sangre , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/patología , Estudios de Evaluación como Asunto , Femenino , Frecuencia de los Genes/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Neoplasias Hepáticas/sangre , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Neoplasias Pulmonares/sangre , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mutación/genética , Páncreas/patología , Neoplasias Pancreáticas/patología , Pronóstico , Supervivencia sin Progresión
20.
Gene ; 730: 144289, 2020 Mar 10.
Artículo en Inglés | MEDLINE | ID: mdl-31846709

RESUMEN

Interferon lambda proteins activate the JAK-STAT signalling pathway, resulting in upregulation of genes with antiviral effects. The interferon lambda family was initially thought to be redundant to the interferon alpha family, which signals through the same pathway, except for the more limited expression of the IFNLR1 receptor. However, recent studies show that interferon lambdas uniquely protect tissue barriers against a wide range of important viral infections. The interferon lambda 4 gene (IFNL4) was discovered in 2013. The IFNL4 protein is determined by the IFNL4-ΔG/TT (rs368234815) variant. The ancestral IFNL4-ΔG allele generates IFNL4, whereas IFNL4-TT causes pre-mature termination of the protein. Surprisingly, although interferons are generally antiviral proteins, the genotypes that generate the IFNL4 protein are strongly linked to impaired clearance of hepatitis C virus (HCV). IFNL4 genotype has also been linked to variation within the HCV genome, as well as risk of hepatic fibrosis, certain cancers and some infectious diseases. There has been very strong evolutionary selection against the ancestral IFNL4-ΔG allele, which is the major form in African populations, but the minor allele in Europeans and Asians. The reason for this selection and the biological mechanisms underlying observed phenotypic associations remain to be explained.


Asunto(s)
Interleucinas/genética , Interleucinas/metabolismo , Alelos , Grupos de Población Continentales/genética , Evolución Molecular , Frecuencia de los Genes/genética , Variación Genética/genética , Genotipo , Hepacivirus/genética , Hepatitis/genética , Humanos , Interleucinas/fisiología , Fenotipo , Polimorfismo de Nucleótido Simple/genética
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