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1.
Medicine (Baltimore) ; 99(29): e20582, 2020 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-32702814

RESUMEN

The morbidity of coronary artery disease (CAD) in the Uygur population of Xinjiang was much higher than the national average. Clopidogrel is the most commonly used medication worldwide in dual antiplatelet therapy for CAD, and the response of clopidogrel is affected by CYP2C19, PON1, and ABCB1 genetic polymorphisms. The distribution of CYP2C19*17, ABCB1, and PON1 genetic polymorphisms in Han and Uygur populations with CAD of Xinjiang has not been investigated.This study aimed to investigate the frequencies of CYP2C19, PON1, and ABCB1 genetic polymorphisms, and to identify the metabolizer phenotype of CYP2C19 in Han and Uygur populations with CAD in Northwestern Xinjiang, China. We identified 602 Han and 527 Uygur patients from 2014 through 2019 and studied genotypes for selected allele polymorphisms using sequencing by hybridization.There were significantly different allele frequencies and genotype frequencies between the 2 ethnic groups in terms of CYP2C19*2, *3, *17, ABCB1 and PON1, (P < .05). For CYP2C19*17, the frequency of TT genotype was 2.5% in Uygur patients, but it was undetectable in Han patients. In both the intermediate and poor metabolizer groups, the genotypes polymorphisms CYP2C19*2, *3, *17 were significantly less common in Uygur patients than in Han patients (P < .001). By contrast, the proportion of ultra-metabolizers as defined by CYP2C19*2, *3, *17 polymorphisms significantly higher in Uygur patients (18.6%) than in Han patients (1.7%, P < .001). The CYP2C19*2 frequency was significantly different between Han patients and Han healthy groups (P < .001), while the CYP2C19*3 frequency was significantly different between Uygur patients and Uygur healthy groups (P < .001).Our study supports the notion of interethnic differences in terms of CYP2C19, PON1, and ABCB1 polymorphisms and CYP2C19 genotype-defined clopidogrel metabolic groups. These finding could provide valuable data and insights into personalized CAD treatment for the Uygur and Han populations in Xinjiang.


Asunto(s)
Enfermedad de la Arteria Coronaria/tratamiento farmacológico , Enfermedad de la Arteria Coronaria/genética , Polimorfismo de Nucleótido Simple/genética , Subfamilia B de Transportador de Casetes de Unión a ATP/genética , Anciano , Arildialquilfosfatasa/genética , China/etnología , Clopidogrel/uso terapéutico , Comorbilidad , Enfermedad de la Arteria Coronaria/mortalidad , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Grupos Étnicos/genética , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Antagonistas del Receptor Purinérgico P2Y/uso terapéutico
2.
Anticancer Res ; 40(8): 4263-4270, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32727753

RESUMEN

BACKGROUND/AIM: Enzymatic variants involved in fluoropyrimidine metabolism have been associated with adverse events (AEs). We assessed the association between C677T (rs1801133) and A1298 (rs1801131) methylenetetrahydrofolate reductase (MTHFR) polymorphisms and AEs in patients with first-line fluoropyrimidine-based chemotherapy. PATIENTS AND METHODS: Fifty patients with metastatic colorectal cancer were prospectively followed-up during the first 4 cycles of fluoropyrimidine-based treatment to assess AEs. Germline DNA was analyzed to determine the C677T and A1298C MTHFR polymorphisms. The associations between MTHFR polymorphisms and toxicity were examined. RESULTS: Individuals carrying at least one mutant allele of the MTHFR C677T polymorphism had increased risk to experience anemia (OR=1.69, 95% CI=1.13-2.53, p=0.005), neutropenia (OR=2.27, 95% CI=1.47-3.42, p<0.001) thrombocytopenia (OR=1.91, 95% CI=1.30-2.70, p<0.001), neuropathy (OR=1.77, 95% CI=1.16-2.70, p=0.02), diarrhea (OR=1.69, 95% CI=1.13-2.53, p=0.005), and hand-foot syndrome (OR=1.56, 95% CI=1.08-2.27, p=0.013), compared to patients carrying the wild type alleles. The presence of the mutant allele C of the MTHFR A1298C polymorphism was associated with increased risk of anemia (OR=2.75, 95% CI=1.01-7.48, p=0.02) and thrombocytopenia (OR=3.14, 95% CI=1.01-9.78, p=0.03); however, the prevalence of this allele in the sample was quite low (20%). CONCLUSION: MTHFR C677T and A1298C polymorphisms predicted toxicity in a subset of Mestizo patients with colorectal adenocarcinoma.


Asunto(s)
Antimetabolitos Antineoplásicos/toxicidad , Antimetabolitos Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias Colorrectales/tratamiento farmacológico , Grupos Étnicos/genética , Metilenotetrahidrofolato Reductasa (NADPH2)/genética , Polimorfismo de Nucleótido Simple , Anciano , Neoplasias Colorrectales/patología , Costa Rica , Femenino , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Compuestos Organoplatinos/administración & dosificación , Estudios Prospectivos
3.
PLoS Biol ; 18(6): e3000742, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32511234

RESUMEN

The genetic adaptation of humans to the consumption of milk from dairying animals is one of the most emblematic cases of recent human evolution. While the phenotypic change under selection, lactase persistence (LP), is known, the evolutionary advantage conferred to persistent individuals remains obscure. One informative but underappreciated observation is that not all populations whose ancestors had access to milk genetically adapted to become lactase persistent. Indeed, Central Asian herders are mostly lactase nonpersistent, despite their significant dietary reliance on dairy products. Investigating the temporal dynamic of the -13.910:C>T Eurasian mutation associated with LP, we found that, after its emergence in Ukraine 5,960 before present (BP), the T allele spread between 4,000 BP and 3,500 BP throughout Eurasia, from Spain to Kazakhstan. The timing and geographical progression of the mutation coincides well with the migration of steppe populations across and outside of Europe. After 3,000 BP, the mutation strongly increased in frequency in Europe, but not in Asia. We propose that Central Asian herders have adapted to milk consumption culturally, by fermentation, and/or by colonic adaptation, rather than genetically. Given the possibility of a nongenetic adaptation to avoid intestinal symptoms when consuming dairy products, the puzzle then becomes this: why has LP been selected for at all?


Asunto(s)
ADN Antiguo , Lactasa/genética , Selección Genética , Animales , Asia , Grupos Étnicos/genética , Europa (Continente) , Fermentación , Frecuencia de los Genes/genética , Genotipo , Humanos , Leche , Factores de Tiempo
4.
Medicine (Baltimore) ; 99(23): e20552, 2020 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-32502021

RESUMEN

BACKGROUND: To assess the association of the interaction between the rs9619311 and rs402007 polymorphisms and smoking with essential hypertension (EH) in a Chinese Han population. METHOD: Peripheral blood samples were extracted from 422 EH patients and 280 normotensive (NT) patients in a Chinese Han population. A whole blood genomic DNA extraction kit was used to extract genomic DNA from the blood samples. Polymerase chain reaction restriction fragment length polymorphism was used to detect the rs402007 polymorphism of a disintegrin and metalloproteinase with thrombospondin type motifs 1 gene and the rs9619311 polymorphism of the tissue inhibitor of metalloproteinase-3 gene. The distributions of the genotypes and alleles between the 2 study groups (EH and NT) were compared. The main risk factors for EH were determined by using logistic regression analysis. The effects of gene-gene and gene-smoking interactions on EH were analyzed using multifactor dimensional reduction. RESULTS: The frequencies of the rs402007 GC + CC genotype and the C allele were significantly different between the EH and NT groups (0.68 vs 0.57, χ = 8.99, P = .003, odds ratio [OR] = 1.19; 0.45 vs 0.32, χ = 22.16, P < .001, OR = 1.38). The frequencies of the rs9619311 TC + CC genotype and the C allele were also significantly different between the 2 groups (0.33 vs 0.25, χ = 4.51, P = .04, OR = 1.44; 0.18 vs 0.13, χ = 7.03, P = .01, OR = 1.50). Logistic regression analysis suggests that the rs402007 and rs9619311 polymorphisms are independent risk factors for EH (OR = 2.37, 1.86; P < .001, respectively). The multifactor dimensionality redundant analysis results showed that the interaction among rs402007, rs9619311, and smoking was statistically significant (P = .001). CONCLUSIONS: A disintegrin and metalloproteinase with thrombospondin type motifs 1 rs402007 and tissue inhibitor of metalloproteinase-3 rs9619311 polymorphisms are associated with EH in a Chinese Han population, and there was a positive interaction among rs402007, rs9619311, and smoking.


Asunto(s)
Proteína ADAMTS1/genética , Hipertensión Esencial/genética , Grupos Étnicos/genética , Predisposición Genética a la Enfermedad , Polimorfismo Genético , Fumar/epidemiología , Inhibidor Tisular de Metaloproteinasa-3/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Grupo de Ascendencia Continental Asiática/genética , Estudios de Casos y Controles , China/epidemiología , Hipertensión Esencial/epidemiología , Femenino , Genotipo , Humanos , Modelos Logísticos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa
5.
Gene ; 754: 144821, 2020 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-32497559

RESUMEN

CC chemokine ligand 3 like-1 (CCL3L1) encodes for CCL3L1 protein, which is a human immunodeficiency virus (HIV) suppressive chemokine and a potent ligand of HIV CCR5 co-receptor. CCL3L1 exhibits variation in the gene copy number (CN) and could influence HIV susceptibility through gene dosage effect. The study aims to determine the distribution of CCL3L1 CN among HIV subjects of Malay, Chinese, and Indian ethnics in Malaysia and to evaluate the impact of CCL3L1 CN on susceptibility to HIV. This study involved 182 HIV patients who attended outpatient clinics of three hospitals in Malaysia and 150 non-HIV (control) subjects. Typing of CCL3L1 CN was conducted via multiplex paralogue ratio tests (PRTs), followed by validation of the CCL3L1 CN by microsatellite analyses. Both Malay and Indian HIV subjects had the CN mode of two, while the CN mode for the Chinese was four. The CCL3L1 gene CN was found to be strongly associated with ethnicity (p < 0.001) with the diverse distribution of CCL3L1 CN between the Malay (range = 0-6), Chinese (range = 0-9), and Indian (range = 1-4) ethnic groups. CCL3L1 CN higher than and equal to the average was associated with reduced HIV susceptibility among the Malays (p < 0.05). However, the negative results found for the Indian and Chinese need to be further analysed in a larger sample size.


Asunto(s)
Quimiocinas CC/genética , Variaciones en el Número de Copia de ADN , Grupos Étnicos/genética , Predisposición Genética a la Enfermedad , Infecciones por VIH/epidemiología , Infecciones por VIH/genética , VIH-1/inmunología , Estudios de Casos y Controles , Genotipo , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Humanos , Malasia/epidemiología , Pronóstico
6.
Gene ; 754: 144840, 2020 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-32505845

RESUMEN

BACKGROUND: Mexico is experiencing an epidemic of childhood obesity and overweight, the factors that determine type 2 diabetes and cardiovascular diseases. Even though variants in genes such as MC4R, LEP, LEPR, and FTO have been associated with the risk of obesity, in Mexico the level of miscegenation is heterogeneous, so this risk must be measured as genetic ancestry. This study aimed at evaluating the association between common SNPs in FTO and MC4R genes in Mexican children with Amerindian, mestizo and predominance European ancestry. METHODS: Anthropometric data and fasting blood samples were collected from 718 unrelated Mexican school children aged 4-13 years old. Variants in the FTO, MC4R, LEP, LEPR genes and 15 ancestry informative markers (AIMs), were genotyped using allelic discrimination assays. RESULTS: High triglycerides and low cholesterol HDL were the most frequent metabolic alterations. The prevalence of minor allele frequency of polymorphism rs8050136, rs9939609, and rs3751812 in the FTO gene; and rs17782313 of MC4R gene were found to be significantly higher among Mexican children with a predominance of European ancestry (EA) compared to native Mexican children (Amerindian predominance), X2 test, p < 0.05. The FTO (rs8050136, rs9939609) and MC4R (rs17782313) genotypes also were significantly associated with obesity (BMI > 2Z) in boys (OR=1.89, P=0.04, OR=3.3, P=0.006 OR=3.11, p=0.04, respectively). Children with AA genotype (minor) of rs8050136 and rs9939609 SNPs have higher triglycerides in relation to native ancestral genotypes. CONCLUSION: Risk variants in the FTO and MC4R genes had a higher frequency in children with EA compared with Amerindian predominance children, showing that miscegenation is associated with the frequency of obesity-related genotypes.


Asunto(s)
Dioxigenasa FTO Dependiente de Alfa-Cetoglutarato/genética , Biomarcadores/metabolismo , Índice de Masa Corporal , Grupos Étnicos/genética , Predisposición Genética a la Enfermedad , Obesidad Pediátrica/epidemiología , Polimorfismo de Nucleótido Simple , Receptor de Melanocortina Tipo 4/genética , Adolescente , Niño , Preescolar , Femenino , Genotipo , Humanos , Masculino , México/epidemiología , Sobrepeso/epidemiología , Sobrepeso/genética , Sobrepeso/metabolismo , Obesidad Pediátrica/genética , Obesidad Pediátrica/metabolismo , Prevalencia
7.
Science ; 369(6502): 456-460, 2020 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-32499399

RESUMEN

The Caribbean was one of the last regions of the Americas to be settled by humans, but where they came from and how and when they reached the islands remain unclear. We generated genome-wide data for 93 ancient Caribbean islanders dating between 3200 and 400 calibrated years before the present and found evidence of at least three separate dispersals into the region, including two early dispersals into the Western Caribbean, one of which seems connected to radiation events in North America. This was followed by a later expansion from South America. We also detected genetic differences between the early settlers and the newcomers from South America, with almost no evidence of admixture. Our results add to our understanding of the initial peopling of the Caribbean and the movements of Archaic Age peoples in the Americas.


Asunto(s)
Genética de Población , Migración Humana , Región del Caribe , Grupos Étnicos/genética , Genómica , Humanos
8.
Gene ; 753: 144806, 2020 Aug 30.
Artículo en Inglés | MEDLINE | ID: mdl-32461018

RESUMEN

BACKGROUND: The aim of the present study was to detect potential gender-specific associations between some common CD36 single nucleotide polymorphisms (SNPs) and the lipid profile, as well as the susceptibility to premature multi-vessel coronary artery heart disease (CHD) in the Han population of Northern China. METHODS: A systematic three-step study process was employed to detect associations between CD36 gene variants and blood lipid profiles, as well as premature multi-vessel CHD in a gender-specific manner. RESULTS: The current study documented the following novel findings: (I) the full population-based association study in 329 Northern Han Chinese showed that four common CD36 polymorphisms were significantly related to extreme lipid profiles, with statistically significant effects based on gender interactions (rs1049673: P = 0.001; rs7755: P = 0.008; rs3211956: P = 0.034; and rs3173798: P = 0.004); (ii) these statistically significant effects could be decomposed into statistically significant atherogenic effects in males, but non-significant non-atherogenic effects in females; (iii) the results of logistic regression analysis indicated that current smoking status, low density lipoprotein cholesterol (LDL-C) levels, and type-2 diabetes were independent risk factors for premature multi-vessel CHD phenotype (P < 0.0001). CONCLUSIONS: Four common CD36 polymorphisms (rs1049673, rs7755, rs3211956, and rs3173798) were identified to be significantly associated with extreme lipid profiles and had statistically opposite gender-specific clinical lipid profile effects. Thus, the 3'-untranslated regions (3'-UTR) CD36 SNPs could be a novel target for metabolic abnormalities in males of the Han nationality from Northern China.


Asunto(s)
Antígenos CD36/genética , Enfermedad de la Arteria Coronaria/genética , Adulto , Grupo de Ascendencia Continental Asiática/genética , Aterosclerosis/sangre , Aterosclerosis/genética , Aterosclerosis/patología , Estudios de Casos y Controles , China/epidemiología , Enfermedad de la Arteria Coronaria/sangre , Enfermedad de la Arteria Coronaria/epidemiología , Enfermedad de la Arteria Coronaria/patología , Vasos Coronarios/patología , Grupos Étnicos/genética , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Lípidos/sangre , Lípidos/genética , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Factores de Riesgo , Caracteres Sexuales
9.
PLoS Genet ; 16(5): e1008747, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32407400

RESUMEN

Abnormal fetal growth is a risk factor for infant morbidity and mortality and is associated with cardiometabolic diseases in adults. Genetic influences on fetal growth can vary at different gestation times, but genome-wide association studies have been limited to birthweight. We performed trans-ethnic genome-wide meta-analyses and fine mapping to identify maternal genetic loci associated with fetal weight estimates obtained from ultrasound measures taken during pregnancy. Data included 1,849 pregnant women from four race/ethnic groups recruited through the NICHD Fetal Growth Studies. We identified a novel genome-wide significant association of rs746039 [G] (ITPR1) with reduced fetal weight from 24 to 33 weeks gestation (P<5x10-8; log10BF>6). Additional tests revealed that the SNP was associated with head circumference (P = 4.85x10-8), but not with abdominal circumference or humerus/femur lengths. Conditional analysis in an independent sample of mother-offspring pairs replicated the findings and showed that the effect was more likely maternal but not fetal. Trans-ethnic approaches successfully narrowed down the haplotype block that contained the 99% credible set of SNPs associated with head circumference. We further demonstrated that decreased placental expression of ITPR1 was correlated with increased placental epigenetic age acceleration, a risk factor for reduced fetal growth, among male fetuses (r = -0.4, P = 0.01). Finally, genetic risk score composed of known maternal SNPs implicated in birthweight among Europeans was associated with fetal weight from mid-gestation onwards among Whites only. The present study sheds new light on the role of common maternal genetic variants in the inositol receptor signaling pathway on fetal growth from late second trimester to early third trimester. Clinical Trial Registration: ClinicalTrials.gov, NCT00912132.


Asunto(s)
Grupos Étnicos/genética , Grupos Étnicos/estadística & datos numéricos , Desarrollo Fetal/genética , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Receptores de Inositol 1,4,5-Trifosfato/genética , Embarazo , Adulto , Comparación Transcultural , Femenino , Peso Fetal/etnología , Peso Fetal/genética , Sitios Genéticos , Estudio de Asociación del Genoma Completo/métodos , Edad Gestacional , Humanos , Polimorfismo de Nucleótido Simple , Embarazo/etnología , Embarazo/genética , Embarazo/estadística & datos numéricos , Adulto Joven
10.
PLoS Genet ; 16(5): e1008749, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32453742

RESUMEN

Indonesia is the world's fourth most populous country, host to striking levels of human diversity, regional patterns of admixture, and varying degrees of introgression from both Neanderthals and Denisovans. However, it has been largely excluded from the human genomics sequencing boom of the last decade. To serve as a benchmark dataset of molecular phenotypes across the region, we generated genome-wide CpG methylation and gene expression measurements in over 100 individuals from three locations that capture the major genomic and geographical axes of diversity across the Indonesian archipelago. Investigating between- and within-island differences, we find up to 10.55% of tested genes are differentially expressed between the islands of Sumba and New Guinea. Variation in gene expression is closely associated with DNA methylation, with expression levels of 9.80% of genes correlating with nearby promoter CpG methylation, and many of these genes being differentially expressed between islands. Genes identified in our differential expression and methylation analyses are enriched in pathways involved in immunity, highlighting Indonesia's tropical role as a source of infectious disease diversity and the strong selective pressures these diseases have exerted on humans. Finally, we identify robust within-island variation in DNA methylation and gene expression, likely driven by fine-scale environmental differences across sampling sites. Together, these results strongly suggest complex relationships between DNA methylation, transcription, archaic hominin introgression and immunity, all jointly shaped by the environment. This has implications for the application of genomic medicine, both in critically understudied Indonesia and globally, and will allow a better understanding of the interacting roles of genomic and environmental factors shaping molecular and complex phenotypes.


Asunto(s)
Metilación de ADN , Grupos Étnicos/genética , Interacción Gen-Ambiente , Transcriptoma , Islas de CpG , Ambiente , Epigénesis Genética/fisiología , Grupos Étnicos/estadística & datos numéricos , Perfilación de la Expresión Génica/estadística & datos numéricos , Genética de Población , Estudio de Asociación del Genoma Completo/estadística & datos numéricos , Genómica/métodos , Humanos , Indonesia/epidemiología , Islas/epidemiología , Islas del Pacífico/epidemiología , Linaje , Fenotipo , Polimorfismo de Nucleótido Simple , RNA-Seq
11.
PLoS One ; 15(5): e0232174, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32380517

RESUMEN

BACKGROUND: Previous studies have reported on several genetic variants related to breast cancer, but a substantial proportion of mutation loci have not yet been identified. In the current study, we aimed to evaluate the association between single nucleotide polymorphisms (SNPs) of interleukin-10 (IL-10) and susceptibility to breast cancer in Shaanxi Han women in China. METHODS: Six SNPs were genotyped in 530 breast cancer patients and 628 healthy women from the First Affiliated Hospital of Xi'an Jiaotong University Hospital. Odds ratios and 95% confidence intervals were calculated by unconditional logistic regression analysis to assess the association between breast cancer risk and polymorphisms of six loci. RESULTS: Two SNPs, rs3024490 and rs1800871, were found to be significantly different between breast cancer patients and healthy women. These SNPs also increased the risk of breast cancer in co-dominant and dominant models. Moreover, another SNP, rs1554286, was significantly associated with an increased risk of breast cancer in the co-dominant model. Functional assessments indicated that these three variants may influence the expression and transcription factor binding of IL-10. CONCLUSIONS: Our findings suggest that variants of IL-10 may be likelihood risk factors for the development and progression of breast cancer. Future studies should replicate this study and evaluate functional assessments in Chinese Han women and women from other regions.


Asunto(s)
Neoplasias de la Mama/genética , Interleucina-10/genética , Adulto , Anciano , Alelos , Grupo de Ascendencia Continental Asiática/genética , Estudios de Casos y Controles , China , Grupos Étnicos/genética , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Interleucina-10/metabolismo , Persona de Mediana Edad , Oportunidad Relativa , Polimorfismo de Nucleótido Simple/genética , Factores de Riesgo
12.
Gene ; 752: 144760, 2020 Aug 20.
Artículo en Inglés | MEDLINE | ID: mdl-32416252

RESUMEN

BACKGROUND: PCOS is a common endocrine disorder that is characterized by hyperandrogenism and chronic anovulation and is the leading cause of female infertility. It is a heterogeneous disorder with the involvement of multiple gene and environmental interactions. This study identified variants that are known to confer susceptibility identified by Genome wide association studies (GWAS) in other ethnicities and replicated the same in individuals with PCOS of Indian ethnicity. METHODS: Study subjects (n = 600) were recruited. Blood samples, demographic and clinical details were collected after obtaining informed consent. Fifteen variants were selected from GWA studies from other ethnicities and genotyped in half of the recruited samples (n = 300) using MassARRAYiPLEX™. Replication of significant variants generated from preliminary data was carried out by PCR and direct sequencing in remainder of the samples (n = 300). Insilco analysis for significant variants was performed using software namely CADD, GWAVA, FATHMM-MKL. Relevant statistics were used to ascertain significance. RESULTS: The mean age of patients and controls was 24.26 ± 3.22 and 30.19 ± 11.21 years respectively. Of the 15 variants, 3 variants (rs13405728 in LHCGR; rs13429458 in THADA and rs2209972 IDE genes) were found to be associated with PCOS. The association was successfully replicated in an independent cohort. Insilico analysis categorized two variants (rs13429458-THADA and rs2209972-IDE genes) as deleterious. CONCLUSION: We demonstrate the association of variants in genes namely LHCGR, THADA and IDE with an increased risk of PCOS. Genotyping for these variants aids in identifying at-risk individuals which is crucial as appropriate early interventions may benefit the patient.


Asunto(s)
Insulisina/genética , Proteínas de Neoplasias/genética , Síndrome del Ovario Poliquístico/genética , Receptores de HL/genética , Adulto , Alelos , Grupo de Ascendencia Continental Asiática/genética , Estudios de Casos y Controles , Estudios de Cohortes , Grupos Étnicos/genética , Grupo de Ascendencia Continental Europea/genética , Femenino , Frecuencia de los Genes/genética , Predisposición Genética a la Enfermedad/genética , Pruebas Genéticas , Estudio de Asociación del Genoma Completo , Genotipo , Humanos , India/epidemiología , Insulisina/metabolismo , Proteínas de Neoplasias/metabolismo , Síndrome del Ovario Poliquístico/metabolismo , Polimorfismo de Nucleótido Simple/genética , Receptores de HL/metabolismo , Análisis de Secuencia de ADN/métodos
13.
J Cancer Res Clin Oncol ; 146(7): 1701-1709, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32350606

RESUMEN

BACKGROUND: To investigate the incidence and prognostication of ERG, PTEN and SPINK1 protein expressions in prostate cancer cohort of Middle Eastern descent in comparison to published data from Western population. METHODS: Immunohistochemistry for ERG, PTEN and SPINK1 was performed in a cohort of localized PCA (n = 340). The data were correlated to pathological and clinical outcomes and compared to Western populations. RESULTS: ERG expression and PTEN loss were noted in 123/288 (42.7%) and 91/297 (30.6%) of patients, respectively. SPINK1 expression was assessed in a subset of cases, noted in 6/150 (4%) of patients. Only ERG expression was associated with grade groups, being more common in the lower grade groups (1-3 vs 4-5; p = 0.04). In contrast to the Western population, PTEN loss foci were more likely to be ERG negative, observed in 81% of tumor foci and patients with PTEN neg/ERG pos were more likely to exhibit biochemical recurrence (OR 2.831; 95% CI 1.10-726, p = 0.03). This association remained significant in multivariate analysis (OR 2.68; 95% CI 0.98-7.33, p = 0.05), after adjusting for GG, path stage and surgical margin. CONCLUSION: This study documents significant differences in key molecular events in PCA in Middle Eastern population compared to Western populations that could explain differences in PCA incidence, progression and prognostication. ERG, PTEN and SPINK1 genomic alteration occur less frequently and the enrichment of ERG for PTEN loss is not observed. Additionally, patients with combined PTEN loss/ERG positive are at highest risk for BCR vs North American Caucasian population where PTEN loss alone seems to be associated with the worst clinical outcome. The data presented here further support differences in clonal evolution between Middle Eastern and Western population in relation to PCA and add further insight to understanding PCA molecular pathways.


Asunto(s)
Biomarcadores de Tumor , Grupos Étnicos , Neoplasias de la Próstata/etiología , Neoplasias de la Próstata/mortalidad , Adulto , Anciano , Árabes/genética , Grupos Étnicos/genética , Grupo de Ascendencia Continental Europea/genética , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Fosfohidrolasa PTEN/genética , Neoplasias de la Próstata/metabolismo , Regulador Transcripcional ERG/genética , Inhibidor de Tripsina Pancreática de Kazal/genética
14.
Hum Genet ; 139(5): 647-655, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32232557

RESUMEN

Gene prioritization is the process of determining which variants and genes identified in genetic analyses are likely to cause a disease or a variation in a phenotype. For many genes, neither in vitro nor in vivo testing is available, thus assessing their pathogenic role could be challenging, leading to false-positive or false-negative results. In this paper, we propose an innovative score of gene prioritization based on the population of interest. We introduce the concept of singleton-cohort variants (SC variant), a variant that has allele count equal to one in the cohort under study. The difference between the normalized count of SC variants in the coding region and the normalized count of SC variants in the non-coding region should give a hint regarding the level of constraints for that gene in a specific population. This scoring system is negative when there are constraints that allow the presence of SC variants only in the non-coding region; on the contrary, it is positive when there are no constraints. A complimentary score is the sum of SC variants normalized count in both coding and non-coding regions, which could be used as a proxy of positive or strong purifying selection in a specific population. Our methodology showed a high level of constraining for genes such as USP34 in all subpopulations tested (1000 G dataset). In contrast, some genes showed a high negative score only in specific populations, e.g., MYT1L in Europeans, UBR5 in East Asians, and FBXO11 in Africans.


Asunto(s)
Grupos Étnicos/genética , Marcadores Genéticos , Variación Genética , Genética de Población , Modelos Teóricos , Herencia Multifactorial/genética , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Fenotipo , Transducción de Señal
15.
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
16.
BMC Med Genet ; 21(1): 63, 2020 03 30.
Artículo en Inglés | MEDLINE | ID: mdl-32228609

RESUMEN

BACKGROUND: Brucellosis is a quite normal zoonotic infection, which is caused by immediate contact with animals infected with Brucella or its products. IL-10 (- 1082 G/A, - 819 C/T, - 592C/A) and IL-6 -174 G/C polymorphisms have a great relationship with IL-10 and IL-6 production, which brings about Brucellosis pathogenesis and development. So far, the results of published literatures were controversial. Now, we perform a meta-analysis in different ethnic populations to get a more precise estimate of above polymorphisms with Brucellosis susceptibility. METHODS: Both OR and corresponding 95%CI were enrolled to make an assessment of the association strength through extracting genotyping frequency of cases and controls. The χ2-test based Q-statistic and I2 statistics were applied. If there was no evident heterogeneity, the fixed-effects model would be applied. If not, the random-effects model would be used. RESULTS: The significant associations were only found in Asian population of - 819 loci under three genetic models as follows: (Allele model: OR = 0.60, 95%CI = 0.44-0.82, P = 0.001), (homozygote comparison: OR = 0.24, 95%CI = 0.09-0.62, P = 0.003), (recessive genetic model: OR = 0.22, 95%CI = 0.05-0.91, P = 0.036). CONCLUSION: In conclusion, IL-10 - 819 loci polymorphism contributes no risk to Caucasian population but may be associated with decreased risk in Asian population. And IL-10 -1082 G/A, 592 loci and IL-6 -174 G/C polymorphism are not associated with Brucellosis risk.


Asunto(s)
Brucelosis/genética , Interleucina-10/genética , Interleucina-6/genética , Polimorfismo de Nucleótido Simple , Alelos , Grupo de Ascendencia Continental Asiática/genética , Grupo de Ascendencia Continental Asiática/estadística & datos numéricos , Brucelosis/etnología , Estudios de Casos y Controles , Grupos Étnicos/genética , Grupo de Ascendencia Continental Europea/genética , Grupo de Ascendencia Continental Europea/estadística & datos numéricos , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , Factores de Riesgo
17.
Mol Genet Genomics ; 295(4): 969-979, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32279092

RESUMEN

The Tibetan-Yi Corridor, located on the eastern edge of the Tibetan Plateau, is the main route of the people of the plateau. Human settlement and diffusion along the corridor have played a pivotal role in shaping the genetic architecture of Sino-Tibetan-speaking (STs) populations in China. In this study, five STs groups (Chengdu Tibetan, Chengdu Han, Muli Tibetan, Lugu Lake Mosuo and Xichang Yi) settling in the Tibetan-Yi Corridor were genotyped via AGCU InDel 50 kit on the capillary electrophoresis platform to decrypt the genetic landscape and phylogenetic relationship of STs populations and investigate the forensic characteristics. Allele frequency distributions of all autosomal insertion/deletion polymorphisms (InDels) in studied groups comply with Hardy-Weinberg equilibrium. The combined power of discrimination values are 0.9999999999999999998, 0.9999999999999999995, 0.9999999999999999999, 0.999999999999999993 and 0.99999999999999999994, respectively, and all the combined probability of exclusion values exceed 0.9990. Forensically relevant statistics implied that these InDels could be used for individual identification and as a promising alternative to STR profiling in paternity testing. Typical population comparisons showed strikingly high homogeneity among studied STs people, indicating complicated genetic admixture among populations in the Tibetan-Yi Corridor. The STs groups in the Tibetan-Yi Corridor keep close genetic affinity with geographically or linguistically close populations, and the genetic components of investigated populations arose from a mixture of multiple ancestral gene pools (resulting from the admixture from the ancestral Highland Tibetans and ancestral Lowland indigenous populations).


Asunto(s)
Evolución Molecular , Genética de Población , Mutación INDEL/genética , Filogenia , China/epidemiología , Grupos Étnicos/genética , Femenino , Genética Forense/estadística & datos numéricos , Frecuencia de los Genes , Humanos , Masculino , Polimorfismo Genético , Tibet/epidemiología
18.
PLoS One ; 15(4): e0232125, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32324809

RESUMEN

BACKGROUND: Few cross-sectional studies report iron deficiency (ID) prevalence in women of different race/ethnicity and ages in US or Canada. MATERIALS AND METHODS: We evaluated screening observations on women who participated between 2001-2003 in a cross-sectional, primary care-based sample of adults ages ≥25 y whose observations were complete: race/ethnicity; age; transferrin saturation; serum ferritin; and HFE p.C282Y and p.H63D alleles. We defined ID using a stringent criterion: combined transferrin saturation <10% and serum ferritin <33.7 pmol/L (<15 µg/L). We compared ID prevalence in women of different race/ethnicity subgrouped by age and determined associations of p.C282Y and p.H63D to ID overall, and to ID in women ages 25-44 y with or without self-reported pregnancy. RESULTS: These 62,685 women included 27,079 whites, 17,272 blacks, 8,566 Hispanics, 7,615 Asians, 449 Pacific Islanders, 441 Native Americans, and 1,263 participants of other race/ethnicity. Proportions of women with ID were higher in Hispanics and blacks than whites and Asians. Prevalence of ID was significantly greater in women ages 25-54 y of all race/ethnicity groups than women ages ≥55 y of corresponding race/ethnicity. In women ages ≥55 y, ID prevalence did not differ significantly across race/ethnicity. p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy. CONCLUSIONS: ID prevalence was greater in Hispanic and black than white and Asian women ages 25-54 y. p.C282Y and p.H63D prevalence did not differ significantly in women with or without ID, regardless of race/ethnicity, age subgroup, or pregnancy.


Asunto(s)
Anemia Ferropénica/epidemiología , Grupos Étnicos/clasificación , Ferritinas/sangre , Proteína de la Hemocromatosis/genética , Transferrina/análisis , Adulto , Anciano , Anemia Ferropénica/genética , Anemia Ferropénica/metabolismo , Canadá/epidemiología , Estudios Transversales , Grupos Étnicos/genética , Femenino , Humanos , Persona de Mediana Edad , Mutación , Prevalencia , Estados Unidos/epidemiología
19.
Mol Genet Genomics ; 295(4): 957-968, 2020 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-32333170

RESUMEN

Studying the genetic structure of each ethnic group is helpful to clarify the genetic background and trace back to the ethnic origin. Tibetan people have lived in the Qinghai-Tibet Plateau (mean elevation over 4500 m) for generations, and have well adapted to the high-altitude environment. Due to the relatively closed geographical environment, Tibetans have preserved their representative physical characteristics and genetic information, thereby become an important research group in human genetics. In this study, genetic characteristics and population structures of two Tibetan groups (Qinghai Tibetans and Tibet Tibetans) were revealed by 35 insertion/deletion polymorphism (DIP) loci, aiming to provide valuable genetic information for population genetic differentiation analyses and forensic identifications. The combined discrimination power, cumulative exclusion probability and combined match probability of the 35 DIP loci in Qinghai Tibetan and Tibet Tibetan groups were 0.9999999999999945, 0.9988, 5.56623 × 10-15; and 0.9999999999999904, 0.9990, 9.69071 × 10-15, respectively, indicating that the panel possessed a strong capability for Tibetan personal identifications. Population differentiations and genetic relationship analyses among the two studied Tibetan groups and other 27 comparison populations were carried out using the Nei's DA genetic distances, population pairwise genetic distances F-statistics (FST), analysis of molecular variance (AMOVA), phylogenetic tree reconstruction, principal component analysis and STRUCTURE methods. Results demonstrated that the most intimate genetic relationships existed in these two Tibetan groups; and genetic similarities between two Tibetan groups and the populations from East Asia were much stronger than that between the Tibetan groups and other geographical populations. Furthermore, forensic ancestral informativeness assessments suggested that several loci could be regarded as ancestry informative markers inferring individual biogeographic origins as well as contributing to forensic anthropology and population genetic researches.


Asunto(s)
Adaptación Fisiológica/genética , Evolución Molecular , Pruebas Genéticas , Mutación INDEL/genética , Altitud , China/epidemiología , Grupos Étnicos/genética , Lejano Oriente , Femenino , Genética Forense , Genética de Población , Humanos , Masculino , Filogenia , Polimorfismo Genético , Análisis de Componente Principal , Tibet/epidemiología
20.
Gene ; 746: 144659, 2020 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-32276000

RESUMEN

The genetic polymorphism of cytochrome P450 (CYPs)drug-metabolizing enzymes are well studied in human populations for drug safety and efficacy. CYP2C9 is a highly polymorphic CYP enzyme that oxidizing the indigenous compounds and xenobiotics. The present study was pursued to evaluate the genetic variation across the CYP2C9 gene among major groups of the Pakistani population. The CYP2C9 genomic region holding important warfarin drug-metabolizing SNPs was sequenced from 159 individuals belong from five major ethnic groups of Pakistani population. The population genetic analyses of the high-quality sequences data was performed using Arlequin v3.5, DnaSP v6.12 and Network 5 resources. The data analyses unveiled that genetic variance among samples mainly arose from population-scale differentiation among these ethnic groups with global Fst of 0.78, P-value < 0.0001. The highest pairwise population genetic variation observed between Saraiki and Baloch groups based on different statistical tests. Whereas, uniform genetic composition across CYP2C9 loci was inferred among Punjabi, Pathan and Sindhi groups with minimal genetic differentiation. Several SNPs, including the previously reported warfarin associated variants, i.e. rs2860905, rs1799853 (CYP2C9*2) and rs72558189 (CYP2C9*14) were detected in these population groups with diverse allelic frequencies. Besides, a novel intronic SNP, i.e. not available in dbSNP and Ensemble databases, was identified for a Sindhi individual sample. This novel SNP predicted to influence the CYP2C9 alternative transcript splicing. The pharmacogeneticsassessment of the CYP2C9 genetic variations identified in current study may important to test against the warfarin efficacy for different ethnicity of Pakistani population.


Asunto(s)
Empalme Alternativo , Citocromo P-450 CYP2C9/genética , Grupos Étnicos/genética , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Citocromo P-450 CYP2C9/metabolismo , Femenino , Humanos , Masculino , Pakistán/etnología , Warfarina/farmacocinética , Warfarina/uso terapéutico
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