Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 6.260
Filtrar
1.
Nat Commun ; 11(1): 4719, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32948767

RESUMO

A small number of de novo assembled human genomes have been reported to date, and few have been complemented with population-based genetic variation, which is particularly important for North Africa, a region underrepresented in current genome-wide references. Here, we combine long- and short-read whole-genome sequencing data with recent assembly approaches into a de novo assembly of an Egyptian genome. The assembly demonstrates well-balanced quality metrics and is complemented with variant phasing via linked reads into haploblocks, which we associate with gene expression changes in blood. To construct an Egyptian genome reference, we identify genome-wide genetic variation within a cohort of 110 Egyptian individuals. We show that differences in allele frequencies and linkage disequilibrium between Egyptians and Europeans may compromise the transferability of European ancestry-based genetic disease risk and polygenic scores, substantiating the need for multi-ethnic genome references. Thus, the Egyptian genome reference will be a valuable resource for precision medicine.


Assuntos
Grupos Étnicos/genética , Genética Populacional , Genômica , Egito , Frequência do Gene , Variação Genética , Genoma Humano , Humanos , Desequilíbrio de Ligação , Masculino , Medicina de Precisão , Sequenciamento Completo do Genoma
3.
Nat Commun ; 11(1): 4556, 2020 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-32917883

RESUMO

Previous genetic studies have identified local population structure within the Netherlands; however their resolution is limited by use of unlinked markers and absence of external reference data. Here we apply advanced haplotype sharing methods (ChromoPainter/fineSTRUCTURE) to study fine-grained population genetic structure and demographic change across the Netherlands using genome-wide single nucleotide polymorphism data (1,626 individuals) with associated geography (1,422 individuals). We identify 40 haplotypic clusters exhibiting strong north/south variation and fine-scale differentiation within provinces. Clustering is tied to country-wide ancestry gradients from neighbouring lands and to locally restricted gene flow across major Dutch rivers. North-south structure is temporally stable, with west-east differentiation more transient, potentially influenced by migrations during the middle ages. Despite superexponential population growth, regional demographic estimates reveal population crashes contemporaneous with the Black Death. Within Dutch and international data, GWAS incorporating fine-grained haplotypic covariates are less confounded than standard methods.


Assuntos
Grupos Étnicos/genética , Genética Populacional , Estudo de Associação Genômica Ampla , Estudos de Casos e Controles , Análise por Conglomerados , Emigração e Imigração , Grupo com Ancestrais do Continente Europeu/genética , Fluxo Gênico , Variação Genética/genética , Genoma , Geografia , Haplótipos , Humanos , Pessoa de Meia-Idade , Modelos Genéticos , Países Baixos , Polimorfismo de Nucleotídeo Único
4.
Med Sci (Paris) ; 36(8-9): 813-816, 2020.
Artigo em Francês | MEDLINE | ID: mdl-32821057

RESUMO

The prediction of a person's aspect from analysis of an anonymous DNA sample has made significant progress in the last decade. Pigmentation (eyes, hair and, more recently, skin colour) can now be determined with good accuracy; face shape is still not amenable to prediction (except, in general lines, from ancestry). Age can apparently also be determined from methylation profiles. Police forces are, understandably, very interested in this technology, with a tendency to over-estimate its accuracy. Legislation varies greatly, with some nations opting for complete prohibition (Germany) and others allowing wide application of the approach (United Kingdom).


Assuntos
Genética Forense/tendências , Fenótipo , Adulto , Grupos Étnicos/genética , Genética Forense/métodos , Estudos de Associação Genética , Humanos , Recém-Nascido , Padrões de Herança/genética , Masculino , Polimorfismo de Nucleotídeo Único , Retratos como Assunto , Pigmentação da Pele/genética , Gêmeos/genética
5.
Anticancer Res ; 40(8): 4263-4270, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32727753

RESUMO

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.


Assuntos
Antimetabólitos Antineoplásicos/toxicidade , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Colorretais/tratamento farmacológico , Grupos Étnicos/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo de Nucleotídeo Único , Idoso , Neoplasias Colorretais/patologia , Costa Rica , Feminino , Fluoruracila/administração & dosagem , Humanos , Leucovorina/administração & dosagem , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/administração & dosagem , Estudos Prospectivos
6.
Medicine (Baltimore) ; 99(29): e20582, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32702814

RESUMO

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.


Assuntos
Doença da Artéria Coronariana/tratamento farmacológico , Doença da Artéria Coronariana/genética , Polimorfismo de Nucleotídeo Único/genética , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Idoso , Arildialquilfosfatase/genética , China/etnologia , Clopidogrel/uso terapêutico , Comorbidade , Doença da Artéria Coronariana/mortalidade , Citocromo P-450 CYP2C19/genética , Citocromo P-450 CYP2C19/metabolismo , Grupos Étnicos/genética , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico
7.
Nat Med ; 26(7): 1089-1095, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32632193

RESUMO

Modern lifestyles increase the risk of chronic diseases, in part by modifying the microbiome, but the health effects of lifestyles enforced on ethnic minorities are understudied1-3. Lifestyle affects the microbiome early in life, when the microbiome is assembled and the immune system is undergoing maturation4-6. Moreover, the influence of lifestyle has been separated from genetic and geographic factors by studies of genetically similar populations and ethnically distinct groups living in the same geographic location7-11. The lifestyle of Irish Travellers, an ethnically distinct subpopulation, changed with legislation in 2002 that effectively ended nomadism and altered their living conditions. Comparative metagenomics of gut microbiomes shows that Irish Travellers retain a microbiota similar to that of non-industrialized societies. Their microbiota is associated with non-dietary factors and is proportionately linked with risk of microbiome-related metabolic disease. Our findings suggest there are microbiome-related public health implications when ethnic minorities are pressured to change lifestyles.


Assuntos
Doença Crônica/epidemiologia , Microbioma Gastrointestinal/genética , Sistema Imunitário/imunologia , Estilo de Vida , Adulto , Grupos Étnicos/genética , Fezes/microbiologia , Microbioma Gastrointestinal/imunologia , Genética Populacional , Humanos , Sistema Imunitário/microbiologia , Irlanda/epidemiologia , Masculino , Metagenômica/métodos , Microbiota/genética , Microbiota/imunologia , Filogenia , Roma/genética , Migrantes
8.
PLoS Biol ; 18(6): e3000742, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32511234

RESUMO

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?


Assuntos
DNA Antigo , Lactase/genética , Seleção Genética , Animais , Ásia , Grupos Étnicos/genética , Europa (Continente) , Fermentação , Frequência do Gene/genética , Genótipo , Humanos , Leite , Fatores de Tempo
9.
Science ; 369(6502): 456-460, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32499399

RESUMO

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.


Assuntos
Genética Populacional , Migração Humana , Região do Caribe , Grupos Étnicos/genética , Genômica , Humanos
10.
Gene ; 754: 144821, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32497559

RESUMO

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.


Assuntos
Quimiocinas CC/genética , Variações do Número de Cópias de DNA , Grupos Étnicos/genética , Predisposição Genética para Doença , Infecções por HIV/epidemiologia , Infecções por HIV/genética , HIV-1/imunologia , Estudos de Casos e Controles , Genótipo , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Malásia/epidemiologia , Prognóstico
11.
Gene ; 754: 144840, 2020 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-32505845

RESUMO

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.


Assuntos
Dioxigenase FTO Dependente de alfa-Cetoglutarato/genética , Biomarcadores/metabolismo , Índice de Massa Corporal , Grupos Étnicos/genética , Predisposição Genética para Doença , Obesidade Pediátrica/epidemiologia , Polimorfismo de Nucleotídeo Único , Receptor Tipo 4 de Melanocortina/genética , Adolescente , Criança , Pré-Escolar , Feminino , Genótipo , Humanos , Masculino , México/epidemiologia , Sobrepeso/epidemiologia , Sobrepeso/genética , Sobrepeso/metabolismo , Obesidade Pediátrica/genética , Obesidade Pediátrica/metabolismo , Prevalência
12.
Medicine (Baltimore) ; 99(23): e20552, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32502021

RESUMO

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.


Assuntos
Proteína ADAMTS1/genética , Hipertensão Essencial/genética , Grupos Étnicos/genética , Predisposição Genética para Doença , Polimorfismo Genético , Fumar/epidemiologia , Inibidor Tecidual de Metaloproteinase-3/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China/epidemiologia , Hipertensão Essencial/epidemiologia , Feminino , Genótipo , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase
13.
Mol Genet Genomics ; 295(6): 1315-1324, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32588126

RESUMO

We have determined the distribution of Y-chromosomal haplotypes and predicted haplogroups in the ethnically diverse Kingdom of Bahrain, a small archipelago in the Arabian Gulf. Paternal population structure within Bahrain was investigated using the 27 Y-STRs (short tandem repeats) in the Yfiler Plus kit to generate haplotypes from 562 unrelated Bahraini males, sub-divided into four geographical regions-Northern, Capital, Southern and Muharraq. Yfiler Plus provided a significant improvement over the 17-locus Yfiler kit in discrimination capacity (from 77% to 87.5% overall), but discrimination capacity differed widely between regions from 98.4% in Muharraq to 75.2% in the Northern region, an unusually low value possibly resulting from recent rapid population expansion. Clusters of closely related male lineages were seen, with only 79.4% of donors displaying unique haplotypes and 59% of instances of shared haplotypes occurring within, rather than between, regions. Haplogroup prediction indicated diverse origins of the population with a predominance of haplogroups J2 and J1, both typical of the Arabian Peninsula, but also haplogroups such as B2 and E1b1a likely originating in Africa, and H, L and R2 likely indicative of migration from South Asia. Haplogroup frequencies differed significantly between regions, with J2 significantly more common in the Northern region compared with the Southern, possibly due to differential settlement by Baharna and Arabs. Our study shows that paternal lineage population structure can exist even over small geographical scales, and that highly discriminating genetic tools are required where rapid expansions have occurred within tightly bounded populations.


Assuntos
Cromossomos Humanos Y/genética , Grupos Étnicos/genética , Variação Genética , Genética Populacional , Haplótipos , Repetições de Microssatélites , Adulto , Barein , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Gene ; 752: 144760, 2020 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-32416252

RESUMO

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.


Assuntos
Insulisina/genética , Proteínas de Neoplasias/genética , Síndrome do Ovário Policístico/genética , Receptores do LH/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Estudos de Coortes , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Testes Genéticos , Estudo de Associação Genômica Ampla , Genótipo , Humanos , Índia/epidemiologia , Insulisina/metabolismo , Proteínas de Neoplasias/metabolismo , Síndrome do Ovário Policístico/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Receptores do LH/metabolismo , Análise de Sequência de DNA/métodos
15.
PLoS One ; 15(5): e0232174, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32380517

RESUMO

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.


Assuntos
Neoplasias da Mama/genética , Interleucina-10/genética , Adulto , Idoso , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , China , Grupos Étnicos/genética , Feminino , Frequência do Gene/genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Interleucina-10/metabolismo , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
16.
PLoS Genet ; 16(5): e1008747, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32407400

RESUMO

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.


Assuntos
Grupos Étnicos/genética , Grupos Étnicos/estatística & dados numéricos , Desenvolvimento Fetal/genética , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Receptores de Inositol 1,4,5-Trifosfato/genética , Gravidez , Adulto , Comparação Transcultural , Feminino , Peso Fetal/etnologia , Peso Fetal/genética , Loci Gênicos , Estudo de Associação Genômica Ampla/métodos , Idade Gestacional , Humanos , Polimorfismo de Nucleotídeo Único , Gravidez/etnologia , Gravidez/genética , Gravidez/estatística & dados numéricos , Adulto Jovem
17.
PLoS Genet ; 16(5): e1008749, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32453742

RESUMO

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.


Assuntos
Metilação de DNA , Grupos Étnicos/genética , Interação Gene-Ambiente , Transcriptoma , Ilhas de CpG , Meio Ambiente , Epigênese Genética/fisiologia , Grupos Étnicos/estatística & dados numéricos , Perfilação da Expressão Gênica/estatística & dados numéricos , Genética Populacional , Estudo de Associação Genômica Ampla/estatística & dados numéricos , Genômica/métodos , Humanos , Indonésia/epidemiologia , Ilhas/epidemiologia , Ilhas do Pacífico/epidemiologia , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , RNA-Seq
18.
Gene ; 753: 144806, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32461018

RESUMO

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.


Assuntos
Antígenos CD36/genética , Doença da Artéria Coronariana/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Estudos de Casos e Controles , China/epidemiologia , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Grupos Étnicos/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Lipídeos/sangue , Lipídeos/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Caracteres Sexuais
19.
Am J Hum Genet ; 106(6): 805-817, 2020 06 04.
Artigo em Inglês | MEDLINE | ID: mdl-32442408

RESUMO

Despite strong transethnic genetic correlations reported in the literature for many complex traits, the non-transferability of polygenic risk scores across populations suggests the presence of population-specific components of genetic architecture. We propose an approach that models GWAS summary data for one trait in two populations to estimate genome-wide proportions of population-specific/shared causal SNPs. In simulations across various genetic architectures, we show that our approach yields approximately unbiased estimates with in-sample LD and slight upward-bias with out-of-sample LD. We analyze nine complex traits in individuals of East Asian and European ancestry, restricting to common SNPs (MAF > 5%), and find that most common causal SNPs are shared by both populations. Using the genome-wide estimates as priors in an empirical Bayes framework, we perform fine-mapping and observe that high-posterior SNPs (for both the population-specific and shared causal configurations) have highly correlated effects in East Asians and Europeans. In population-specific GWAS risk regions, we observe a 2.8× enrichment of shared high-posterior SNPs, suggesting that population-specific GWAS risk regions harbor shared causal SNPs that are undetected in the other GWASs due to differences in LD, allele frequencies, and/or sample size. Finally, we report enrichments of shared high-posterior SNPs in 53 tissue-specific functional categories and find evidence that SNP-heritability enrichments are driven largely by many low-effect common SNPs.


Assuntos
Grupos Étnicos/genética , Estudo de Associação Genômica Ampla , Herança Multifatorial/genética , Polimorfismo de Nucleotídeo Único/genética , Teorema de Bayes , Europa (Continente)/etnologia , Extremo Oriente/etnologia , Frequência do Gene , Humanos , Desequilíbrio de Ligação , Especificidade de Órgãos/genética
20.
Am J Hum Genet ; 107(1): 149-157, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32470374

RESUMO

The Iron and Classical Ages in the Near East were marked by population expansions carrying cultural transformations that shaped human history, but the genetic impact of these events on the people who lived through them is little-known. Here, we sequenced the whole genomes of 19 individuals who each lived during one of four time periods between 800 BCE and 200 CE in Beirut on the Eastern Mediterranean coast at the center of the ancient world's great civilizations. We combined these data with published data to traverse eight archaeological periods and observed any genetic changes as they arose. During the Iron Age (∼1000 BCE), people with Anatolian and South-East European ancestry admixed with people in the Near East. The region was then conquered by the Persians (539 BCE), who facilitated movement exemplified in Beirut by an ancient family with Egyptian-Lebanese admixed members. But the genetic impact at a population level does not appear until the time of Alexander the Great (beginning 330 BCE), when a fusion of Asian and Near Easterner ancestry can be seen, paralleling the cultural fusion that appears in the archaeological records from this period. The Romans then conquered the region (31 BCE) but had little genetic impact over their 600 years of rule. Finally, during the Ottoman rule (beginning 1516 CE), Caucasus-related ancestry penetrated the Near East. Thus, in the past 4,000 years, three limited admixture events detectably impacted the population, complementing the historical records of this culturally complex region dominated by the elite with genetic insights from the general population.


Assuntos
DNA/genética , Genética Populacional/história , Egito , Grupos Étnicos/genética , Grupos Étnicos/história , Genoma Humano/genética , Haplótipos/genética , História Antiga , Migração Humana/história , Humanos , Oriente Médio
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA