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2.
Hum Genomics ; 13(1): 12, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30786938

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the first cause of cancer deaths among Puerto Ricans. The incidence and mortality of CRC in Puerto Rico continue to be on the rise. The burden of CRC in Puerto Rico is higher than among US Hispanics and is second only to African Americans, thus supporting the importance of studying this CRC health disparity. The genetic background of the Puerto Rican population is a mix of European, African, and Amerindian races, which may account, in part, for the differences observed in the CRC mortality rates among Puerto Ricans. The objective of the study was to assess the role of genetic ancestry in CRC risk and its association with clinicopathological features of CRC tumors in Puerto Ricans. RESULTS: We used a validated panel of 105 ancestry informative markers (AIMs) to estimate genetic ancestry in 406 Puerto Rican CRC cases and 425 Puerto Rican controls. We examined the association of genetic ancestry with CRC risk and tumor clinicopathological characteristics. CONCLUSIONS: The mean ancestry proportions in the study population were 61% European, 21% African, and 18% Amerindian. No association was observed between genetic ancestry and risk of CRC. However, African ancestry was associated with an increased risk of developing rectal tumors (OR = 1.55, 95% CI 1.04-2.31). Additional studies are needed to fully elucidate the role of African ancestry in CRC carcinogenesis.


Assuntos
Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Afro-Americanos/genética , Idoso , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Hispano-Americanos/genética , Humanos , Índios Centro-Americanos/genética , Masculino , Pessoa de Meia-Idade , Porto Rico
3.
Nat Commun ; 10(1): 880, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787307

RESUMO

Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12-q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations.


Assuntos
Afro-Americanos/genética , Asma/genética , Predisposição Genética para Doença/genética , Asma/epidemiologia , Cromossomos Humanos Par 12/genética , Cromossomos Humanos Par 17/genética , Cromossomos Humanos Par 8/genética , Loci Gênicos , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Polimorfismo de Nucleotídeo Único/genética , Estados Unidos/epidemiologia
4.
Genet Test Mol Biomarkers ; 23(2): 75-83, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30676117

RESUMO

AIMS: This study compared facilitators and barriers to genetic testing and determined awareness about the Genetic Information Nondiscrimination Act (GINA) across young Hispanic and non-Hispanic white (NHW) breast cancer (BC) survivors. MATERIALS AND METHODS: Women diagnosed with BC of age ≤50 years in 2009-2012 were recruited through the Florida State Cancer Registry to complete a questionnaire. RESULTS: There were 1182 participants of which 61% (174/285) of Hispanic patients, and 65% (580/897) of NHW patients had BC testing. Among untested participants, the most common barriers were lack of testing recommendation (44% Hispanics, 32% NHW; p = 0.02) and cost-related concerns (41% Hispanics, 40% NHW; p = 0.83). Among tested participants, the top facilitators were as follows: (1) "To benefit my family's future" (70% Hispanic, 68% NHW), (2) "My doctor recommended testing" (60% Hispanic, 54% NHW), and (3) "Minimal cost to me" (59% Hispanic, 72% NHW). Only 27% of tested and 15% of untested women were aware of GINA; misuse of test results was reported as a barrier for only 6.5%. CONCLUSIONS: Rates of genetic testing recommendation are lower among Hispanics, but both groups reported additional barriers. Most are unaware of GINA, yet misuse is not a highly cited barrier. Findings suggest the need to educate providers on the importance of recommending testing to all who meet criteria; increase awareness of newer options for more affordable testing; and bolster facilitators that may increase testing uptake.


Assuntos
Grupo com Ancestrais do Continente Europeu/etnologia , Conhecimentos, Atitudes e Prática em Saúde/etnologia , Hispano-Americanos/psicologia , Adulto , Neoplasias da Mama/diagnóstico , Sobreviventes de Câncer , Barreiras de Comunicação , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Florida , Testes Genéticos/métodos , Hispano-Americanos/genética , Humanos , Pessoa de Meia-Idade , Fatores de Risco , Fatores Socioeconômicos , Sobreviventes
5.
Gastroenterology ; 156(6): 1707-1716.e2, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30664875

RESUMO

BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility. METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings. RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 × 10-9 and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P = .01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 × 10-6; allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 × 10-6; allele frequency = 11.5%). Among amoxicillin- and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A*02:01 and DRB1*15:01. CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.


Assuntos
Afro-Americanos/genética , Doença Hepática Induzida por Substâncias e Drogas/genética , Grupo com Ancestrais do Continente Europeu/genética , Hispano-Americanos/genética , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Adulto , Amoxicilina/efeitos adversos , Antibacterianos/efeitos adversos , Estudos de Casos e Controles , Ácido Clavulânico/efeitos adversos , Feminino , Frequência do Gene , Estudo de Associação Genômica Ampla , Antígeno HLA-A2/genética , Cadeias HLA-DRB1/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Fatores de Risco
6.
Nat Commun ; 10(1): 376, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30670697

RESUMO

Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 locus. The CLASP1, LHX1, and SNTA1 regions harbor genes linked to muscle function and lipid metabolism. Our results elucidate the role of physical activity interactions in the genetic contribution to blood lipid levels.


Assuntos
Exercício , Loci Gênicos/genética , Lipídeos/sangue , Lipídeos/genética , Adolescente , Adulto , Grupo com Ancestrais do Continente Africano/genética , Idoso , Idoso de 80 Anos ou mais , Grupo com Ancestrais do Continente Asiático/genética , Brasil , Proteínas de Ligação ao Cálcio/genética , Colesterol/sangue , HDL-Colesterol/sangue , HDL-Colesterol/genética , LDL-Colesterol/sangue , LDL-Colesterol/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Hispano-Americanos/genética , Humanos , Proteínas com Homeodomínio LIM/genética , Metabolismo dos Lipídeos/genética , Masculino , Proteínas de Membrana/genética , Proteínas Associadas aos Microtúbulos/genética , Pessoa de Meia-Idade , Proteínas Musculares/genética , Proteínas do Tecido Nervoso/genética , Fatores de Transcrição/genética , Triglicerídeos/sangue , Triglicerídeos/genética , Adulto Jovem
7.
Breast Cancer Res ; 21(1): 3, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-30642363

RESUMO

BACKGROUND: Breast cancer is a partially heritable trait and genome-wide association studies (GWAS) have identified over 180 common genetic variants associated with breast cancer. We have previously performed breast cancer GWAS in Latinas and identified a strongly protective single nucleotide polymorphism (SNP) at 6q25, with the protective minor allele originating from indigenous American ancestry. Here we report on fine mapping of the 6q25 locus in an expanded sample of Latinas. METHODS: We performed GWAS in 2385 cases and 6416 controls who were either US Latinas or Mexican women. We replicated the top SNPs in 2412 cases and 1620 controls of US Latina, Mexican, and Colombian women. In addition, we validated the top novel variants in studies of African, Asian and European ancestry. In each dataset we used logistic regression models to test the association between SNPs and breast cancer risk and corrected for genetic ancestry using either principal components or genetic ancestry inferred from ancestry informative markers using a model-based approach. RESULTS: We identified a novel set of SNPs at the 6q25 locus associated with genome-wide levels of significance (p = 3.3 × 10- 8 - 6.0 × 10- 9) not in linkage disequilibrium (LD) with variants previously reported at this locus. These SNPs were in high LD (r2 > 0.9) with each other, with the top SNP, rs3778609, associated with breast cancer with an odds ratio (OR) and 95% confidence interval (95% CI) of 0.76 (0.70-0.84). In a replication in women of Latin American origin, we also observed a consistent effect (OR 0.88; 95% CI 0.78-0.99; p = 0.037). We also performed a meta-analysis of these SNPs in East Asians, African ancestry and European ancestry populations and also observed a consistent effect (rs3778609, OR 0.95; 95% CI 0.91-0.97; p = 0.0017). CONCLUSION: Our study adds to evidence about the importance of the 6q25 locus for breast cancer susceptibility. Our finding also highlights the utility of performing additional searches for genetic variants for breast cancer in non-European populations.


Assuntos
Neoplasias da Mama/genética , Cromossomos Humanos Par 6/genética , Loci Gênicos/genética , Predisposição Genética para Doença , Adulto , Idoso , Mama , Estudos de Casos e Controles , Mapeamento Cromossômico , Conjuntos de Dados como Assunto , Feminino , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Humanos , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único
8.
Gastroenterology ; 156(5): 1496-1507.e7, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30593799

RESUMO

BACKGROUND & AIMS: Spontaneous clearance of hepatitis C virus (HCV) occurs in approximately 30% of infected persons and less often in populations of African ancestry. Variants in major histocompatibility complex (MHC) and in interferon lambda genes are associated with spontaneous HCV clearance, but there have been few studies of these variants in persons of African ancestry. We performed a dense multi-ancestry genome-wide association study of spontaneous clearance of HCV, focusing on individuals of African ancestry. METHODS: We performed genotype analyses of 4423 people from 3 ancestry groups: 2201 persons of African ancestry (445 with HCV clearance and 1756 with HCV persistence), 1739 persons of European ancestry (701 with HCV clearance and 1036 with HCV persistence), and 486 multi-ancestry Hispanic persons (173 with HCV clearance and 313 with HCV persistence). Samples were genotyped using Illumina (San Diego, CA) arrays and statistically imputed to the 1000 Genomes Project. For each ancestry group, the association of single-nucleotide polymorphisms with HCV clearance was tested by log-additive analysis, and then a meta-analysis was performed. RESULTS: In the meta-analysis, significant associations with HCV clearance were confirmed at the interferon lambda gene locus IFNL4-IFNL3 (19q13.2) (P = 5.99 × 10-50) and the MHC locus 6p21.32 (P = 1.15 × 10-21). We also associated HCV clearance with polymorphisms in the G-protein-coupled receptor 158 gene (GPR158) at 10p12.1 (P = 1.80 × 10-07). These 3 loci had independent, additive effects of HCV clearance, and account for 6.8% and 5.9% of the variance of HCV clearance in persons of European and African ancestry, respectively. Persons of African or European ancestry carrying all 6 variants were 24-fold and 11-fold, respectively, more likely to clear HCV infection compared with individuals carrying none or 1 of the clearance-associated variants. CONCLUSIONS: In a meta-analysis of data from 3 studies, we found variants in MHC genes, IFNL4-IFNL3, and GPR158 to increase odds of HCV clearance in patients of European and African ancestry. These findings could increase our understanding of immune response to and clearance of HCV infection.


Assuntos
Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Europeu/genética , Hepacivirus/fisiologia , Hepatite C/genética , Hispano-Americanos/genética , Feminino , Estudo de Associação Genômica Ampla , Hepatite C/diagnóstico , Hepatite C/etnologia , Hepatite C/virologia , Interações Hospedeiro-Patógeno , Humanos , Interleucinas/genética , Complexo Principal de Histocompatibilidade/genética , Masculino , Receptores Acoplados a Proteínas-G/genética , Remissão Espontânea , Estados Unidos/epidemiologia , Carga Viral
9.
Biodemography Soc Biol ; 64(2): 152-170, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30570413

RESUMO

This study examines associations between ethnic identity, regional history, and genomic ancestry in New Mexicans of Spanish-speaking descent (NMS). In structured interviews, we asked 507 NMS to select from a list of eight ethnic identity terms identified in previous research. We estimated genomic ancestry for each individual from 291,917 single nucleotide polymorphisms (SNPs) and compared genomic ancestry, age, and birthplace between groups of individuals who identified using each ethnic identity term. Eighty-eight per cent of NMS who identified as "Hispanic," "Nuevomexicano/a," and "Spanish," on average, were born in New Mexico, as were the vast majority of their parents and grandparents. Thirty-three per cent of NMS who identified as "Mexican" and "Mexican American" were born in Mexico, as were 59 per cent of their parents and 67 per cent of their grandparents. Average Native American and African ancestry proportions in "Hispanic" (0.26, 0.02, respectively), "Spanish" (0.25, 0.01), and "Nuevomexicano/a" (0.24, 0.01) NMS were significantly lower than in "Mexican American" (0.37, 0.04) NMS. Significant age differences between older "Spanish" and younger "Nuevomexicano/a" individuals, combined with widespread use of the term "Hispanic," may reflect ongoing nomenclature changes. Patterns of correspondence between ethnic identity, ethnic nomenclatures, and genomic ancestry reflect historical patterns of migration, colonization, and cultural change.


Assuntos
Grupos Étnicos/genética , Hispano-Americanos/psicologia , Adulto , Grupos Étnicos/psicologia , Feminino , Instabilidade Genômica/genética , Genômica , Hispano-Americanos/genética , Humanos , Entrevistas como Assunto/métodos , Masculino , Americanos Mexicanos/genética , Americanos Mexicanos/psicologia , New Mexico/etnologia
10.
Medicine (Baltimore) ; 97(43): e12884, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30412083

RESUMO

OBJECTIVE: Although the relationship between apolipoprotein E (ApoE) gene polymorphisms and the risk of Parkinson disease (PD) has been established, the results were inconsistent and inconclusive. METHODS: A comprehensive search examining the association between APOE polymorphisms and PD through PubMed, Embase, Chinese National Knowledge Infrastructure (CNKI), and Cochrane Library databases was performed without published year limited. RESULTS: A total of 47 studies with 7533 cases and 14442 controls were included in present study. The results showed statistically significant association between risk factor ApoE ε4 allele and PD in Asian population (P = .003, odds ratio, OR [95% confidence interval, CI] = 1.43 [1.13,1.80]). Genotype ε2ε4 have significantly associated with PD in Asian population (P = .004, OR [95% CI] = 4.43 [1.62,12.10]). Genotype ε3ε4 was significantly associated with PD in Latin-American population (P = .01, OR [95% CI] = 1.44 [1.08,1.91]). In addition, the frequency of the genotype ε3ε4 is lower in PD group than that in the control group in Caucasian population, and the difference of genotype ε3ε4 is also statistically significant (P = .006, OR [95% CI] = 0.86 [0.77,0.96]). Although significant heterogeneity was observed among all studies, the results were shown to be stabilized by sensitive analysis. No publish bias was observed. CONCLUSIONS: This meta-analysis suggests that the APOE ε4, but no ε2, might be a risk factor for PD in Asian population. Furthermore, the genotype ε2ε4 may be a susceptible factor for PD in Asian population, and the genotype ε3ε4 may be a susceptible factor for PD in both Caucasian and Latin-American populations.


Assuntos
Apolipoproteína E4/genética , Doença de Parkinson/genética , Polimorfismo Genético/genética , Idoso , Idoso de 80 Anos ou mais , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Heterozigoto , Hispano-Americanos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/etnologia , Fatores de Risco
11.
Cancer Genomics Proteomics ; 15(4): 265-271, 2018 Jul-Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29976631

RESUMO

BACKGROUND/AIM: Microsatellite instability (MSI) results from genetic alterations involving the mismatch repair (MMR) genes MLH1, PSM2, MSH2, and MSH6. MSI has been implicated in both sporadic CRC and Lynch syndrome. The aim of the study was to assess the frequency of alterations in MMR protein expression in both primary colorectal cancer and precursor lesions among Puerto Rican patients. PATIENTS AND METHODS: A retrospective study of 84 Puerto Rican patients was performed to assess the frequency of MMR protein expression alterations in both primary CRC and precursor lesions using tissue microarray and immunohistochemistry. RESULTS: The loss of expression of both MLH1 and PMS2 proteins was present in 6.3% of adenomas, 9.1% of adenomas with high-grade dysplasia and 9.4% of colon adenocarcinomas. Negative nuclear staining for both MSH2 and MSH6 proteins was found in 2.4% of colon adenocarcinomas. CONCLUSION: When compared to prior reports, this study suggests a lower frequency of MSI among the Puerto Rican population. The higher prevalence of MLH1 mutations correlates with previous studies of protein expression among the Hispanic community including Colombian, Uruguay and Brazilian populations.


Assuntos
Adenocarcinoma/metabolismo , Adenoma/metabolismo , Neoplasias do Colo/metabolismo , Hispano-Americanos/genética , Endonuclease PMS2 de Reparo de Erro de Pareamento/genética , Proteína 1 Homóloga a MutL/genética , Mutação , Adenocarcinoma/epidemiologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenoma/epidemiologia , Adenoma/genética , Adenoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Estudos de Casos e Controles , Neoplasias do Colo/epidemiologia , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Reparo de Erro de Pareamento de DNA , Proteínas de Ligação a DNA/genética , Feminino , Seguimentos , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Membrana Mucosa/metabolismo , Proteína 2 Homóloga a MutS/genética , Prognóstico , Porto Rico/epidemiologia , Estudos Retrospectivos
12.
Genet Epidemiol ; 42(6): 500-515, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29862559

RESUMO

Multipoint linkage analysis is an important approach for localizing disease-associated loci in pedigrees. Linkage analysis, however, is sensitive to misspecification of marker allele frequencies. Pedigrees from recently admixed populations are particularly susceptible to this problem because of the challenge of accurately accounting for population structure. Therefore, increasing emphasis on use of multiethnic samples in genetic studies requires reevaluation of best practices, given data currently available. Typical strategies have been to compute allele frequencies from the sample, or to use marker allele frequencies determined by admixture proportions averaged over the entire sample. However, admixture proportions vary among pedigrees and throughout the genome in a family-specific manner. Here, we evaluate several approaches to model admixture in linkage analysis, providing different levels of detail about ancestral origin. To perform our evaluations, for specification of marker allele frequencies, we used data on 67 Caribbean Hispanic admixed families from the Alzheimer's Disease Sequencing Project. Our results show that choice of admixture model has an effect on the linkage analysis results. Variant-specific admixture proportions, computed for individual families, provide the most detailed regional admixture estimates, and, as such, are the most appropriate allele frequencies for linkage analysis. This likely decreases the number of false-positive results, and is straightforward to implement.


Assuntos
Doença de Alzheimer/genética , Pool Gênico , Hispano-Americanos/genética , Linhagem , Filogenia , Análise de Sequência de DNA , Região do Caribe , Grupos Étnicos , Família , Feminino , Frequência do Gene/genética , Ligação Genética , Genética Populacional , Humanos , Escore Lod , Masculino , Modelos Genéticos , Análise de Componente Principal
13.
PLoS Genet ; 14(5): e1007385, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29795556

RESUMO

Populations change in size over time due to factors such as population growth, migration, bottleneck events, natural disasters, and disease. The historical effective size of a population affects the power and resolution of genetic association studies. For admixed populations, it is not only the overall effective population size that is of interest, but also the effective sizes of the component ancestral populations. We use identity by descent and local ancestry inferred from genome-wide genetic data to estimate overall and ancestry-specific effective population size during the past hundred generations for nine admixed American populations from the Hispanic Community Health Study/Study of Latinos, and for African-American and European-American populations from two US cities. In these populations, the estimated pre-admixture effective sizes of the ancestral populations vary by sampled population, suggesting that the ancestors of different sampled populations were drawn from different sub-populations. In addition, we estimate that overall effective population sizes dropped substantially in the generations immediately after the commencement of European and African immigration, reaching a minimum around 12 generations ago, but rebounded within a small number of generations afterwards. Of the populations that we considered, the population of individuals originating from Puerto Rico has the smallest bottleneck size of one thousand, while the Pittsburgh African-American population has the largest bottleneck size of two hundred thousand.


Assuntos
Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Genoma Humano/genética , Hispano-Americanos/genética , Afro-Americanos/estatística & dados numéricos , Américas , Simulação por Computador , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Estudos de Associação Genética/métodos , Genética Populacional/métodos , Haplótipos , Hispano-Americanos/estatística & dados numéricos , Humanos , Densidade Demográfica , Estados Unidos
14.
PLoS One ; 13(4): e0194480, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29624624

RESUMO

Atrial fibrillation (AF) is the most prevalent cardiac rhythm disorder worldwide but the underlying genetic and molecular mechanisms and the response to therapies is not fully understood. Despite a greater burden of AF risk factors in Hispanics/Latinos the prevalence of AF remains low. Over the last decade, genome-wide association studies have identified numerous AF susceptibility loci in mostly whites of European descent. The goal of this study was to determine if the top 9 single nucleotide polymorphisms (SNPs) associated with AF in patients of European descent also increase susceptibility to AF in Hispanics/Latinos. AF cases were prospectively enrolled in the University of Illinois at Chicago (UIC) AF Registry and control subjects were identified from the UIC Cohort of Patients, Family and Friends. AF cases and controls were genotyped for 9 AF risk SNPs at chromosome 1q21: rs13376333, rs6666258; chr1q24: rs3903239; chr4q25: rs2200733; rs10033464; chr10q22: rs10824026; chr14q23: rs1152591; chr16q22: rs2106261 and rs7193343. The study sample consisted of 713 Hispanic/Latino subjects including 103 AF cases and 610 controls. Among the 8 AF risk SNPs genotyped, only rs10033464 SNP at chromosome (chr) 4q25 (near PITX2) was significantly associated with development of AF after multiple risk factor adjustment and multiple testing (adj. odds ratio [OR] 2.27, 95% confidence interval [CI] 1.31-3.94; P = 3.3 x 10-3). Furthermore, the association remained significant when the analysis was restricted to Hispanics of Mexican descent (adj. OR 2.32, 95% CI 1.35-3.99; P = 0.002. We confirm for the first time the association between a chromosome 4q25 SNP and increased susceptibility to AF in Hispanics/Latinos. While the underlying molecular mechanisms by which the chr4q25 SNP modulates AF risk remains unclear, this study supports a genetic basis for non-familial AF in patients of Hispanic descent.


Assuntos
Fibrilação Atrial/epidemiologia , Fibrilação Atrial/genética , Predisposição Genética para Doença , Hispano-Americanos/genética , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Estudos de Coortes , Comorbidade , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Medição de Risco
15.
Gynecol Oncol ; 149(1): 84-88, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29605055

RESUMO

OBJECTIVE: We sought to characterize referral patterns for genetic counseling for women with ovarian cancer and hypothesized that differences in referral and testing rates are shaped by socioeconomic factors. METHODS: Patients were identified by pathology reports from August 2012 to January 2016 containing the words "serous" or "ovarian." Patient information was obtained via electronic medical record. Primary outcomes were placement of a genetics referral and completion of counseling. A secondary outcome was completion of genetic testing. RESULTS: We identified 246 women with a diagnosis of ovarian cancer. Ten were previously counseled and excluded. 53% of patients were referred for counseling with mean time from diagnosis to counseling of 4.6months. Age and family history were not associated with referral, however rates differed by race with 61% of Caucasian and 40%, 38% and 33% of Asian, Latina and Black women, respectively, referred (p=0.035). Overall, 36% of patients diagnosed underwent counseling, and 33% were tested. English language (p<0.0001), high-grade serous histology (p=<0.0001) and private or Medicare insurance (p<0.0001) were significantly associated with referral. CONCLUSION: We have not yet reached the Society of Gynecologic Oncology recommendation for referral to genetics. Women of color and those with public insurance have lower referral rates. This disparity in care impacts cancer treatment options and prevents appropriate screening for other hereditary malignancies. To provide comprehensive oncology care, including genetic assessment, we recommend focusing on these barriers including improving outreach and interpreter services.


Assuntos
Testes Genéticos/estatística & dados numéricos , Neoplasias Ovarianas/etnologia , Neoplasias Ovarianas/genética , Grupo com Ancestrais do Continente Africano/genética , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Grupo com Ancestrais do Continente Asiático/genética , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/genética , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Testes Genéticos/normas , Disparidades em Assistência à Saúde , Hispano-Americanos/genética , Hispano-Americanos/estatística & dados numéricos , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/economia , Encaminhamento e Consulta/estatística & dados numéricos , Estudos Retrospectivos , Programa de SEER , Estados Unidos/epidemiologia
16.
Pregnancy Hypertens ; 12: 144-149, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29580923

RESUMO

OBJECTIVE: The purpose of this study was to validate our previous genetic association findings related to the endoglin (ENG) pathway from an American Caucasian preeclampsia cohort in independent preeclampsia cohorts. We also sought to explore the ENG pathway for new genetic associations in these independent cohorts. STUDY DESIGN: We used a tagging single nucleotide (tSNP) approach to assess genetic variability across five ENG pathway genes (ENG, TGFß1, TGFßR1, ALK1, and TGFßR2) in a Caucasian cohort from Norway (n = 77 preeclampsia cases & n = 63 normotensive controls) and a White Hispanic cohort from Southern California (n = 69 preeclampsia cases & n = 106 normotensive controls). MAIN OUTCOME MEASURES: Univariate analyses (Chi Square, Fisher's Exact) and multivariate logistic regression were conducted to evaluate the association between tSNP genotype distributions and pregnancy outcome in each cohort. Logistic regression models were adjusted for maternal age at delivery, infant sex, parity, smoking during pregnancy, and pre-pregnancy BMI. RESULTS: Although we were unable to replicate our previous SNP-specific findings (ENG rs11792480, rs10121110; TGFßR2 rs6550005; p's > 0.05), we found that genetic variation in TGFßR1[ALK5] (rs6478974) and TGFßR2 (rs11129420, rs6802220, rs1155708, rs3773640, rs3773663) was significantly associated with preeclampsia in the Norwegian cohort and genetic variation in ALK1 (rs706819) and TGFßR2 (rs9843942) was significantly associated with preeclampsia in the Latina cohort. CONCLUSION: Overall, our results provide further support for the involvement and investigation of the endoglin pathway in preeclampsia.


Assuntos
Endoglina/genética , Grupo com Ancestrais do Continente Europeu/genética , Hispano-Americanos/genética , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/genética , Receptores de Activinas Tipo II/genética , Adolescente , Adulto , California/epidemiologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Modelos Logísticos , Análise Multivariada , Noruega/epidemiologia , Fenótipo , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/etnologia , Gravidez , Proteínas Serina-Treonina Quinases/genética , Receptor do Fator de Crescimento Transformador beta Tipo I , Receptor do Fator de Crescimento Transformador beta Tipo II , Receptores de Fatores de Crescimento Transformadores beta/genética , Fatores de Risco , Fator de Crescimento Transformador beta1/genética , Adulto Jovem
17.
Drug Metab Dispos ; 46(5): 619-627, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29386232

RESUMO

The breast cancer resistance protein (BCRP/ABCG2) is a maternally-facing efflux transporter that regulates the placental disposition of chemicals. Transcription factors and gene variants are important regulatory factors that influence transporter expression. In this study, we sought to identify the genetic and transcriptional mechanisms underlying the interindividual expression of BCRP mRNA and protein across 137 term placentas from uncomplicated pregnancies. Placental expression of BCRP and regulatory transcription factor mRNAs was measured using multiplex-branched DNA analysis. BCRP expression and ABCG2 genotypes were determined using Western blot and Fluidigm Biomark genetic analysis, respectively. Placentas were obtained from a racially and ethnically diverse population, including Caucasian (33%), African American (14%), Asian (14%), Hispanic (15%), and mixed (16%) backgrounds, as well as unknown origins (7%). Between placentas, BCRP mRNA and protein varied up to 47-fold and 14-fold, respectively. In particular, BCRP mRNA correlated significantly with known transcription factor mRNAs, including nuclear factor erythroid 2-related factor 2 and aryl hydrocarbon receptor. Somewhat surprisingly, single-nucleotide polymorphisms (SNPs) in the ABCG2 noncoding regions were not associated with variation in placental BCRP mRNA or protein. Instead, the coding region polymorphism (C421A/Q141K) corresponded with 40%-50% lower BCRP protein in 421C/A and 421A/A placentas compared with wild types (421C/C). Although BCRP protein and mRNA expression weakly correlated (r = 0.25, P = 0.040), this relationship was absent in individuals expressing the C421A variant allele. Study results contribute to our understanding of the interindividual regulation of BCRP expression in term placentas and may help to identify infants at risk for increased fetal exposure to chemicals due to low expression of this efflux protein.


Assuntos
Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Neoplasias da Mama/genética , Proteínas de Neoplasias/genética , Adulto , Afro-Americanos/genética , Alelos , Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Hispano-Americanos/genética , Humanos , Placenta/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Gravidez , RNA Mensageiro/genética
18.
Nutrients ; 10(2)2018 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-29414925

RESUMO

Blacks have different dominant polymorphisms in the vitamin D-binding protein (DBP) gene that result in higher bioavailable vitamin D than whites. This study tested whether the lack of association between 25-hydroxyvitamin D (25OHD) and multiple sclerosis (MS) risk in blacks and Hispanics is due to differences in these common polymorphisms (rs7041, rs4588). We recruited incident MS cases and controls (blacks 116 cases/131 controls; Hispanics 183/197; whites 247/267) from Kaiser Permanente Southern California. AA is the dominant rs7041 genotype in blacks (70.0%) whereas C is the dominant allele in whites (79.0% AC/CC) and Hispanics (77.1%). Higher 25OHD levels were associated with a lower risk of MS in whites who carried at least one copy of the C allele but not AA carriers. No association was found in Hispanics or blacks regardless of genotype. Higher ultraviolet radiation exposure was associated with a lower risk of MS in blacks (OR = 0.06), Hispanics and whites who carried at least one copy of the C allele but not in others. Racial/ethnic variations in bioavailable vitamin D do not explain the lack of association between 25OHD and MS in blacks and Hispanics. These findings further challenge the biological plausibility of vitamin D deficiency as causal for MS.


Assuntos
Esclerose Múltipla/genética , Polimorfismo Genético , Luz Solar , Proteína de Ligação a Vitamina D/genética , Vitamina D/análogos & derivados , Adulto , Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Genótipo , Hispano-Americanos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/etnologia , Fatores de Risco , Vitamina D/sangue , Vitamina D/metabolismo
19.
J Diabetes ; 10(6): 524-533, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29417738

RESUMO

BACKGROUND: Sex hormones are implicated in the development of diabetes. However, whether genetic variations in sex hormone pathways (SHPs) contribute to the risk of type 2 diabetes mellitus (T2DM) remains to be determined. This study investigated associations between genetic variations in all candidate genes in SHPs and T2DM risk among a cohort of women participating in the Women's Health Initiative (WHI). METHODS: Single nucleotide polymorphisms (SNPs) located within 30 kb upstream and downstream of SHP genes were comprehensively examined in 8180 African American, 3498 Hispanic American, and 3147 European American women in the WHI. In addition, whether significant SNPs would be replicated in independent populations was examined. RESULTS: After adjusting for age, region, and ancestry estimates and correcting for multiple testing, seven SNPs were significantly associated with the risk of T2DM among Hispanic American women were identified in the progesterone receptor (PGR) gene, with rs948516 showing the greatest significance (odds ratio 0.67; 95% confidence interval 0.57-0.78; P = 8.8 × 10-7 ; false discovery rate, Q = 7.8 × 10-4 ). These findings were not replicated in other ethnic groups in the WHI or in sex-combined analyses in replication studies. CONCLUSION: Significant signals were identified implicating the PGR gene in T2DM development in Hispanic American women in the WHI, which are consistent with genome-wide association studies findings linking PGR to glucose homeostasis. Nevertheless, the PGR SNPs-T2DM association was not statistically significant in other ethnic populations. Further studies, especially sex-specific analyses, are needed to confirm the findings and clarify the role of SHPs in T2DM.


Assuntos
Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/etnologia , Diabetes Mellitus Tipo 2/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único , Pós-Menopausa/genética , Afro-Americanos/genética , Idoso , Estudos de Casos e Controles , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Seguimentos , Hispano-Americanos/genética , Humanos , Pessoa de Meia-Idade , Pós-Menopausa/etnologia , Prognóstico , Receptores de Progesterona/genética
20.
Proc Natl Acad Sci U S A ; 115(10): 2341-2346, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29463742

RESUMO

The Caribbean was one of the last parts of the Americas to be settled by humans, but how and when the islands were first occupied remains a matter of debate. Ancient DNA can help answering these questions, but the work has been hampered by poor DNA preservation. We report the genome sequence of a 1,000-year-old Lucayan Taino individual recovered from the site of Preacher's Cave in the Bahamas. We sequenced her genome to 12.4-fold coverage and show that she is genetically most closely related to present-day Arawakan speakers from northern South America, suggesting that the ancestors of the Lucayans originated there. Further, we find no evidence for recent inbreeding or isolation in the ancient genome, suggesting that the Lucayans had a relatively large effective population size. Finally, we show that the native American components in some present-day Caribbean genomes are closely related to the ancient Taino, demonstrating an element of continuity between precontact populations and present-day Latino populations in the Caribbean.


Assuntos
Grupo com Ancestrais Nativos do Continente Americano/genética , Genoma Humano/genética , Migração Humana/estatística & dados numéricos , Adulto , Arqueologia , Bahamas , DNA Antigo , DNA Mitocondrial/genética , Feminino , Genética Populacional , Genômica , Hispano-Americanos/genética , História Antiga , Migração Humana/história , Humanos , Masculino , Paleontologia , Filogenia , Adulto Jovem
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