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1.
PLoS One ; 15(9): e0236209, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32986714

RESUMO

The genetic risk for prostate cancer has been governed by a few rare variants with high penetrance and over 150 commonly occurring variants with lower impact on risk; however, most of these variants have been identified in studies containing exclusively European individuals. People of non-European ancestries make up less than 15% of prostate cancer GWAS subjects. Across the globe, incidence of prostate cancer varies with population due to environmental and genetic factors. The discrepancy between disease incidence and representation in genetics highlights the need for more studies of the genetic risk for prostate cancer across diverse populations. To better understand the genetic risk for prostate cancer across diverse populations, we performed PrediXcan and GWAS in a case-control study of 4,769 self-identified African American (2,463 cases and 2,306 controls), 2,199 Japanese American (1,106 cases and 1,093 controls), and 2,147 Latin American (1,081 cases and 1,066 controls) individuals from the Multiethnic Genome-wide Scan of Prostate Cancer. We used prediction models from 46 tissues in GTEx version 8 and five models from monocyte transcriptomes in the Multi-Ethnic Study of Atherosclerosis. Across the three populations, we predicted 19 gene-tissue pairs, including five unique genes, to be significantly (lfsr < 0.05) associated with prostate cancer. One of these genes, NKX3-1, replicated in a larger European study. At the SNP level, 110 SNPs met genome-wide significance in the African American study while 123 SNPs met significance in the Japanese American study. Fine mapping revealed three significant independent loci in the African American study and two significant independent loci in the Japanese American study. These identified loci confirm findings from previous GWAS of prostate cancer in diverse populations while PrediXcan-identified genes suggest potential new directions for prostate cancer research in populations across the globe.


Assuntos
Neoplasias da Próstata/genética , Transcriptoma , Afro-Americanos/genética , Americanos Asiáticos/genética , Estudos de Casos e Controles , Regulação Neoplásica da Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hispano-Americanos/genética , Proteínas de Homeodomínio/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/etnologia , Fatores de Transcrição/genética
2.
PLoS One ; 15(7): e0235466, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32663211

RESUMO

INTRODUCTION: Chagas disease presents bio-psycho-social and cultural determinants for infected patients, their family members, close friends, and society. For this reason, diagnosis and treatment require an active approach and an integral focus, so that we can prevent the disease from creating stigma and exclusion, as is actively promoting access to diagnosis, medical attention and social integration. METHODOLOGY: The study was conducted in the Metropolitan Area of Barcelona (Catalonia, Spain) from 2004 to 2017. After an increased detection rates of CHD in our region, the process of construction of community strategies started (2004-2013). Different community interventions with informational, educational, and communication components were designed, developed, implemented, and evaluated. The results of the evaluation helped to determine which intervention should be prioritized: 1) workshop; 2) community event; 3) in situ screening. Afterwards, those strategies were implemented (2014-2017). RESULTS: Each of the three strategies resulted in a different level of coverage, or number of people reached. The in situ screening interventions reached the highest coverage (956 persons, 58.98%).Clear differences exist (p-value<0.001) between the three strategies regarding the percentage of screenings and diagnoses carried out. The largest number was in the in situ screening intervention, with a total of 830 persons screened despite the greatest number of diagnoses was among the workshop participants (33 persons, 20.75% of those screened). The prevalence of infection found is similar among the three strategies, ranging from 16.63% to 22.32% of the screened patients (p-value = 0.325). CONCLUSIONS: The results of the study show that community interventions seem to be necessary to improve access to diagnosis and treatment of CHD in the area of Barcelona. They also show which strategy is the most appropriate based on the detected needs of the community, the proposed objectives of the intervention, and the given socio-temporal context.


Assuntos
Doença de Chagas/epidemiologia , Emigrantes e Imigrantes , Doença de Chagas/genética , Doença de Chagas/patologia , Medicina Comunitária , Família , Feminino , Hispano-Americanos/genética , Humanos , América Latina/epidemiologia , Masculino , Espanha/epidemiologia
3.
PLoS One ; 15(7): e0236402, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32701999

RESUMO

BACKGROUND: Endometrial cancer (EC) mortality is particularly high among non-Hispanic Blacks and is twice that of non-Hispanic Whites. However, comparisons of EC survival outcomes by race/ethnicity are often confounded by histology and grade. Here, we analyze EC survival disparities in multiracial Florida with a focus on EC types (1 and 2) and subtypes, defined according to histology and grade. METHODS: All 27,809 cases of EC diagnosed during 2005-2016 were obtained from the Florida Cancer Registry. Age-standardized, 5-year cause-specific survival by race/ethnicity and histological type were calculated. Fine and Gray competing risk regression was used to estimate sub-distribution hazard ratios (sHRs) for associations between risk of death due to EC and potential predictive factors such as histology/grade, age, stage at diagnosis, and insurance. RESULTS: Type 2 EC accounted for only 38.7% of all incident EC-cases but 74.6% of all EC-deaths. Blacks were disproportionately affected by type 2 EC (57.6%) compared to Whites, Hispanics, and Asians (35.6%, 37.7%, and 43.0%, respectively). Age-adjusted 5-year survival for types 1 and 2 were 85.3% and 51.6%, respectively; however, there was wide variation within type 2 subtypes, ranging from 60.2% for mixed cell EC to as low as 30.1% for carcinosarcoma. In the multivariable model, Blacks with type 2 EC had a 23% higher risk of death due to EC (sHR: 1.23, 95%CI: 1.12-1.36) compared to Whites. CONCLUSIONS: Population-based analyses should consider the histological heterogeneity of EC because the less common type 2 EC drives racial/ethnic survival disparities in EC. Black women have a higher proportion of more aggressive histological types and an overall higher risk of death due to EC than Whites. To the extent that some of these histological types may be considered different diseases and require specific treatment approaches, further research on etiology and prognosis for detailed type 2 EC subtypes is warranted.


Assuntos
Sobreviventes de Câncer , Neoplasias do Endométrio/epidemiologia , Endométrio/patologia , Neoplasias Uterinas/epidemiologia , Adolescente , Adulto , Afro-Americanos/genética , Idoso , Grupo com Ancestrais do Continente Asiático/genética , Intervalo Livre de Doença , Neoplasias do Endométrio/genética , Neoplasias do Endométrio/patologia , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Florida/epidemiologia , Disparidades nos Níveis de Saúde , Hispano-Americanos/genética , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Adulto Jovem
5.
BMC Med Genet ; 21(Suppl 2): 132, 2020 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-32580712

RESUMO

BACKGROUND: Hispanic/Latino (HL) populations bear a disproportionately high burden of type 2 diabetes (T2D). The ability to predict T2D genetic risk using polygenic risk scores (PRS) offers great promise for improved screening and prevention. However, there are a number of complications related to the accurate inference of genetic risk across HL populations with distinct ancestry profiles. We investigated how ancestry affects the inference of T2D genetic risk using PRS in diverse HL populations from Colombia and the United States (US). In Colombia, we compared T2D genetic risk for the Mestizo population of Antioquia to the Afro-Colombian population of Chocó, and in the US, we compared European-American versus Mexican-American populations. METHODS: Whole genome sequences and genotypes from the 1000 Genomes Project and the ChocoGen Research Project were used for genetic ancestry inference and for T2D polygenic risk score (PRS) calculation. Continental ancestry fractions for HL genomes were inferred via comparison with African, European, and Native American reference genomes, and PRS were calculated using T2D risk variants taken from multiple genome-wide association studies (GWAS) conducted on cohorts with diverse ancestries. A correction for ancestry bias in T2D risk inference based on the frequencies of ancestral versus derived alleles was developed and applied to PRS calculations in the HL populations studied here. RESULTS: T2D genetic risk in Colombian and US HL populations is positively correlated with African and Native American ancestry and negatively correlated with European ancestry. The Afro-Colombian population of Chocó has higher predicted T2D risk than Antioquia, and the Mexican-American population has higher predicted risk than the European-American population. The inferred relative risk of T2D is robust to differences in the ancestry of the GWAS cohorts used for variant discovery. For trans-ethnic GWAS, population-specific variants and variants with same direction effects across populations yield consistent results. Nevertheless, the control for bias in T2D risk prediction confirms that explicit consideration of genetic ancestry can yield more reliable cross-population genetic risk inferences. CONCLUSIONS: T2D associations that replicate across populations provide for more reliable risk inference, and modeling population-specific frequencies of ancestral and derived risk alleles can help control for biases in PRS estimation.


Assuntos
Diabetes Mellitus Tipo 2/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Hispano-Americanos/genética , Colômbia , Diabetes Mellitus Tipo 2/epidemiologia , Estudo de Associação Genômica Ampla , Humanos , Polimorfismo de Nucleotídeo Único/genética , Prevalência , Fatores de Risco , Estados Unidos
6.
Am J Hum Genet ; 106(5): 707-716, 2020 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-32386537

RESUMO

Because polygenic risk scores (PRSs) for coronary heart disease (CHD) are derived from mainly European ancestry (EA) cohorts, their validity in African ancestry (AA) and Hispanic ethnicity (HE) individuals is unclear. We investigated associations of "restricted" and genome-wide PRSs with CHD in three major racial and ethnic groups in the U.S. The eMERGE cohort (mean age 48 ± 14 years, 58% female) included 45,645 EA, 7,597 AA, and 2,493 HE individuals. We assessed two restricted PRSs (PRSTikkanen and PRSTada; 28 and 50 variants, respectively) and two genome-wide PRSs (PRSmetaGRS and PRSLDPred; 1.7 M and 6.6 M variants, respectively) derived from EA cohorts. Over a median follow-up of 11.1 years, 2,652 incident CHD events occurred. Hazard and odds ratios for the association of PRSs with CHD were similar in EA and HE cohorts but lower in AA cohorts. Genome-wide PRSs were more strongly associated with CHD than restricted PRSs were. PRSmetaGRS, the best performing PRS, was associated with CHD in all three cohorts; hazard ratios (95% CI) per 1 SD increase were 1.53 (1.46-1.60), 1.53 (1.23-1.90), and 1.27 (1.13-1.43) for incident CHD in EA, HE, and AA individuals, respectively. The hazard ratios were comparable in the EA and HE cohorts (pinteraction = 0.77) but were significantly attenuated in AA individuals (pinteraction= 2.9 × 10-3). These results highlight the potential clinical utility of PRSs for CHD as well as the need to assemble diverse cohorts to generate ancestry- and ethnicity PRSs.


Assuntos
Afro-Americanos/genética , Doença das Coronárias/genética , Grupo com Ancestrais do Continente Europeu/genética , Predisposição Genética para Doença , Hispano-Americanos/genética , Herança Multifatorial/genética , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances
7.
Cancer Res ; 80(9): 1893-1901, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32245796

RESUMO

Women of Latin American origin in the United States are more likely to be diagnosed with advanced breast cancer and have a higher risk of mortality than non-Hispanic White women. Studies in U.S. Latinas and Latin American women have reported a high incidence of HER2 positive (+) tumors; however, the factors contributing to this observation are unknown. Genome-wide genotype data for 1,312 patients from the Peruvian Genetics and Genomics of Breast Cancer Study (PEGEN-BC) were used to estimate genetic ancestry. We tested the association between HER2 status and genetic ancestry using logistic and multinomial logistic regression models. Findings were replicated in 616 samples from Mexico and Colombia. Average Indigenous American (IA) ancestry differed by subtype. In multivariate models, the odds of having an HER2+ tumor increased by a factor of 1.20 with every 10% increase in IA ancestry proportion (95% CI, 1.07-1.35; P = 0.001). The association between HER2 status and IA ancestry was independently replicated in samples from Mexico and Colombia. Results suggest that the high prevalence of HER2+ tumors in Latinas could be due in part to the presence of population-specific genetic variant(s) affecting HER2 expression in breast cancer. SIGNIFICANCE: The positive association between Indigenous American genetic ancestry and HER2+ breast cancer suggests that the high incidence of HER2+ subtypes in Latinas might be due to population and subtype-specific genetic risk variants.


Assuntos
Neoplasias da Mama/química , Neoplasias da Mama/etnologia , Hispano-Americanos/genética , Receptor ErbB-2/análise , Adulto , Grupo com Ancestrais do Continente Africano/etnologia , Grupo com Ancestrais do Continente Africano/estatística & dados numéricos , Idoso , Grupo com Ancestrais do Continente Asiático/etnologia , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Neoplasias da Mama/genética , Colômbia/etnologia , Grupo com Ancestrais do Continente Europeu/etnologia , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Feminino , Humanos , Índios Norte-Americanos , Índios Sul-Americanos , América Latina/etnologia , Modelos Lineares , Modelos Logísticos , México/etnologia , Pessoa de Meia-Idade , Peru/etnologia , Receptor ErbB-2/genética , Receptores Estrogênicos/sangue , Receptores de Progesterona/sangue , Estados Unidos , Adulto Jovem
8.
Am J Respir Crit Care Med ; 202(2): 259-274, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32255672

RESUMO

Rationale: Obesity-related asthma disproportionately affects minority children and is associated with nonatopic T-helper type 1 (Th1) cell polarized inflammation that correlates with pulmonary function deficits. Its underlying mechanisms are poorly understood.Objectives: To use functional genomics to identify cellular mechanisms associated with nonatopic inflammation in obese minority children with asthma.Methods: CD4+ (cluster of differentiation 4-positive) Th cells from 59 obese Hispanic and African American children with asthma and 61 normal-weight Hispanic and African American children with asthma underwent quantification of the transcriptome and DNA methylome and genotyping. Expression and methylation quantitative trait loci revealed the contribution of genetic variation to transcription and DNA methylation. Adjusting for Th-cell subtype proportions discriminated loci where transcription or methylation differences were driven by differences in subtype proportions from loci that were independently associated with obesity-related asthma.Measurements and Main Results: Obese children with asthma had more memory and fewer naive Th cells than normal-weight children with asthma. Differentially expressed and methylated genes and methylation quantitative trait loci in obese children with asthma, independent of Th-cell subtype proportions, were enriched in Rho-GTPase pathways. Inhibition of CDC42 (cell division cycle 42), one of the Rho-GTPases associated with Th-cell differentiation, was associated with downregulation of the IFNγ, but not the IL-4, gene. Differential expression of the RPS27L (40S ribosomal protein S27-like) gene, part of the p53/mammalian target of rapamycin pathway, was due to nonrandom distribution of expression quantitative trait loci variants between groups. Differentially expressed and/or methylated genes, including RPS27L, were associated with pulmonary function deficits in obese children with asthma.Conclusions: We found enrichment of Rho-GTPase pathways in obese asthmatic Th cells, identifying them as a novel therapeutic target for obesity-related asthma, a disease that is suboptimally responsive to current therapies.


Assuntos
Afro-Americanos/genética , Asma/genética , Proteínas Ativadoras de GTPase/genética , Genômica , Hispano-Americanos/genética , Obesidade Pediátrica/genética , Fenótipo , Adolescente , Asma/fisiopatologia , Criança , Pré-Escolar , Feminino , Proteínas Ativadoras de GTPase/metabolismo , Voluntários Saudáveis , Humanos , Lactente , Masculino
9.
Cancer Res ; 80(11): 2114-2124, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32269045

RESUMO

Hispanic/Latino patients have a higher incidence of gastric cancer and worse cancer-related outcomes compared with patients of other backgrounds. Whether there is a molecular basis for these disparities is unknown, as very few Hispanic/Latino patients have been included in previous studies. To determine the genomic landscape of gastric cancer in Hispanic/Latino patients, we performed whole-exome sequencing (WES) and RNA sequencing on tumor samples from 57 patients; germline analysis was conducted on 83 patients. The results were compared with data from Asian and White patients published by The Cancer Genome Atlas. Hispanic/Latino patients had a significantly larger proportion of genomically stable subtype tumors compared with Asian and White patients (65% vs. 21% vs. 20%, P < 0.001). Transcriptomic analysis identified molecular signatures that were prognostic. Of the 43 Hispanic/Latino patients with diffuse-type cancer, 7 (16%) had germline variants in CDH1. Variant carriers were significantly younger than noncarriers (41 vs. 50 years, P < 0.05). In silico algorithms predicted five variants to be deleterious. For two variants that were predicted to be benign, in vitro modeling demonstrated that these mutations conferred increased migratory capability, suggesting pathogenicity. Hispanic/Latino patients with gastric cancer possess unique genomic landscapes, including a high rate of CDH1 germline variants that may partially explain their aggressive clinical phenotypes. Individualized screening, genetic counseling, and treatment protocols based on patient ethnicity and race may be necessary. SIGNIFICANCE: Gastric cancer in Hispanic/Latino patients has unique genomic profiles that may contribute to the aggressive clinical phenotypes seen in these patients.


Assuntos
Adenocarcinoma/genética , Antígenos CD/genética , Caderinas/genética , Hispano-Americanos/genética , Neoplasias Gástricas/genética , Adenocarcinoma/sangue , Adenocarcinoma/etnologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Células CHO , Cricetulus , Metilação de DNA , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Regiões Promotoras Genéticas , Neoplasias Gástricas/sangue , Neoplasias Gástricas/etnologia , Sequenciamento Completo do Exoma , Adulto Jovem
10.
Gynecol Obstet Invest ; 85(3): 214-221, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32203957

RESUMO

OBJECTIVE: Germline BRCA mutation rates in the Latina population are yet to be well described. We aimed to quantitate the rates of referral for genetic testing in qualifying women and testing completion rates in a population of women presenting for gynecologic oncology care. Results were then stratified by ethnic/racial background. METHODS: Charts of new patients evaluated at a comprehensive cancer center in Southern California were reviewed. Patients qualifying for genetic testing in accordance with NCCN Guidelines version 1.2017 for breast and/or ovarian cancer genetic assessment were identified. The actual rates of prescriptions for genetic testing placed, testing completion rates, test results, as well as patients' family history were abstracted. Data were analyzed with chi-square tests. RESULTS: Five hundred and seventy-two of 2,053 patients met testing criteria, and 256/572 (45%) were prescribed testing in accordance with the guidelines. By ethnicity, testing was prescribed in 44% of Non-Hispanic White (NHW), 44% of Latina, 46% of African-American, and 60% of Asian (p = 0.6) patients. Testing was completed in 65% of NHW, 66% of Latina, 65% of African-American, and 67% of Asian patients (p = 0.97). Completion rates were low overall: 28% of those who met testing criteria were tested (p = 0.85). Pathogenic BRCA mutations were found in 29% of NHW and 21% of Latina, 45% of African-American, and 20% of Asian patients (p = 0.4). CONCLUSIONS: There was no difference by ethnicity in rates of testing prescription, completion, or presence of BRCA mutations. Overall, testing rates were suboptimal. BRCA mutations were found in large percentage of Latinas (21%). Further studies are underway to identify barriers to testing prescriptions and completion for Latina women.


Assuntos
Proteína BRCA1/análise , Proteína BRCA2/análise , Neoplasias da Mama/etnologia , Detecção Precoce de Câncer/estatística & dados numéricos , Hispano-Americanos/genética , Neoplasias Ovarianas/etnologia , Adulto , Afro-Americanos/genética , Grupo com Ancestrais do Continente Asiático/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , California/epidemiologia , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Testes Genéticos/estatística & dados numéricos , Mutação em Linhagem Germinativa , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/diagnóstico , Neoplasias Ovarianas/genética , Encaminhamento e Consulta/estatística & dados numéricos
11.
BMC Genomics ; 21(1): 228, 2020 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-32171239

RESUMO

BACKGROUND: Quantitative red blood cell (RBC) traits are highly polygenic clinically relevant traits, with approximately 500 reported GWAS loci. The majority of RBC trait GWAS have been performed in European- or East Asian-ancestry populations, despite evidence that rare or ancestry-specific variation contributes substantially to RBC trait heritability. Recently developed combined-phenotype methods which leverage genetic trait correlation to improve statistical power have not yet been applied to these traits. Here we leveraged correlation of seven quantitative RBC traits in performing a combined-phenotype analysis in a multi-ethnic study population. RESULTS: We used the adaptive sum of powered scores (aSPU) test to assess combined-phenotype associations between ~ 21 million SNPs and seven RBC traits in a multi-ethnic population (maximum n = 67,885 participants; 24% African American, 30% Hispanic/Latino, and 43% European American; 76% female). Thirty-nine loci in our multi-ethnic population contained at least one significant association signal (p < 5E-9), with lead SNPs at nine loci significantly associated with three or more RBC traits. A majority of the lead SNPs were common (MAF > 5%) across all ancestral populations. Nineteen additional independent association signals were identified at seven known loci (HFE, KIT, HBS1L/MYB, CITED2/FILNC1, ABO, HBA1/2, and PLIN4/5). For example, the HBA1/2 locus contained 14 conditionally independent association signals, 11 of which were previously unreported and are specific to African and Amerindian ancestries. One variant in this region was common in all ancestries, but exhibited a narrower LD block in African Americans than European Americans or Hispanics/Latinos. GTEx eQTL analysis of all independent lead SNPs yielded 31 significant associations in relevant tissues, over half of which were not at the gene immediately proximal to the lead SNP. CONCLUSION: This work identified seven loci containing multiple independent association signals for RBC traits using a combined-phenotype approach, which may improve discovery in genetically correlated traits. Highly complex genetic architecture at the HBA1/2 locus was only revealed by the inclusion of African Americans and Hispanics/Latinos, underscoring the continued importance of expanding large GWAS to include ancestrally diverse populations.


Assuntos
Afro-Americanos/genética , Eritrócitos/metabolismo , Grupo com Ancestrais do Continente Europeu/genética , Estudo de Associação Genômica Ampla/métodos , Hispano-Americanos/genética , Característica Quantitativa Herdável , Feminino , Genética Populacional , Humanos , Masculino , Herança Multifatorial , Fenótipo , Polimorfismo de Nucleotídeo Único , Análise de Sequência de DNA , Estados Unidos/etnologia
12.
Respir Res ; 21(1): 31, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31992292

RESUMO

BACKGROUND: Global gene expression levels are known to be highly dependent upon gross demographic features including age, yet identification of age-related genomic indicators has yet to be comprehensively undertaken in a disease and treatment-specific context. METHODS: We used gene expression data from CD4+ lymphocytes in the Asthma BioRepository for Integrative Genomic Exploration (Asthma BRIDGE), an open-access collection of subjects participating in genetic studies of asthma with available gene expression data. Replication population participants were Puerto Rico islanders recruited as part of the ongoing Genes environments & Admixture in Latino Americans (GALA II), who provided nasal brushings for transcript sequencing. The main outcome measure was chronic asthma control as derived by questionnaires. Genomic associations were performed using regression of chronic asthma control score on gene expression with age in years as a covariate, including a multiplicative interaction term for gene expression times age. RESULTS: The SMARCD1 gene (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1) interacted with age to influence chronic asthma control on inhaled corticosteroids, with a doubling of expression leading to an increase of 1.3 units of chronic asthma control per year (95% CI [0.86, 1.74], p = 6 × 10- 9), suggesting worsening asthma control with increasing age. This result replicated in GALA II (p = 3.8 × 10- 8). Cellular assays confirmed the role of SMARCD1 in glucocorticoid response in airway epithelial cells. CONCLUSION: Focusing on age-dependent factors may help identify novel indicators of asthma medication response. Age appears to modulate the effect of SMARCD1 on asthma control with inhaled corticosteroids.


Assuntos
Corticosteroides/administração & dosagem , Asma/tratamento farmacológico , Asma/genética , Proteínas Cromossômicas não Histona/biossíntese , Proteínas Cromossômicas não Histona/genética , Hispano-Americanos/genética , Administração por Inalação , Adolescente , Adulto , Fatores Etários , Asma/metabolismo , Criança , Estudos de Coortes , Feminino , Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
13.
Cancer Epidemiol ; 65: 101680, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31986316

RESUMO

BACKGROUND: Microsatellite instability (MSI) is a prognostic and predictive factor in colorectal cancer (CRC). Previous trials have acknowledged that MSI prevalence varies according to ethnicity. The aim of this study was to determine the prevalence of MSI among CRC patients from Costa Rica and to analyze its influence on overall survival (OS) and response to fluoropyrimidine-based chemotherapy. METHODS: We conducted a retrospective cohort study with all diagnosed CRC cases from 2010 to 2015 in a referral center in San José, Costa Rica. MSI was determined by immunohistochemical analysis. Clinical and epidemiological variables were retrieved from medical records. An univariate and multivariate COX regression analysis was performed to evaluate the association between MSI and mortality in the overall population and in those patients treated or not with fluoropyrimidine-based chemotherapy. RESULTS: 553 CRC patients were identified during the study timeframe, and 165 of them were diagnosed with MSI (29.84 %; 95 % Confidence Interval CI: 26.02-33.65%). MSI was associated with M1 disease, and right-sided tumor location. After adjusting for potential confounders, MSI was an independent prognostic factor for OS (Hazard Ratio (HR): 0.56; 95 %CI: 0.43-0.67; Log-rankp = 0.03). MSI status did not modify the response to fluoropyrimidine-based chemotherapy (HR: 0.56; 95 %CI: 0.18-1.80; Log-rank: p = 0.33). CONCLUSIONS: MSI was detected in a higher proportion of CRC patients than previously reported for other non-Hispanic populations. MSI was an independent prognostic factor for OS, but did not predict the efficacy of cytotoxic treatment with Fluoropyrimidine-based chemotherapy.


Assuntos
Adenocarcinoma/diagnóstico , Neoplasias Colorretais/diagnóstico , Instabilidade de Microssatélites , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma/genética , Adenocarcinoma/mortalidade , Adulto , Idoso , Estudos de Coortes , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/mortalidade , Costa Rica , Reparo de Erro de Pareamento de DNA , Feminino , Hispano-Americanos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos
14.
Am J Respir Crit Care Med ; 201(11): 1407-1415, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31916850

RESUMO

Rationale: Limited information is available on racial/ethnic differences in pulmonary arterial hypertension (PAH).Objectives: Determine effects of race/ethnicity and ancestry on mortality and disease outcomes in diverse patients with PAH.Methods: Patients with Group 1 PAH were included from two national registries with genome-wide data and two local cohorts, and further incorporated in a global meta-analysis. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated for transplant-free, all-cause mortality in Hispanic patients with non-Hispanic white (NHW) patients as the reference group. Odds ratios (ORs) for inpatient-specific mortality in patients with PAH were also calculated for race/ethnic groups from an additional National Inpatient Sample dataset not included in the meta-analysis.Measurements and Main Results: After covariate adjustment, self-reported Hispanic patients (n = 290) exhibited significantly reduced mortality versus NHW patients (n = 1,970) after global meta-analysis (HR, 0.60 [95% CI, 0.41-0.87]; P = 0.008). Although not significant, increasing Native American genetic ancestry appeared to account for part of the observed mortality benefit (HR, 0.48 [95% CI, 0.23-1.01]; P = 0.053) in the two national registries. Finally, in the National Inpatient Sample, an inpatient mortality benefit was also observed for Hispanic patients (n = 1,524) versus NHW patients (n = 8,829; OR, 0.65 [95% CI, 0.50-0.84]; P = 0.001). An inpatient mortality benefit was observed for Native American patients (n = 185; OR, 0.38 [95% CI, 0.15-0.93]; P = 0.034).Conclusions: This study demonstrates a reproducible survival benefit for Hispanic patients with Group 1 PAH in multiple clinical settings. Our results implicate contributions of genetic ancestry to differential survival in PAH.


Assuntos
Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Hispano-Americanos/genética , Hipertensão Arterial Pulmonar/genética , Hipertensão Arterial Pulmonar/mortalidade , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida , Estados Unidos/epidemiologia
15.
JAMA ; 322(22): 2191-2202, 2019 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-31821430

RESUMO

Importance: Hereditary transthyretin (TTR) amyloid cardiomyopathy (hATTR-CM) due to the TTR V122I variant is an autosomal-dominant disorder that causes heart failure in elderly individuals of African ancestry. The clinical associations of carrying the variant, its effect in other African ancestry populations including Hispanic/Latino individuals, and the rates of achieving a clinical diagnosis in carriers are unknown. Objective: To assess the association between the TTR V122I variant and heart failure and identify rates of hATTR-CM diagnosis among carriers with heart failure. Design, Setting, and Participants: Cross-sectional analysis of carriers and noncarriers of TTR V122I of African ancestry aged 50 years or older enrolled in the Penn Medicine Biobank between 2008 and 2017 using electronic health record data from 1996 to 2017. Case-control study in participants of African and Hispanic/Latino ancestry with and without heart failure in the Mount Sinai BioMe Biobank enrolled between 2007 and 2015 using electronic health record data from 2007 to 2018. Exposures: TTR V122I carrier status. Main Outcomes and Measures: The primary outcome was prevalent heart failure. The rate of diagnosis with hATTR-CM among TTR V122I carriers with heart failure was measured. Results: The cross-sectional cohort included 3724 individuals of African ancestry with a median age of 64 years (interquartile range, 57-71); 1755 (47%) were male, 2896 (78%) had a diagnosis of hypertension, and 753 (20%) had a history of myocardial infarction or coronary revascularization. There were 116 TTR V122I carriers (3.1%); 1121 participants (30%) had heart failure. The case-control study consisted of 2307 individuals of African ancestry and 3663 Hispanic/Latino individuals; the median age was 73 years (interquartile range, 68-80), 2271 (38%) were male, 4709 (79%) had a diagnosis of hypertension, and 1008 (17%) had a history of myocardial infarction or coronary revascularization. There were 1376 cases of heart failure. TTR V122I was associated with higher rates of heart failure (cross-sectional cohort: n = 51/116 TTR V122I carriers [44%], n = 1070/3608 noncarriers [30%], adjusted odds ratio, 1.7 [95% CI, 1.2-2.4], P = .006; case-control study: n = 36/1376 heart failure cases [2.6%], n = 82/4594 controls [1.8%], adjusted odds ratio, 1.8 [95% CI, 1.2-2.7], P = .008). Ten of 92 TTR V122I carriers with heart failure (11%) were diagnosed as having hATTR-CM; the median time from onset of symptoms to clinical diagnosis was 3 years. Conclusions and Relevance: Among individuals of African or Hispanic/Latino ancestry enrolled in 2 academic medical center-based biobanks, the TTR V122I genetic variant was significantly associated with heart failure.


Assuntos
Afro-Americanos/genética , Neuropatias Amiloides Familiares/genética , Insuficiência Cardíaca/genética , Hispano-Americanos/genética , Pré-Albumina/genética , Centros Médicos Acadêmicos , Idoso , Neuropatias Amiloides Familiares/complicações , Neuropatias Amiloides Familiares/etnologia , Bancos de Espécimes Biológicos , Estudos de Casos e Controles , Estudos Transversais , Feminino , Variação Genética , Insuficiência Cardíaca/etnologia , Humanos , Masculino , Pessoa de Meia-Idade
16.
PLoS Genet ; 15(12): e1008500, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31869403

RESUMO

Most genome-wide association and fine-mapping studies to date have been conducted in individuals of European descent, and genetic studies of populations of Hispanic/Latino and African ancestry are limited. In addition, these populations have more complex linkage disequilibrium structure. In order to better define the genetic architecture of these understudied populations, we leveraged >100,000 phased sequences available from deep-coverage whole genome sequencing through the multi-ethnic NHLBI Trans-Omics for Precision Medicine (TOPMed) program to impute genotypes into admixed African and Hispanic/Latino samples with genome-wide genotyping array data. We demonstrated that using TOPMed sequencing data as the imputation reference panel improves genotype imputation quality in these populations, which subsequently enhanced gene-mapping power for complex traits. For rare variants with minor allele frequency (MAF) < 0.5%, we observed a 2.3- to 6.1-fold increase in the number of well-imputed variants, with 11-34% improvement in average imputation quality, compared to the state-of-the-art 1000 Genomes Project Phase 3 and Haplotype Reference Consortium reference panels. Impressively, even for extremely rare variants with minor allele count <10 (including singletons) in the imputation target samples, average information content rescued was >86%. Subsequent association analyses of TOPMed reference panel-imputed genotype data with hematological traits (hemoglobin (HGB), hematocrit (HCT), and white blood cell count (WBC)) in ~21,600 African-ancestry and ~21,700 Hispanic/Latino individuals identified associations with two rare variants in the HBB gene (rs33930165 with higher WBC [p = 8.8x10-15] in African populations, rs11549407 with lower HGB [p = 1.5x10-12] and HCT [p = 8.8x10-10] in Hispanics/Latinos). By comparison, neither variant would have been genome-wide significant if either 1000 Genomes Project Phase 3 or Haplotype Reference Consortium reference panels had been used for imputation. Our findings highlight the utility of the TOPMed imputation reference panel for identification of novel rare variant associations not previously detected in similarly sized genome-wide studies of under-represented African and Hispanic/Latino populations.


Assuntos
Afro-Americanos/genética , Hispano-Americanos/genética , Medicina de Precisão/métodos , Sequenciamento Completo do Genoma/métodos , Globinas beta/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biologia Computacional/métodos , Bases de Dados Genéticas , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genética Populacional , Estudo de Associação Genômica Ampla , Técnicas de Genotipagem , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Estados Unidos
17.
PLoS Negl Trop Dis ; 13(11): e0007859, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31751351

RESUMO

Host genetic factors have been suggested to play an important role in the susceptibility to Chagas disease. Given the influence of interleukin 18 (IL-18) in the development of the disease, in the present study, we analyzed three IL18 genetic variants (rs2043055, rs1946518, rs360719) regarding the predisposition to Trypanosoma cruzi infection and the development of chronic Chagas cardiomyopathy (CCC), in different Latin America populations. Genetic data of 3,608 patients from Colombia, Bolivia, Argentina, and Brazil were meta-analyzed to validate previous findings with increased statistical power. Seropositive and seronegative individuals were compared for T. cruzi infection susceptibility. In the Colombian cohort, the allelic frequencies of the three variants showed a significant association, with adjustment for sex and age, and also after applying multiple testing adjustments. Among the Colombian and Argentinean cohorts, rs360719 showed a significant genetic effect in a fixed-effects meta-analysis after a Bonferroni correction (OR: 0.76, CI: 0.66-0.89, P = 0.001). For CCC, the rs2043055 showed an association with protection from cardiomyopathy in the Colombian cohort (OR: 0.79, CI: 0.64-0.99, P = 0.037), with adjustment for sex and age, and after applying multiple testing adjustments. The meta-analysis of the CCC vs. asymptomatic patients from the four cohorts showed no evidence of association. In conclusion, our results validated the association found previously in the Colombian cohort suggesting that IL18 rs360719 plays an important role in the susceptibility to T. cruzi infection and no evidence of association was found between the IL18 genetic variants and CCC in the Latin American population studied.


Assuntos
Doença de Chagas/genética , Interleucina-18/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Argentina , Bolívia , Brasil , Doença de Chagas/parasitologia , Estudos de Coortes , Colômbia , Feminino , Predisposição Genética para Doença , Hispano-Americanos/genética , Humanos , América Latina , Masculino , Pessoa de Meia-Idade , Trypanosoma cruzi/fisiologia , Adulto Jovem
18.
Genet Test Mol Biomarkers ; 23(12): 877-881, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31742438

RESUMO

Background: Melanocortin 4 receptor (MC4R) is a G-protein-coupled receptor involved in appetite regulation. Mutations in the MC4R gene are the most common cause of monogenic obesity. More than 200 sequence variants in the MC4R gene have been associated with obesity, although the vast majority of these data have been obtained from populations of European ancestry. The prevalence and mutation profile of MC4R is thus poorly characterized in other ancestries/ethnicities. Materials and Methods: We surveyed the allele frequencies of the MC4R variants of multiple racial/ethnic populations represented in the Genome Aggregation Database (gnomAD) and sequenced the MC4R gene in a diverse population of 60 individuals with extreme obesity. Results: Allele frequencies were similar for most classes of variants except for a higher rate of synonymous substitutions in the African gnomAD population. We also identified two apparently novel MC4R variants and two variants with much higher allele frequencies in African populations whose functional impacts are not yet known. Conclusion: These results highlight the need for characterizing MC4R variants in diverse populations with extreme obesity.


Assuntos
Obesidade/genética , Receptor Tipo 4 de Melanocortina/genética , Adulto , Afro-Americanos/genética , Idoso , Alelos , Índice de Massa Corporal , Bases de Dados Genéticas , Grupos Étnicos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Frequência do Gene/genética , Variação Genética/genética , Hispano-Americanos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Mutação/genética , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Receptor Tipo 4 de Melanocortina/metabolismo , Análise de Sequência
19.
Genes (Basel) ; 10(11)2019 11 07.
Artigo em Inglês | MEDLINE | ID: mdl-31703377

RESUMO

While approximately 200 autosomal genetic associations outside of the major histocompatibility complex (MHC) have been identified for multiple sclerosis (MS) risk in European populations, causal variants identified at the majority of these associated loci have been much more elusive. We propose that knowledge gained from replication efforts in Hispanic and African American populations can be utilized to more efficiently fine-map these risk loci. To this end, we have customized a genotyping array by adding ~20,000 bead types (~17,000 variants) to the base content of the Ilumina Infinium expanded multi-ethnic genotyping array and the Infinium ImmunoArray-24 v2 BeadChip. These custom bead types were chosen to allow for the detection of causal variation (1) in the presence of allelic and locus heterogeneity, by incorporating regulatory and coding variation within 1-Mb of previously identified risk variants and (2) in the absence of allelic and locus heterogeneity by incorporation of variants using linkage disequilibrium criteria, which are based on knowledge of replication status in Hispanic and African American study samples. This array has been designed to maximize fine-mapping potential for currently identified MS susceptibility loci, particularly in multi-ethnic populations. The strategies described here could be additionally informative for fine-mapping of other disease phenotypes.


Assuntos
Afro-Americanos/genética , Estudo de Associação Genômica Ampla/métodos , Hispano-Americanos/genética , Esclerose Múltipla/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla/normas , Humanos , Esclerose Múltipla/etnologia
20.
Medicine (Baltimore) ; 98(44): e17519, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689753

RESUMO

BACKGROUND: Accumulated evidence has indicated the associations between single-nucleotide polymorphisms (SNPs) in microRNAs (miRNAs) and the susceptibility to diabetes mellitus (DM), but the conclusions remain controversial. This study was to investigate the true contribution of miRNA SNPs to the risk of DM by using a meta-analysis of all the published studies. METHODS: Relevant studies were identified in the databases of PubMed and the Cochrane Library databases. The strength of associations between miRNA polymorphisms and DM risk was assessed by odds ratios (ORs) and 95% confidence intervals (95% CIs) under five genetic models using the STATA software. RESULTS: Six studies, containing 2773 cases and 2632 controls, were enrolled, 5 of which evaluated miR-146a (rs2910164), 4 for miR-27a (rs895819), and 3 for miR-124 (rs531564) and 2 for miR-375 (rs6715345), miR-128a (rs11888095), miR-194a (rs3820455). The meta-analysis indicated that the G allele or GG genotype of miR-146a rs2910164 was associated with a significantly increased risk for DM compared with C allele or GC/CC genotype in Latin American population; CC genotype of miR-27a rs895819 polymorphism was associated with a significantly decreased risk for DM in Asian population compared with the TT genotype; patients carrying with CC genotype of miR-124 rs531564 had a lower probability to develop DM regardless of ethnicity; no associations were identified between polymorphisms in miR-375, miR-128a, miR-194a and the susceptibility to DM. CONCLUSION: Our study suggests that miR-146a/miR-27a and miR-124 polymorphisms may be ethnicity-dependent or -independent susceptibility factors to DM, respectively.


Assuntos
Diabetes Mellitus/etnologia , Diabetes Mellitus/genética , MicroRNAs/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , Genótipo , Hispano-Americanos/genética , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único
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