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1.
Anticancer Res ; 39(8): 4043-4053, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31366486

RESUMO

BACKGROUND/AIM: Triple-negative breast cancer (TNBC) is the most aggressive subtype, predominant in African American women. In this study, the antioxidant/anticancer activity of muscadine grape extracts and the role of their phenolic and flavonoid contents in exerting these properties were investigated in TNBC cells. MATERIALS AND METHODS: Berry extracts from muscadine genotypes were investigated for total phenolic content (TPC), total flavonoid content (TFC), antioxidant capacity, and anticancer effects using breast cancer cell lines, representing Caucasians and African Americans. RESULTS: The antioxidant activity was associated with high TPC content. Extracts showed cytotoxicity up to 78.6% in Caucasians and 90.7% in African American cells, with an association with high antioxidant capacity. There was a strong correlation between TPC and anticancer/antioxidant activities. CONCLUSION: The anticancer and antioxidant effects of muscadine grapes are attributed to the TPC of extracts, which showed a stronger positive correlation with growth inhibition of African American breast cancer cells compared to Caucasians.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Extratos Vegetais/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Vitis/química , Afro-Americanos/genética , Antineoplásicos Fitogênicos/química , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Cromatografia Líquida de Alta Pressão , Feminino , Flavonoides/química , Flavonoides/farmacologia , Frutas/química , Humanos , Células MCF-7 , Fenóis/química , Fenóis/farmacologia , Extratos Vegetais/química , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologia
3.
J Urol ; 202(2): 247-255, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31107158

RESUMO

PURPOSE: Most prostate cancer in African American men lacks the ETS (E26 transforming specific) family fusion event (ETS-). We aimed to establish clinically relevant biomarkers in African American men by studying ETS dependent gene expression patterns to identified race specific genes predictive of outcomes. MATERIALS AND METHODS: Two multicenter cohorts of a total of 1,427 men were used for the discovery and validation (635 and 792 men, respectively) of race specific predictive biomarkers. We used false discovery rate adjusted q values to identify race and ETS dependent genes which were differentially expressed in African American men who experienced biochemical recurrence within 5 years. Principal component modeling along with survival analysis was done to assess the accuracy of the gene panel in predicting recurrence. RESULTS: We identified 3,047 genes which were differentially expressed based on ETS status. Of these genes 362 were differentially expressed in a race specific manner (false discovery rate 0.025 or less). A total of 81 genes were race specific and over expressed in African American men who experienced biochemical recurrence. The final gene panel included APOD, BCL6, EMP1, MYADM, SRGN and TIMP3. These genes were associated with 5-year biochemical recurrence (HR 1.97, 95% CI 1.27-3.06, p = 0.002) and they improved the predictive accuracy of clinicopathological variables only in African American men (60-month time dependent AUC 0.72). CONCLUSIONS: In an effort to elucidate biological features associated with prostate cancer aggressiveness in African American men we identified ETS dependent biomarkers predicting early onset biochemical recurrence only in African American men. Thus, these ETS dependent biomarkers representing ideal candidates for biomarkers of aggressive disease in this patient population.


Assuntos
Afro-Americanos/genética , Neoplasias da Próstata/genética , Idoso , Biomarcadores Tumorais/genética , Estudos de Coortes , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Prognóstico , Proteínas Proto-Oncogênicas c-ets/genética
4.
BMC Genomics ; 20(1): 395, 2019 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-31113383

RESUMO

BACKGROUND: Many genome-wide association studies have detected genomic regions associated with traits, yet understanding the functional causes of association often remains elusive. Utilizing systems approaches and focusing on intermediate molecular phenotypes might facilitate biologic understanding. RESULTS: The availability of exome sequencing of two populations of African-Americans and European-Americans from the Atherosclerosis Risk in Communities study allowed us to investigate the effects of annotated loss-of-function (LoF) mutations on 122 serum metabolites. To assess the findings, we built metabolomic causal networks for each population separately and utilized structural equation modeling. We then validated our findings with a set of independent samples. By use of methods based on concepts of Mendelian randomization of genetic variants, we showed that some of the affected metabolites are risk predictors in the causal pathway of disease. For example, LoF mutations in the gene KIAA1755 were identified to elevate the levels of eicosapentaenoate (p-value = 5E-14), an essential fatty acid clinically identified to increase essential hypertension. We showed that this gene is in the pathway to triglycerides, where both triglycerides and essential hypertension are risk factors of metabolomic disorder and heart attack. We also identified that the gene CLDN17, harboring loss-of-function mutations, had pleiotropic actions on metabolites from amino acid and lipid pathways. CONCLUSION: Using systems biology approaches for the analysis of metabolomics and genetic data, we integrated several biological processes, which lead to findings that may functionally connect genetic variants with complex diseases.


Assuntos
Pleiotropia Genética , Genoma Humano , Metaboloma/genética , Metabolômica , Mutação , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Afro-Americanos/genética , Algoritmos , Grupo com Ancestrais do Continente Europeu/genética , Humanos
5.
Front Biosci (Schol Ed) ; 11: 75-88, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844737

RESUMO

Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen and progesterone receptors and absence of amplification of human epidermal growth factor receptor (HER2). This disease has no approved treatment with a poor prognosis particularly in African-American (AA) as compared to European-American (EA) patients. Gene ontology analysis showed specific gene pathways that are differentially regulated and gene signatures that are differentially expressed in AA as compared to EA. Such differences might underlie the basis for the aggressive nature and poor prognosis of TNBC in AA patients. In-depth studies of these pathways and differential genetic signature might give significant clues to improve our understanding of tumor biology associated with AA TNBC to advance the prognosis and survival rates. Along with gene ontology analysis, we suggest that post-translational modifications (PTM) could also play a crucial role in the dismal survival rate of AA TNBC patients. Further investigations are necessary to explore this terrain of PTMs to identify the racially disparate burden in TNBC.


Assuntos
Disparidades nos Níveis de Saúde , Receptores de Progesterona/metabolismo , Neoplasias de Mama Triplo Negativas/etnologia , Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Fenótipo , Prognóstico , Receptor ErbB-2/metabolismo , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/mortalidade , Microambiente Tumoral
6.
Front Biosci (Schol Ed) ; 11: 136-160, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844741

RESUMO

African-American (AA) women are more likely to die from breast cancer (BC), at any age, compared to European-American women. Although breakthroughs in pre-clinical studies have resulted in potentially actionable targets in AA BC, drugs that were rationally designed for these targets have performed poorly in clinical trials. Challenges with interpatient and intratumoral heterogeneity, lack of drug sensitivity and specificity, suboptimal biomarker cut-offs, lack of drug response predictive biomarkers, drug side effects, high costs of drug development, and under-representation of AAs in clinical trials complicate the development of targeted therapies for AA BC patients. Accumulating evidence suggests that racial disparities exist in non-genetic risk factors that can alter genetic and epigenetic programs to promote breast tumorigenesis. Herein, we present a "roadmap" that addresses non-genetic risk factors that are suspected to contribute to the racial disparity in BC mortality. Increased targeting of these non-genetic risk factors may proffer a safer and more economical route to alleviating the racially disparate burden in BC.


Assuntos
Neoplasias da Mama/etnologia , Neoplasias da Mama/genética , Afro-Americanos/genética , Consumo de Bebidas Alcoólicas , Biomarcadores , Tamanho Corporal , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Características Culturais , Diabetes Mellitus/etnologia , Diabetes Mellitus/genética , Escolaridade , Disruptores Endócrinos , Grupo com Ancestrais do Continente Europeu/genética , Medo , Feminino , Disparidades nos Níveis de Saúde , Terapia de Reposição Hormonal , Humanos , Hipertensão/complicações , Hipertensão/etnologia , Hipertensão/genética , Seguro Saúde , Estilo de Vida , Menarca , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/etnologia , Obesidade/genética , Religião , Características de Residência , Fatores de Risco , Sono , Estresse Psicológico , Transportes
7.
Front Biosci (Schol Ed) ; 11: 178-192, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30844743

RESUMO

Growing evidence now links circadian disruption (CD) to increased risk of developing multiple types of cancer, including breast cancer (BC). In the US, African-American (AA) BC patients have a higher mortality rate than European-Americans (EAs) with BC, and a prime suspect in this racially disparate burden has been the greater incidence of an aggressive and highly heterogeneous BC subtype called triple-negative BC (TNBC), among AAs. AAs are also more prone to CD as larger proportions of AAs engage in night shift work than EAs, and the chronotype of AAs makes it harder for them to adapt to CD than EAs. Although clock gene dysregulation has been shown to perturb transactivation of key cell cycle and apoptosis regulators, little is known about how clock gene mis-expression affects TNBC outcomes. This review examines the prognostic value of clock genes in TNBC, and evaluates patterns of clock gene dysregulation in the individual TNBC molecular subtypes. Better understanding of how CD contributes to TNBC biology may illuminate new paths to improving disease outcomes and reducing BC-related racial disparities.


Assuntos
Relógios Circadianos , Neoplasias de Mama Triplo Negativas/genética , Afro-Americanos/genética , Ciclo Celular , Grupos Étnicos , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Perfilação da Expressão Gênica , Disparidades nos Níveis de Saúde , Humanos , Incidência , Prognóstico , Fatores de Risco , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/epidemiologia , Tolerância ao Trabalho Programado
8.
Int J Mol Sci ; 20(5)2019 Mar 02.
Artigo em Inglês | MEDLINE | ID: mdl-30832344

RESUMO

Hypertension is the leading cause of cardiovascular disease in the United States, affecting up to one-third of adults. When compared to other ethnic or racial groups in the United States, African Americans and other people of African descent show a higher incidence of hypertension and its related comorbidities; however, the genetics of hypertension in these populations has not been studied adequately. Several genes have been identified to play a role in the genetics of hypertension. They include genes regulating the renin-aldosterone-angiotensin system (RAAS), such as Sodium Channel Epithelial 1 Beta Subunit (SCNN1B), Armadillo Repeat Containing 5 (ARMC5), G Protein-Coupled Receptor Kinase 4 (GRK4), and Calcium Voltage-Gated Channel Subunit Alpha1 D (CACNA1D). In this review, we focus on recent genetic findings available in the public domain for potential differences between African Americans and other populations. We also cover some recent and relevant discoveries in the field of low-renin hypertension from our laboratory at the National Institutes of Health. Understanding the different genetics of hypertension among various groups is essential for effective precision-guided medical therapy of high blood pressure.


Assuntos
Afro-Americanos/genética , Hipertensão/genética , Canais de Cálcio Tipo L/genética , Canais Epiteliais de Sódio/genética , Quinase 4 de Receptor Acoplado a Proteína G/genética , Humanos , Hipertensão/etnologia , Proteínas Supressoras de Tumor/genética
9.
Mil Med ; 184(Suppl 1): 652-657, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30901475

RESUMO

African American (AA) women are often diagnosed with more aggressive breast cancers and have worse survival outcomes than their Caucasian American (CA) counterparts. However, a comprehensive understanding of this disparity remains unclear. In this study, we attempted to identify the race-specific non-invasive protein biomarkers that may particularly benefit interventions aimed at reducing the risk of recurrence and metastasis in breast cancers (BrCa). Our technical strategy has been to discover candidate protein biomarkers in patient sera using a high throughput antibody microarray platform. A total of 240 subjects were selected, composed of controls and all immunohistochemistry-based subtypes of breast cancer cases, subdivided by pre- and post-menopausal status and by race. A global Wilcoxon analysis comparing no-cancer controls and cancer patients identified Pyk2, SAPK/JNK, and phosphatase and tensin homolog as present in higher concentrations in cancer patient serum. A paired t-test revealed that c-kit and Rb are significantly over-represented in AA cancer serum when compared to CA cancer serum. Interestingly, VEGFR2, a protein linked to BrCa metastasis and poor prognosis, was significantly over-represented in AA cancer serum compared to AA controls; however, this was not found in CA cancer serum compared to CA controls, suggesting a possible explanation for the higher incidence of aggressive BrCa in AA versus CA patients. Through examining race-specific differences in the protein landscape of BrCa patient serum, the identified proteins could lay the groundwork for the development of an all-inclusive "liquid mammogram test."


Assuntos
Biomarcadores/sangue , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/fisiopatologia , Grupos de Populações Continentais/estatística & dados numéricos , Disparidades nos Níveis de Saúde , Adulto , Afro-Americanos/genética , Idoso , Biomarcadores/análise , Neoplasias da Mama/classificação , Feminino , Predisposição Genética para Doença/genética , Humanos , Incidência , Pessoa de Meia-Idade
10.
N Engl J Med ; 380(9): 833-841, 2019 02 28.
Artigo em Inglês | MEDLINE | ID: mdl-30763140

RESUMO

BACKGROUND: Central centrifugal cicatricial alopecia (CCCA) is the most common form of scarring alopecia among women of African ancestry. The disease is occasionally observed to affect women in families in a manner that suggests an autosomal dominant trait and usually manifests clinically after intense hair grooming. We sought to determine whether there exists a genetic basis of CCCA and, if so, what it is. METHODS: We used exome sequencing in a group of women with alopecia (discovery set), compared the results with those in a public repository, and applied other filtering criteria to identify candidate genes. We then performed direct sequencing to identify disease-associated DNA variations and RNA sequencing, protein modeling, immunofluorescence staining, immunoblotting, and an enzymatic assay to evaluate the consequences of potential etiologic mutations. We used a replication set that consisted of women with CCCA to confirm the data obtained with the discovery set. RESULTS: In the discovery set, which included 16 patients, we identified one splice site and three heterozygous missense mutations in PADI3 in 5 patients (31%). (The approximate prevalence of the disease is up to 5.6%.) PADI3 encodes peptidyl arginine deiminase, type III (PADI3), an enzyme that post-translationally modifies other proteins that are essential to hair-shaft formation. All three CCCA-associated missense mutations in PADI3 affect highly conserved residues and are predicted to be pathogenic; protein modeling suggests that they result in protein misfolding. These mutations were found to result in reduced PADI3 expression, abnormal intracellular localization of the protein, and decreased enzymatic activity - findings that support their pathogenicity. Immunofluorescence staining showed decreased expression of PADI3 in biopsy samples of scalp skin obtained from patients with CCCA. We then directly sequenced PADI3 in an additional 42 patients (replication set) and observed genetic variants in 9 of them. A post hoc analysis of the combined data sets showed that the prevalence of PADI3 mutation was higher among patients with CCCA than in a control cohort of women of African ancestry (P = 0.002 by the chi-square test; P = 0.006 by Fisher's exact test; and after adjustment for relatedness of persons, P = 0.03 and P = 0.04, respectively). CONCLUSIONS: Mutations in PADI3, which encodes a protein that is essential to proper hair-shaft formation, were associated with CCCA. (Funded by the Ram Family Foundation and others.).


Assuntos
Afro-Americanos/genética , Alopecia/genética , Predisposição Genética para Doença , Cabelo/crescimento & desenvolvimento , Mutação , Desiminases de Arginina em Proteínas/genética , Adolescente , Adulto , Idade de Início , Alopecia/etnologia , Distribuição de Qui-Quadrado , Cicatriz/genética , Exoma , Feminino , Heterozigoto , Humanos , Pessoa de Meia-Idade , Mutagênese , Linhagem , Desiminases de Arginina em Proteínas/metabolismo , Couro Cabeludo/patologia , Análise de Sequência de DNA
11.
Biol Res Nurs ; 21(3): 279-285, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30781968

RESUMO

With the rapid advancement of omics-based research, particularly big data such as genome- and epigenome-wide association studies that include extensive environmental and clinical variables, data analytics have become increasingly complex. Researchers face significant challenges regarding how to analyze multifactorial data and make use of the findings for clinical translation. The purpose of this article is to provide a scientific exemplar for use of genetic burden scores as a data analysis method for studies with both genotype and DNA methylation data in which the goal is to evaluate associations with chronic conditions such as metabolic syndrome (MetS). This study included 739 African American men and women from the Genetic Epidemiology Network of Arteriopathy Study who met diagnostic criteria for MetS and had available genetic and epigenetic data. Genetic burden scores for evaluated genes were not significant after multiple testing corrections, but DNA methylation at 2 CpG sites (dihydroorotate dehydrogenase cg22381196 pFDR = .014; CTNNA3 cg00132141 pFDR = .043) was significantly associated with MetS after controlling for multiple comparisons. Interactions between the marginally significant CpG sites and burden scores, however, were not significant. More work is required in this area to identify intermediate biological pathways influenced by environmental, genetic, and epigenetic variation that may explain the high prevalence of MetS among African Americans. This study does serve, however, as an example of the use of the genetic burden score as an alternative data analysis approach for complex studies involving the analysis of genetic and epigenetic data simultaneously.


Assuntos
Afro-Americanos/genética , Ilhas de CpG/genética , Metilação de DNA/genética , Epigênese Genética , Síndrome Metabólica/genética , Síndrome Metabólica/fisiopatologia , Idoso , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade
12.
J Neurooncol ; 142(2): 375-384, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30706176

RESUMO

PURPOSE: To study whether the clinical outcome and molecular biology of gliomas in African-American patients fundamentally differ from those occurring in Whites. METHODS: The clinical information and molecular profiles (including gene expression array, non-silent somatic mutation, DNA methylation and protein expression) were downloaded from The Cancer genome atlas (TCGA). Electronic medical records were abstracted from Northwestern Medicine Enterprise Data Warehouse (NMEDW) for analysis as well. Grade II-IV Glioma patients were all included. RESULTS: 931 Whites and 64 African-American glioma patients from TCGA were analyzed. African-American with Karnofsky performance score (KPS) ≥ 80 have significantly lower risk of death than similar white Grade IV Glioblastoma (GBM) patients [HR (95% CI) = 0.47 (0.23, 0.98), P = 0.0444, C-index = 0.68]. Therefore, we further compared gene expression profiles between African-American GBM patients and Whites with KPS ≥ 80. Extrapolation of genes significantly associated with increased African-American patient survival revealed a set of 13 genes with a possible role in this association, including elevated expression of genes previously identified as increased in African-American breast and colon cancer patients (e.g. CRYBB2). Furthermore, gene set enrichment analysis revealed retinoic acid (RA) metabolism as a pathway significantly upregulated in African-American GBM patients who survive longer than Whites (Z-score = - 2.10, Adjusted P-value = 0.0449). CONCLUSIONS: African Americans have prolonged survival with glioma which is influenced only by initial KPS score. Genes previously associated with both racial disparities in cancer and pathways associated with RA metabolism may play an important role in glioma etiology. In the future exploration of these genes and pathways may inform novel therapies for this incurable disease.


Assuntos
Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/genética , Glioma/epidemiologia , Glioma/genética , Tretinoína/metabolismo , Adulto , Afro-Americanos/genética , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/terapia , Metilação de DNA , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Regulação Neoplásica da Expressão Gênica , Glioma/metabolismo , Glioma/terapia , Humanos , Avaliação de Estado de Karnofsky , Masculino , Pessoa de Meia-Idade , Mutação , Gradação de Tumores , Análise de Sobrevida , Resultado do Tratamento
13.
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
14.
Genet Epidemiol ; 43(4): 414-426, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30793815

RESUMO

The etiology of many complex diseases involves both environmental exposures and inherited genetic predisposition as well as interactions between them. Gene-environment-wide interaction studies (GEWIS) provide a means to identify the interactions between genetic variation and environmental exposures that underlie disease risk. However, current GEWIS methods lack the capability to adjust for the potentially complex correlations in studies with varying degrees of relationships (both known and unknown) among individuals in admixed populations. We developed novel generalized estimating equation (GEE) based methods-GEE-adaptive and GEE-joint-to account for phenotypic correlations due to kinship while accounting for covariates, including, measures of genome-wide ancestry. In simulation studies of admixed individuals, both methods controlled family-wise error rates, an advantage over the case-only approach. They demonstrated higher power than traditional case-control methods across a wide range of underlying alternative hypotheses, especially where both marginal and interaction effects were present. We applied the proposed method to conduct a GEWIS of a known sarcoidosis risk factor (insecticide exposure) and risk of sarcoidosis in African Americans and identified two novel loci with suggestive evidence of G × E interaction.


Assuntos
Família , Interação Gene-Ambiente , Estudo de Associação Genômica Ampla/métodos , Sarcoidose/genética , Afro-Americanos/genética , Alelos , Estudos de Casos e Controles , Simulação por Computador , Frequência do Gene , Predisposição Genética para Doença , Humanos , Modelos Genéticos , Linhagem , Polimorfismo de Nucleotídeo Único , Sarcoidose/etnologia
15.
PLoS Genet ; 15(2): e1007916, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30768591

RESUMO

In the U.S., more than 80% of African-American smokers use mentholated cigarettes, compared to less than 30% of Caucasian smokers. The reasons for these differences are not well understood. To determine if genetic variation contributes to mentholated cigarette smoking, we performed an exome-wide association analysis in a multiethnic population-based sample from Dallas, TX (N = 561). Findings were replicated in an independent cohort of African Americans from Washington, DC (N = 741). We identified a haplotype of MRGPRX4 (composed of rs7102322[G], encoding N245S, and rs61733596[G], T43T), that was associated with a 5-to-8 fold increase in the odds of menthol cigarette smoking. The variants are present solely in persons of African ancestry. Functional studies indicated that the variant G protein-coupled receptor encoded by MRGPRX4 displays reduced agonism in both arrestin-based and G protein-based assays, and alteration of agonism by menthol. These data indicate that genetic variation in MRGPRX4 contributes to inter-individual and inter-ethnic differences in the preference for mentholated cigarettes, and that the existence of genetic factors predisposing vulnerable populations to mentholated cigarette smoking can inform tobacco control and public health policies.


Assuntos
Afro-Americanos/genética , Fumar Cigarros/genética , Haplótipos/genética , Mentol , Receptores Acoplados a Proteínas-G/genética , Adulto , Estudos de Coortes , Feminino , Variação Genética/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fumar/efeitos adversos , Tabaco/efeitos adversos
16.
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
17.
Artigo em Inglês | MEDLINE | ID: mdl-30610941

RESUMO

T. gondii (TOXO) infects over one billion people worldwide, yet the literature lacks a Genome Wide Association Study (GWAS) focused on genetic variants controlling the persistence of TOXO infection. To identify putative T. gondii susceptibility genes, we performed a GWAS using IgG seropositivity as the outcome variable in a discovery sample (n = 790) from an Ashkenazi dataset, and a second sample of predominately African Americans (The Grady Trauma Project, n = 285). We also performed a meta-analyses of the 2 cohorts. None of the SNPs in these analyses was statistically significant after Bonferroni correction for multiple comparisons. In the Ashkenazi population, the gene region of CHIA (chitinase) showed the most nominally significant association with TOXO. Prior studies have shown that the production of chitinase by macrophages in the brain responding to TOXO infection is crucial for controlling the burden of T. gondii cysts. We found a surprising number of genes involved in neurodevelopment and psychiatric disorders among our top hits even though our outcome variable was TOXO infection. In the meta-analysis combining the Ashkenazi and Grady Trauma Project samples, there was enrichment for genes implicated in schizophrenia spectrum disorders (p < .05). Upon limiting our sample to those without mental illness, two schizophrenia related genes (CNTNAP2, GABAR2) still had significant TOXO-associated variants at the p < .05 level, but did not pass the genome wide significance threshold after correction for multiple comparisons. Using Ingenuity Systems molecular network analysis, we identified molecular nodes suggesting that while different genetic variants associated with TOXO in the two population samples, the molecular pathways for TOXO susceptibility nevertheless converged on common pathways. Molecular nodes in these common pathways included NOTCH1, CD44, and RXRA. Prior studies show that CD44 participates in TOXO-induced immunopathology and that RXRA is instrumental in regulating T-helper immune responses. These data provide new insights into the pathophysiology of this common neurotropic parasite.


Assuntos
Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Esquizofrenia/genética , Toxoplasmose/genética , Adulto , Afro-Americanos/genética , Anticorpos Antiprotozoários/sangue , Estudos de Coortes , Feminino , Estudo de Associação Genômica Ampla , Humanos , Imunoglobulina G/sangue , Judeus/genética , Masculino , Pessoa de Meia-Idade , Toxoplasmose/sangue
18.
Transl Psychiatry ; 9(1): 22, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30655502

RESUMO

In 2015, ~800,000 people died by suicide worldwide. For every death by suicide there are as many as 25 suicide attempts, which can result in serious injury even when not fatal. Despite this large impact on morbidity and mortality, the genetic influences on suicide attempt are poorly understood. We performed a genome-wide association study (GWAS) of severity of suicide attempts to investigate genetic influences. A discovery GWAS was performed in Yale-Penn sample cohorts of European Americans (EAs, n = 2,439) and African Americans (AAs, n = 3,881). We found one genome-wide significant (GWS) signal in EAs near the gene LDHB (rs1677091, p = 1.07 × 10-8) and three GWS associations in AAs: ARNTL2 on chromosome 12 (rs683813, p = 2.07 × 10-8), FAH on chromosome 15 (rs72740082, p = 2.36 × 10-8), and on chromosome 18 (rs11876255, p = 4.61 × 10-8) in the Yale-Penn discovery sample. We conducted a limited replication analysis in the completely independent Army-STARRS cohorts. rs1677091 replicated in Latinos (LAT, p = 6.52 × 10-3). A variant in LD with FAH rs72740082 (rs72740088; r2 = 0.68) was replicated in AAs (STARRS AA p = 5.23 × 10-3; AA meta, 1.51 × 10-9). When combined for a trans-population meta-analysis, the final sample size included n = 20,153 individuals. Finally, we found significant genetic overlap with major depressive disorder (MDD) using polygenic risk scores from a large GWAS (r2 = 0.007, p = 6.42 × 10-5). To our knowledge, this is the first GWAS of suicide attempt severity. We identified GWS associations near genes involved in anaerobic energy production (LDHB), circadian clock regulation (ARNTL2), and catabolism of tyrosine (FAH). These findings provide evidence of genetic risk factors for suicide attempt severity, providing new information regarding the molecular mechanisms involved.


Assuntos
Transtorno Depressivo Maior/genética , Transtorno Depressivo Maior/psicologia , Polimorfismo de Nucleotídeo Único , Tentativa de Suicídio/psicologia , Adulto , Afro-Americanos/genética , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Modelos Lineares , Masculino , Herança Multifatorial , Índice de Gravidade de Doença , Estados Unidos
19.
Pancreas ; 48(2): 242-249, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30629027

RESUMO

OBJECTIVES: African Americans (AAs) have disproportionately higher incidence and lower survival rates from pancreatic cancer compared with whites. Historically, this disparity has been attributed to modifiable risk factors. Recent studies suggest that nonmodifiable aspects may also play an important role. We review these new contributions as potential targets for closing the disparity. METHODS: A PubMed search was conducted to review studies of nonmodifiable elements contributing to pancreatic cancer disparities in AAs. RESULTS: Several nonmodifiable risks are associated with the racial disparity in pancreatic cancer. SSTR5 P335L, Kaiso, and KDM4/JMJD2A demonstrate differential racial expression, increasing their potential as therapeutic targets. Many social determinants of health and their associations with diabetes, obesity, and the microbiome are partially modifiable risk factors that significantly contribute to outcomes in minorities. Barriers to progress include the low minority inclusion in research studies. CONCLUSIONS: Genomics, epigenetics, the microbiome, and social determinants of health are components that contribute to the pancreatic cancer disparity in AAs. These factors can be researched, targeted, and modified to improve mortality rates. Closing the disparity in pancreatic cancer will require an integrated approach of personalized medicine, increased minority recruitment to studies, and advanced health care/education access.


Assuntos
Neoplasias Pancreáticas/terapia , Afro-Americanos/genética , Afro-Americanos/estatística & dados numéricos , Grupo com Ancestrais do Continente Europeu/genética , Grupo com Ancestrais do Continente Europeu/estatística & dados numéricos , Disparidades nos Níveis de Saúde , Disparidades em Assistência à Saúde , História Antiga , Humanos , Neoplasias Pancreáticas/etnologia , Neoplasias Pancreáticas/genética , Fatores de Risco , Estados Unidos
20.
Fertil Steril ; 111(1): 122-131, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30611402

RESUMO

OBJECTIVE: To examine the relationships between age at menarche, antral follicle count (AFC), and body mass index (BMI) in a multi-ethnic population of women. DESIGN: Community-based, cross-sectional study. SETTING: Academic setting. PATIENT(S): A total of 245 African American women and 273 European American women, aged 25-45 years, with regular menstrual cycles and no reproductive disorders. The ethnicity of these women was self-reported and genetically validated. INTERVENTION(S): The AFCs were measured by transvaginal ultrasound during the early follicular phase. Anthropometric measurements were taken, and age at menarche was gathered by questionnaire. MAIN OUTCOME MEASURE(S): Determination of the associations between age of menarche and adult AFC and BMI. RESULT(S): Earlier age of menarche was associated with both higher BMIs and higher AFCs in adulthood, with control for female age. The antral follicle difference between early (<12 years) vs. late (≥15 years) initiation of menarche in both white and black women was +3.81 and +3.34 follicles, respectively, which is equivalent to an approximately 20% difference in AFC. CONCLUSION(S): This study provides the first evidence that timing of menarche may influence AFC. Because of limited studies on African American women, this work provides additional needed data and may enhance our ability to prospectively screen and better treat various diseases associated with the female reproductive lifespan.


Assuntos
Afro-Americanos/genética , Índice de Massa Corporal , Grupo com Ancestrais do Continente Europeu/genética , Menarca/fisiologia , Folículo Ovariano/fisiologia , Adolescente , Adulto , Fatores Etários , Criança , Estudos de Coortes , Estudos Transversais , Feminino , Líquido Folicular/fisiologia , Humanos , Pessoa de Meia-Idade
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