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1.
Clin Cancer Res ; 2021 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-33504553

RESUMO

PURPOSE: The World Trade Center (WTC) attack of September 11, 2001 created an unprecedented environmental exposure to known and suspected carcinogens. High incidence of multiple myeloma and precursor conditions has been reported among first responders to the WTC disaster. To expand on our prior screening studies, and to characterize the genomic impact of the exposure to known and potential carcinogens in the WTC debris, we were motivated to perform whole-genome sequencing (WGS) of WTC first responders and recovery workers who developed a plasma cell disorder after the attack. EXPERIMENTAL DESIGN: We performed WGS of nine CD138-positive bone marrow mononuclear samples from patients who were diagnosed with plasma cell disorders after the WTC disaster. RESULTS: No significant differences were observed in comparing the post-WTC driver and mutational signature landscapes with 110 previously published WGSs from 56 patients with multiple myeloma and the CoMMpass WGS cohort (n = 752). Leveraging constant activity of the single-base substitution mutational signatures 1 and 5 over time, we estimated that tumor-initiating chromosomal gains were windowed to both pre- and post-WTC exposure. CONCLUSIONS: Although limitations in sample size preclude any definitive conclusions, our findings suggest that the observed increased incidence of plasma cell neoplasms in this population is due to complex and heterogeneous effects of the WTC exposure that may have initiated or contributed to progression of malignancy.

2.
Cancer Res ; 2020 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-33272927

RESUMO

Human leukocyte antigen (HLA) gene variation is associated with risk of cancers, particularly those with infectious etiology or hematopoietic origin given its role in immune presentation. Previous studies focused primarily on HLA allele/haplotype-specific associations. To answer whether associations are driven by HLA class I (essential for T-cell cytotoxicity) or class II (important for T-cell helper responses) genes, we analyzed GWAS from 24 case-control studies and consortia comprising 27 cancers (totaling >71,000 individuals). Associations for most cancers with infectious etiology or of hematopoietic origin were driven by multiple HLA regions, suggesting that both cytotoxic and helper T-cell responses are important. Notable exceptions were observed for nasopharyngeal carcinoma, an EBV-associated cancer, and CLL/SLL forms of non-Hodgkin lymphomas; these cancers were associated with HLA class I region only and HLA class II region only, implying the importance of cytotoxic T-cell responses for the former and CD4+ T-cell helper responses for the latter. Our findings suggest that increased understanding of the pattern of HLA associations for individual cancers could lead to better insights into specific mechanisms involved in cancer pathogenesis.

3.
medRxiv ; 2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33269365

RESUMO

Acquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. 1-4 These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. 2,5,6 A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. 7,8 Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 515 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we found that CH was associated with severe Covid-19 outcomes (OR=1.9, 95%=1.2-2.9, p=0.01). We further explored the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH was significantly associated with risk of Clostridium Difficile (HR=2.0, 95% CI: 1.2-3.3, p=6×10 -3 ) and Streptococcus/Enterococcus infections (HR=1.5, 95% CI=1.1-2.1, p=5×10 -3 ). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

4.
NPJ Breast Cancer ; 6: 41, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32964115

RESUMO

Terminal duct lobular units (TDLUs) are the predominant anatomical structures where breast cancers originate. Having lesser degrees of age-related TDLU involution, measured as higher TDLUs counts or more epithelial TDLU substructures (acini), is related to increased breast cancer risk among women with benign breast disease (BBD). We evaluated whether a recently developed polygenic risk score (PRS) based on 313-common variants for breast cancer prediction is related to TDLU involution in the background, normal breast tissue, as this could provide mechanistic clues on the genetic predisposition to breast cancer. Among 1398 women without breast cancer, higher values of the PRS were significantly associated with higher TDLU counts (P = 0.004), but not with acini counts (P = 0.808), in histologically normal tissue samples from donors and diagnostic BBD biopsies. Mediation analysis indicated that TDLU counts may explain a modest proportion (≤10%) of the association of the 313-variant PRS with breast cancer risk. These findings suggest that TDLU involution might be an intermediate step in the association between common genetic variation and breast cancer risk.

5.
Blood ; 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32871587

RESUMO

Plasmacytoid dendritic cells (pDC) are the principal natural type I interferon producing dendritic cells. Neoplastic expansion of pDCs and pDC precursors leads to blastic plasmacytoid dendritic cell neoplasm (BPDCN) and clonal expansion of mature pDCs has been described in chronic myelomonocytic leukemia (CMML). The role of pDC expansion in acute myeloid leukemia (AML) is poorly studied. Here we characterize AML patients with pDC expansion (pDC-AML), which we observe in approximately 5% of AML. pDC-AML often possess cross-lineage antigen expression and have adverse risk stratification with poor outcome. RUNX1 mutations are the most common somatic alterations in pDC-AML (>70%) and are much more common than in AML without pDC expansion and BPDCN. We demonstrate that pDCs are clonally related to, and originate from, leukemic blasts in pDC-AML. We further demonstrate that leukemic blasts from RUNX1-mutated AML upregulate a pDC transcriptional program, poising the cells towards pDC differentiation and expansion. Finally, tagraxofusp, a targeted therapy directed to CD123, reduces leukemic burden and eliminates pDCs in a patient-derived xenograft model. In conclusion, pDC-AML is characterized by a high frequency of RUNX1 mutations and increased expression of a pDC transcriptional program. CD123 targeting represents a potential treatment approach for pDC-AML.

6.
Cancer Epidemiol Biomarkers Prev ; 29(11): 2289-2299, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32855266

RESUMO

BACKGROUND: Obesity is an established risk factor for multiple cancer types. Lower microbial richness has been linked to obesity, but human studies are inconsistent, and associations of early-life body mass index (BMI) with the fecal microbiome and metabolome are unknown. METHODS: We characterized the fecal microbiome (n = 563) and metabolome (n = 340) in the Northern Finland Birth Cohort 1966 using 16S rRNA gene sequencing and untargeted metabolomics. We estimated associations of adult BMI and BMI history with microbial features and metabolites using linear regression and Spearman correlations (rs ) and computed correlations between bacterial sequence variants and metabolites overall and by BMI category. RESULTS: Microbial richness, including the number of sequence variants (rs = -0.21, P < 0.0001), decreased with increasing adult BMI but was not independently associated with BMI history. Adult BMI was associated with 56 metabolites but no bacterial genera. Significant correlations were observed between microbes in 5 bacterial phyla, including 18 bacterial genera, and metabolites in 49 of the 62 metabolic pathways evaluated. The genera with the strongest correlations with relative metabolite levels (positively and negatively) were Blautia, Oscillospira, and Ruminococcus in the Firmicutes phylum, but associations varied by adult BMI category. CONCLUSIONS: BMI is strongly related to fecal metabolite levels, and numerous associations between fecal microbial features and metabolite levels underscore the dynamic role of the gut microbiota in metabolism. IMPACT: Characterizing the associations between the fecal microbiome, the fecal metabolome, and BMI, both recent and early-life exposures, provides critical background information for future research on cancer prevention and etiology.

7.
J Clin Oncol ; 38(30): 3538-3546, 2020 10 20.
Artigo em Inglês | MEDLINE | ID: mdl-32795225

RESUMO

PURPOSE: Coronavirus-2019 (COVID-19) mortality is higher in patients with cancer than in the general population, yet the cancer-associated risk factors for COVID-19 adverse outcomes are not fully characterized. PATIENTS AND METHODS: We reviewed clinical characteristics and outcomes from patients with cancer and concurrent COVID-19 at Memorial Sloan Kettering Cancer Center until March 31, 2020 (n = 309), and observed clinical end points until April 13, 2020. We hypothesized that cytotoxic chemotherapy administered within 35 days of a COVID-19 diagnosis is associated with an increased hazard ratio (HR) of severe or critical COVID-19. In secondary analyses, we estimated associations between specific clinical and laboratory variables and the incidence of a severe or critical COVID-19 event. RESULTS: Cytotoxic chemotherapy administration was not significantly associated with a severe or critical COVID-19 event (HR, 1.10; 95% CI, 0.73 to 1.60). Hematologic malignancy was associated with increased COVID-19 severity (HR, 1.90; 95% CI, 1.30 to 2.80). Patients with lung cancer also demonstrated higher rates of severe or critical COVID-19 events (HR, 2.0; 95% CI, 1.20 to 3.30). Lymphopenia at COVID-19 diagnosis was associated with higher rates of severe or critical illness (HR, 2.10; 95% CI, 1.50 to 3.10). Patients with baseline neutropenia 14-90 days before COVID-19 diagnosis had worse outcomes (HR, 4.20; 95% CI, 1.70 to 11.00). Findings from these analyses remained consistent in a multivariable model and in multiple sensitivity analyses. The rate of adverse events was lower in a time-matched population of patients with cancer without COVID-19. CONCLUSION: Recent cytotoxic chemotherapy treatment was not associated with adverse COVID-19 outcomes. Patients with active hematologic or lung malignancies, peri-COVID-19 lymphopenia, or baseline neutropenia had worse COVID-19 outcomes. Interactions among antineoplastic therapy, cancer type, and COVID-19 are complex and warrant further investigation.


Assuntos
Antineoplásicos/efeitos adversos , Betacoronavirus , Infecções por Coronavirus/complicações , Neoplasias/tratamento farmacológico , Pneumonia Viral/complicações , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/complicações , Neutropenia/complicações , Pandemias
10.
Stat Med ; 39(18): 2423-2436, 2020 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-32363646

RESUMO

We consider the scenario where there is an exposure, multiple biologically defined sets of biomarkers, and an outcome. We propose a new two-step procedure that tests if any of the sets of biomarkers mediate the exposure/outcome relationship, while maintaining a prespecified familywise error rate. The first step of the proposed procedure is a screening step that removes all groups that are unlikely to be strongly associated with both the exposure and the outcome. The second step adapts recent advances in postselection inference to test if there are true mediators in each of the remaining candidate sets. We use simulation to show that this simple two-step procedure has higher statistical power to detect true mediating sets when compared with existing procedures. We then use our two-step procedure to identify a set of Lysine-related metabolites that potentially mediate the known relationship between increased body mass index and the increased risk of estrogen-receptor positive breast cancer in postmenopausal women.

11.
Gut ; 69(11): 2008-2015, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32060129

RESUMO

OBJECTIVE: To assess whether prediagnostic metabolites were associated with incident pancreatic ductal adenocarcinoma (PDAC) in a prospective cohort study. DESIGN: We conducted an untargeted analysis of 554 known metabolites measured in prediagnostic serum (up to 24 years) to determine their association with incident PDAC in a nested case-control study of male smokers (372 matched case-control sets) and an independent nested case-control study that included women and non-smokers (107 matched sets). Metabolites were measured using Orbitrap Elite or Q-Exactive high-resolution/accurate mass spectrometers. Controls were matched to cases by age, sex, race, date of blood draw, and follow-up time. We used conditional logistic regression adjusted for age to calculate ORs and 95% CIs for a 1 SD increase in log-metabolite level separately in each cohort and combined the two ORs using a fixed-effects meta-analysis. RESULTS: Thirty-one metabolites were significantly associated with PDAC at a false discovery rate <0.05 with 12 metabolites below the Bonferroni-corrected threshold (p<9.04×10-5). Similar associations were observed in both cohorts. The dipeptides glycylvaline, aspartylphenylalanine, pyroglutamylglycine, phenylalanylphenylalanine, phenylalanylleucine and tryptophylglutamate and amino acids aspartate and glutamate were positively while the dipeptides tyrosylglutamine and α-glutamyltyrosine, fibrinogen cleavage peptide DSGEGDFXAEGGGVR and glutathione-related amino acid cysteine-glutathione disulfide were inversely associated with PDAC after Bonferroni correction. Five top metabolites demonstrated significant time-varying associations (p<0.023) with the strongest associations observed 10-15 years after participants' blood collection and attenuated thereafter. CONCLUSION: Our results suggest that prediagnostic metabolites related to subclinical disease, γ-glutamyl cycle metabolism and adiposity/insulin resistance are associated with PDAC.

12.
J Natl Cancer Inst ; 112(3): 286-294, 2020 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-31168595

RESUMO

BACKGROUND: Coffee has been consistently associated with lower risk of liver cancer and chronic liver disease, suggesting that coffee affects mechanisms underlying disease development. METHODS: We measured serum metabolites using untargeted metabolomics in 1:1 matched nested case-control studies of liver cancer (n = 221 cases) and fatal liver disease (n = 242 cases) in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention cohort (n = 29 133). Associations between baseline coffee drinking and metabolites were identified using linear regression; conditional logistic regression models were used to identify associations with subsequent outcomes. RESULTS: Overall, 21 metabolites were associated with coffee drinking and also each subsequent endpoint; nine metabolites and trigonelline, a known coffee biomarker, were identified. Tyrosine and two bile acids, glycochenodeoxycholic acid (GCDCA) and glycocholic acid (GCA), were inversely associated with coffee but positively associated with both outcomes; odds ratios (ORs) comparing the 90th to 10th percentile (modeled on a continuous basis) ranged from 3.93 (95% confidence interval [CI] = 2.00 to 7.74) for tyrosine to 4.95 (95% CI = 2.64 to 9.29) for GCA and from 4.00 (95% CI = 2.42 to 6.62) for GCA to 6.77 (95% CI = 3.62 to 12.65) for GCDCA for liver cancer and fatal liver disease, respectively. The remaining six metabolites and trigonelline were positively associated with coffee drinking but inversely associated with both outcomes; odds ratio ranged from 0.16 to 0.37. Associations persisted following diet adjustment and for outcomes occurring greater than 10 years after blood collection. CONCLUSIONS: A broad range of compounds were associated with coffee drinking, incident liver cancer, and liver disease death over 27 years of follow-up. These associations provide novel insight into chronic liver disease and liver cancer etiology and support a possible hepatoprotective effect of coffee.


Assuntos
Café , Hepatopatias/sangue , Hepatopatias/mortalidade , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/mortalidade , Idoso , Alcaloides/sangue , Estudos de Casos e Controles , Finlândia/epidemiologia , Ácido Glicoquenodesoxicólico/sangue , Ácido Glicocólico/sangue , Humanos , Incidência , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
13.
Am J Epidemiol ; 188(6): 991-1012, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31155658

RESUMO

The Consortium of Metabolomics Studies (COMETS) was established in 2014 to facilitate large-scale collaborative research on the human metabolome and its relationship with disease etiology, diagnosis, and prognosis. COMETS comprises 47 cohorts from Asia, Europe, North America, and South America that together include more than 136,000 participants with blood metabolomics data on samples collected from 1985 to 2017. Metabolomics data were provided by 17 different platforms, with the most frequently used labs being Metabolon, Inc. (14 cohorts), the Broad Institute (15 cohorts), and Nightingale Health (11 cohorts). Participants have been followed for a median of 23 years for health outcomes including death, cancer, cardiovascular disease, diabetes, and others; many of the studies are ongoing. Available exposure-related data include common clinical measurements and behavioral factors, as well as genome-wide genotype data. Two feasibility studies were conducted to evaluate the comparability of metabolomics platforms used by COMETS cohorts. The first study showed that the overlap between any 2 different laboratories ranged from 6 to 121 metabolites at 5 leading laboratories. The second study showed that the median Spearman correlation comparing 111 overlapping metabolites captured by Metabolon and the Broad Institute was 0.79 (interquartile range, 0.56-0.89).


Assuntos
Epidemiologia/organização & administração , Saúde Global , Metabolômica/organização & administração , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Índice de Massa Corporal , Criança , Métodos Epidemiológicos , Feminino , Comportamentos Relacionados com a Saúde , Testes Hematológicos , Humanos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores Socioeconômicos , Adulto Jovem
14.
Genet Epidemiol ; 43(5): 492-505, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30920058

RESUMO

Meta-analysis of multiple genome-wide association studies (GWAS) is effective for detecting single- or multimarker associations with complex traits. We develop a flexible procedure (subset testing and analysis of multiple phenotypes [STAMP]) based on mixture models to perform a region-based meta-analysis of different phenotypes using data from different GWAS and identify subsets of associated phenotypes. Our model framework helps distinguish true associations from between-study heterogeneity. As a measure of association, we compute for each phenotype the posterior probability that the genetic region under investigation is truly associated. Extensive simulations show that STAMP is more powerful than standard approaches for meta-analyses when the proportion of truly associated outcomes is between 25% and 50%. For other settings, the power of STAMP is similar to that of existing methods. We illustrate our method on two examples, the association of a region on chromosome 9p21 with the risk of 14 cancers, and the associations of expression of quantitative trait loci from two genetic regions with their cis-single-nucleotide polymorphisms measured in 17 tissue types using data from The Cancer Genome Atlas.


Assuntos
Estudo de Associação Genômica Ampla/métodos , Estudos de Casos e Controles , Simulação por Computador , Humanos , Modelos Genéticos , Neoplasias/patologia , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética
15.
Metabolomics ; 15(4): 48, 2019 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-30879189

RESUMO

INTRODUCTION: Sleep is increasingly being viewed as an issue of public health concern, yet few epidemiologic studies have explored associations between sleep habits and metabolomic profile. OBJECTIVES: To assess the association between sleep and blood metabolites. METHODS: We examined the association between sleep and 891 fasting plasma metabolites in a subgroup of 106 participants from the Dietary Approaches to Stop Hypertension (DASH)-Sodium feeding trial (1997-1999). We produced two sleep variables to analyze, sleep midpoint (median time between bedtime and waketime) and sleep duration, as well as bedtime and wake time. Metabolites were measured using liquid and gas chromatography, coupled with mass spectrometry. We assessed associations between sleep variables and log transformed metabolites using linear mixed-effects models. We combined the resulting p-values using Fisher's method to calculate associations between sleep and 38 metabolic pathways. RESULTS: Sixteen pathways were associated (p < 0.05) with midpoint. Only the γ-glutamyl amino acid metabolism pathway reached Bonferroni-corrected threshold (0.0013). Eighty-three metabolites were associated with midpoint (FDR < 0.20). Similar associations were found for wake time. Neither bed time nor duration were strongly associated. The top metabolites (pathways given in brackets) associated with sleep were erythrulose (advanced glycation end-product) (positive association) and several γ-glutamyl pathway metabolites, including CMPF (fatty acid, dicarboxylate), isovalerate (valine, leucine and isoleucine and fatty acid metabolism) and HWESASXX (polypeptide) (inverse association). CONCLUSION: Within our study, several metabolites that have previously been linked to inflammation and oxidative stress (processes involved in diseases such as cardiovascular disease and cancer) were found to be associated with sleep.


Assuntos
Redes e Vias Metabólicas/fisiologia , Sono/fisiologia , Adulto , Idoso , Doenças Cardiovasculares , Comportamento Alimentar/fisiologia , Feminino , Cromatografia Gasosa-Espectrometria de Massas/métodos , Humanos , Hipertensão/sangue , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade
16.
Biometrics ; 75(3): 745-756, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30859548

RESUMO

We propose a model for high dimensional mediation analysis that includes latent variables. We describe our model in the context of an epidemiologic study for incident breast cancer with one exposure and a large number of biomarkers (i.e., potential mediators). We assume that the exposure directly influences a group of latent, or unmeasured, factors which are associated with both the outcome and a subset of the biomarkers. The biomarkers associated with the latent factors linking the exposure to the outcome are considered "mediators." We derive the likelihood for this model and develop an expectation-maximization algorithm to maximize an L1-penalized version of this likelihood to limit the number of factors and associated biomarkers. We show that the resulting estimates are consistent and that the estimates of the nonzero parameters have an asymptotically normal distribution. In simulations, procedures based on this new model can have significantly higher power for detecting the mediating biomarkers compared with the simpler approaches. We apply our method to a study that evaluates the relationship between body mass index, 481 metabolic measurements, and estrogen-receptor positive breast cancer.


Assuntos
Algoritmos , Neoplasias da Mama/epidemiologia , Funções Verossimilhança , Modelos Teóricos , Animais , Biomarcadores/análise , Simulação por Computador , Feminino , Humanos
17.
Int J Cancer ; 145(12): 3231-3243, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-30779128

RESUMO

Impaired metabolism may play an important role in the pathogenesis of lethal prostate cancer, yet there is a paucity of evidence regarding the association. We conducted a large prospective serum metabolomic analysis of lethal prostate cancer in 523 cases and 523 matched controls nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Median time from baseline fasting serum collection to prostate cancer death was 18 years (maximum 30 years). We identified 860 known biochemicals through an ultrahigh-performance LC-MS/MS platform. Conditional logistic regression models estimated odds ratios (OR) and 95% confidence intervals of risk associated with 1-standard deviation (s.d.) increases in log-metabolite signals. We identified 34 metabolites associated with lethal prostate cancer with a false discovery rate (FDR) < 0.15. Notably, higher serum thioproline, and thioproline combined with two other cysteine-related amino acids and redox metabolites, cystine and cysteine, were associated with reduced risk (1-s.d. OR = 0.75 and 0.71, respectively; p ≤ 8.2 × 10-5 ). By contrast, the dipeptide leucylglycine (OR = 1.36, p = 8.2 × 10-5 ), and three gamma-glutamyl amino acids (OR = 1.28-1.30, p ≤ 4.6 × 10-4 ) were associated with increased risk of lethal prostate cancer. Cases with metastatic disease at diagnosis (n = 179) showed elevated risk for several lipids, including especially the ketone body 3-hydroxybutyrate (BHBA), acyl carnitines, and dicarboxylic fatty acids (1.37 ≤ OR ≤ 1.49, FDR < 0.15). These findings provide a prospective metabolomic profile of lethal prostate cancer characterized by altered biochemicals in the redox, dipeptide, pyrimidine, and gamma-glutamyl amino acid pathways, whereas ketone bodies and fatty acids were associated specifically with metastatic disease.


Assuntos
Neoplasias da Próstata/sangue , Neoplasias da Próstata/metabolismo , Aminoácidos/sangue , Aminoácidos/metabolismo , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Cromatografia Líquida/métodos , Método Duplo-Cego , Ácidos Graxos/sangue , Ácidos Graxos/metabolismo , Humanos , Modelos Logísticos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Fatores de Risco , Espectrometria de Massas em Tandem/métodos , alfa-Tocoferol/sangue , alfa-Tocoferol/metabolismo , beta Caroteno/sangue , beta Caroteno/metabolismo
18.
EBioMedicine ; 39: 358-368, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30579868

RESUMO

BACKGROUND: Endemic Burkitt lymphoma (eBL) is an aggressive childhood B-cell lymphoma linked to Plasmodium falciparum (Pf) malaria in sub-Saharan Africa. We investigated antibody reactivity to several human receptor-binding domains of the Pf erythrocyte membrane protein 1 (PfEMP1) that play a key role in malaria pathogenesis and are targets of acquired immunity to malaria. METHODS: Serum/plasma IgG antibody reactivity was measured to 22 Pf antigens, including 18 to PfEMP1 CIDR domains between cases and controls from two populations (149 eBL cases and 150 controls from Ghana and 194 eBL cases and 600 controls from Uganda). Adjusted odds ratios (aORs) for case-control associations were estimated by logistic regression. FINDINGS: There was stronger reactivity to the severe malaria associated CIDRα1 domains than other CIDR domains both in cases and controls. eBL cases reacted to fewer antigens than controls (Ghana: p = 0·001; Uganda: p = 0·03), with statistically significant lower ORs associated with reactivity to 13+ antigens in Ghana (aOR 0·39, 95% CI 0·24-0·63; pheterogeneity = 0·00011) and Uganda (aOR 0·60, 95% CI 0.41-0·88; pheterogeneity = 0·008). eBL was inversely associated with reactivity, coded as quartiles, to group A variant CIDRδ1 (ptrend = 0·035) in Ghana and group B CD36-binding variants CIDRα2·2 (ptrend = 0·006) and CIDRα2·4 (ptrend = 0·033) in Uganda, and positively associated with reactivity to SERA5 in Ghana (ptrend = 0·017) and Uganda (ptrend = 0·007) and group A CIDRα1·5 variant in Uganda only (ptrend = 0·034). INTERPRETATION: eBL cases reacted to fewer antigens than controls using samples from two populations, Ghana and Uganda. Attenuated humoral immunity to Pf EMP1 may contribute to susceptibility to low-grade malaria and eBL risk. FUNDING: Intramural Research Program, National Cancer Institute and National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services.


Assuntos
Linfoma de Burkitt/parasitologia , Imunoglobulina G/metabolismo , Malária Falciparum/imunologia , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/imunologia , Adolescente , Anticorpos Antiprotozoários/metabolismo , Sítios de Ligação , Linfoma de Burkitt/imunologia , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Gana , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Masculino , Razão de Chances , Plasmodium falciparum/imunologia , Proteínas de Protozoários/química , Uganda
19.
J Gerontol A Biol Sci Med Sci ; 74(6): 853-859, 2019 05 16.
Artigo em Inglês | MEDLINE | ID: mdl-29878065

RESUMO

Impaired metabolism may play a role in the development and lethality of prostate cancer, yet a comprehensive analysis of the interrelationships appears lacking. We measured 625 metabolites using ultrahigh performance liquid chromatography/mass spectrometry (LC-MS) and gas chromatography/mass spectrometry (GC-MS) of prediagnostic serum from 197 prostate cancer cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (ages at diagnosis, 55-86 years). Cox proportional hazards models estimated associations between circulating metabolites and prostate cancer mortality for 1 SD differences (log-metabolite scale), adjusted for age, year of diagnosis, and disease stage. Associations between metabolite chemical classes and survival were examined through pathway analysis, and Cox models assessed the relationship with a sterol/steroid metabolite principal component analysis factor score. Elevated serum N-oleoyl taurine was significantly associated with prostate cancer-specific mortality (hazard ratios [HR] = 1.72 per 1 SD, p < .00008, Bonferroni-corrected threshold = 0.05/625; HR = 3.6 for highest vs lowest tertile, p < .001). Pathway analyses revealed a statistically significant association between lipids and prostate cancer death (p < .006, Bonferroni-corrected threshold = 0.05/8), and sterol/steroid metabolites showed the strongest chemical sub-class association (p = .0014, Bonferroni-corrected threshold = 0.05/45). In the principal component analysis, a 1-SD increment in the sterol/steroid metabolite score increased the risk of prostate cancer death by 46%. Prediagnostic serum N-oleoyl taurine and sterol/steroid metabolites were associated with prostate cancer survival.


Assuntos
Metabolômica , Ácidos Oleicos/sangue , Neoplasias da Próstata/mortalidade , Esteroides/sangue , Esteróis/sangue , Taurina/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/sangue , Cromatografia Gasosa , Cromatografia Líquida de Alta Pressão , Finlândia/epidemiologia , Humanos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Análise de Componente Principal , Modelos de Riscos Proporcionais , Neoplasias da Próstata/sangue , Sistema de Registros , Taurina/sangue
20.
Biol Psychiatry ; 83(9): 780-789, 2018 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-29628042

RESUMO

BACKGROUND: The genetic risk factors of schizophrenia (SCZ), a severe psychiatric disorder, are not yet fully understood. Multiple lines of evidence suggest that mitochondrial dysfunction may play a role in SCZ, but comprehensive association studies are lacking. We hypothesized that variants in nuclear-encoded mitochondrial genes influence susceptibility to SCZ. METHODS: We conducted gene-based and gene-set analyses using summary association results from the Psychiatric Genomics Consortium Schizophrenia Phase 2 (PGC-SCZ2) genome-wide association study comprising 35,476 cases and 46,839 control subjects. We applied the MAGMA method to three sets of nuclear-encoded mitochondrial genes: oxidative phosphorylation genes, other nuclear-encoded mitochondrial genes, and genes involved in nucleus-mitochondria crosstalk. Furthermore, we conducted a replication study using the iPSYCH SCZ sample of 2290 cases and 21,621 control subjects. RESULTS: In the PGC-SCZ2 sample, 1186 mitochondrial genes were analyzed, among which 159 had p values < .05 and 19 remained significant after multiple testing correction. A meta-analysis of 818 genes combining the PGC-SCZ2 and iPSYCH samples resulted in 104 nominally significant and nine significant genes, suggesting a polygenic model for the nuclear-encoded mitochondrial genes. Gene-set analysis, however, did not show significant results. In an in silico protein-protein interaction network analysis, 14 mitochondrial genes interacted directly with 158 SCZ risk genes identified in PGC-SCZ2 (permutation p = .02), and aldosterone signaling in epithelial cells and mitochondrial dysfunction pathways appeared to be overrepresented in this network of mitochondrial and SCZ risk genes. CONCLUSIONS: This study provides evidence that specific aspects of mitochondrial function may play a role in SCZ, but we did not observe its broad involvement even using a large sample.


Assuntos
Genes Mitocondriais , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Esquizofrenia/genética , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
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