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1.
Metabolites ; 11(3)2021 Feb 24.
Artigo em Inglês | MEDLINE | ID: mdl-33668370

RESUMO

The identification of patients at high-risk for colorectal cancer (CRC) recurrence remains an unmet clinical need. The aim of this study was to investigate associations of metabolites with risk of recurrence in stage II/III CRC patients. A targeted metabolomics assay (128 metabolites measured) was performed on pre-surgery collected EDTA plasma samples from n = 440 newly diagnosed stage II/III CRC patients. Patients have been recruited from four prospective cohort studies as part of an international consortium: Metabolomic profiles throughout the continuum of CRC (MetaboCCC). Cox proportional hazard models were computed to investigate associations of metabolites with recurrence, adjusted for age, sex, tumor stage, tumor site, body mass index, and cohort; false discovery rate (FDR) was used to account for multiple testing. Sixty-nine patients (15%) had a recurrence after a median follow-up time of 20 months. We identified 13 metabolites that were nominally associated with a reduced risk of recurrence. None of the associations were statistically significant after controlling for multiple testing. Pathway topology analyses did not reveal statistically significant associations between recurrence and alterations in metabolic pathways (e.g., sphingolipid metabolism p = 0.04; pFDR = 1.00). To conclude, we did not observe statistically significant associations between metabolites and CRC recurrence using a well-established metabolomics assay. The observed results require follow-up in larger studies.

2.
Metabolites ; 11(2)2021 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-33669644

RESUMO

Sporadic colorectal cancer is characterized by a multistep progression from normal epithelium to precancerous low-risk and high-risk adenomas to invasive cancer. Yet, the underlying molecular mechanisms of colorectal carcinogenesis are not completely understood. Within the "Metabolomic profiles throughout the continuum of colorectal cancer" (MetaboCCC) consortium we analyzed data generated by untargeted, mass spectrometry-based metabolomics using plasma from 88 colorectal cancer patients, 200 patients with high-risk adenomas and 200 patients with low-risk adenomas recruited within the "Colorectal Cancer Study of Austria" (CORSA). Univariate logistic regression models comparing colorectal cancer to adenomas resulted in 442 statistically significant molecular features. Metabolites discriminating colorectal cancer patients from those with adenomas in our dataset included acylcarnitines, caffeine, amino acids, glycerophospholipids, fatty acids, bilirubin, bile acids and bacterial metabolites of tryptophan. The data obtained discovers metabolite profiles reflecting metabolic differences between colorectal cancer and colorectal adenomas and delineates a potentially underlying biological interpretation.

3.
Hum Mol Genet ; 2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33527138

RESUMO

Sexual dimorphism in cancer incidence and outcome is widespread. Understanding the underlying mechanisms is fundamental to improve cancer prevention and clinical management. Sex disparities are particularly striking in kidney cancer: across diverse populations, men consistently show unexplained two-fold increased incidence and worse prognosis. We have characterized genome-wide expression and regulatory networks of 609 renal tumors and 256 non-tumor renal tissues. Normal kidney displayed sex-specific transcriptional signatures, including higher expression of X-linked tumor suppressor genes in women. Sex-dependent genotype-phenotype associations unraveled women-specific immune regulation. Sex differences were markedly expanded in tumors, with male-biased expression of key genes implicated in metabolism, non-malignant diseases with male predominance, and carcinogenesis, including markers of tumor infiltrating leukocytes. Analysis of sex-dependent RCC progression and survival uncovered prognostic markers involved in immune response and oxygen homeostasis. In summary, human kidney tissues display remarkable sexual dimorphism at the molecular level. Sex-specific transcriptional signatures further shape renal cancer, with relevance for clinical management.

4.
Mol Nutr Food Res ; 65(7): e2001141, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33592132

RESUMO

SCOPE: Processed meat intake has been associated with adverse health outcomes. However, little is known about the type of processed meat more particularly responsible for these effects. This study aims to identify novel biomarkers for processed meat intake. METHODS AND RESULTS: In a controlled randomized cross-over dietary intervention study, 12 healthy volunteers consume different processed and non-processed meats for 3 consecutive days each. Metabolomics analyses are applied on post-intervention fasting blood and urine samples to identify discriminating molecular features of processed meat intake. Nine and five pepper alkaloid metabolites, including piperine, are identified as major discriminants of salami intake in urine and plasma, respectively. The associations with processed meat intake are tested for replication in a cross-sectional study (n = 418) embedded within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Three of the serum metabolites including piperine are associated with habitual intake of sausages and to a lesser extent of total processed meat. CONCLUSION: Pepper alkaloids are major discriminants of intake for sausages that contain high levels of pepper used as ingredient. Further work is needed to assess if pepper alkaloids in combination with other metabolites may serve as biomarkers of processed meat intake.

5.
Environ Sci Technol ; 54(22): 14502-14513, 2020 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-33124810

RESUMO

Mechanisms underlying adverse birth and later in life health effects from exposure to air pollution during the prenatal period have not been not fully elucidated, especially in the context of mixtures. We assessed the effects of prenatal exposure to mixtures of air pollutants of particulate matter (PM), PM2.5, PM10, nitrogen oxides, NO2, NOx, ultrafine particles (UFP), and oxidative potential (OP) of PM2.5 on infant birthweight in four European birth cohorts and the mechanistic underpinnings through cross-omics of metabolites and inflammatory proteins. The association between mixtures of air pollutants and birthweight z-scores (standardized for gestational age) was assessed for three different mixture models, using Bayesian machine kernel regression (BKMR). We determined the direct effect for PM2.5, PM10, NO2, and mediation by cross-omic signatures (identified using sparse partial least-squares regression) using causal mediation BKMR models. There was a negative association with birthweight z-scores and exposure to mixtures of air pollutants, where up to -0.21 or approximately a 96 g decrease in birthweight, comparing the 75th percentile to the median level of exposure to the air pollutant mixture could occur. Shifts in birthweight z-scores from prenatal exposure to PM2.5, PM10, and NO2 were mediated by molecular mechanisms, represented by cross-omics scores. Interleukin-17 and epidermal growth factor were identified as important inflammatory responses underlyingair pollution-associated shifts in birthweight. Our results signify that by identifying mechanisms through which mixtures of air pollutants operate, the causality of air pollution-associated shifts in birthweight is better supported, substantiating the need for reducing exposure in vulnerable populations.

6.
Int J Cancer ; 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32734650

RESUMO

Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.

7.
Metabolites ; 10(7)2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32635215

RESUMO

The intake of processed meat has been associated with several adverse health outcomes such as type II diabetes and cancer; however, the mechanisms are not fully understood. A better knowledge of the metabolite profiles of different processed and non-processed meat products from this heterogeneous food group could help in elucidating the mechanisms associated with these health effects. Thirty-three different commercial samples of ten processed and non-processed meat products were digested in triplicate with a standardized static in vitro digestion method in order to mimic profiles of small molecules formed in the gut upon digestion. A metabolomics approach based on high-resolution mass spectrometry was used to identify metabolite profiles specific to the various meat products. Processed meat products showed metabolite profiles clearly distinct from those of non-processed meat. Several discriminant features related to either specific ingredients or processing methods were identified. Those were, in particular, syringol compounds deposited in meat during smoking, biogenic amines formed during meat fermentation and piperine and related compounds characteristic of pepper used as an ingredient. These metabolites, characteristic of specific processed meat products, might be used as potential biomarkers of intake for these foods. They may also help in understanding the mechanisms linking processed meat intake and adverse health outcomes such as cancer.

8.
Metabolism ; 110: 154292, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32553738

RESUMO

BACKGROUND: Birthweight reflects in utero exposures and later health evolution. Despite existing studies employing high-dimensional molecular measurements, the understanding of underlying mechanisms of birthweight remains limited. METHODS: To investigate the systems biology of birthweight, we cross-sectionally integrated the methylome, the transcriptome, the metabolome and a set of inflammatory proteins measured in cord blood samples, collected from four birth-cohorts (n = 489). We focused on two sets of 68 metabolites and 903 CpGs previously related to birthweight and investigated the correlation structures existing between these two sets and all other omic features via bipartite Pearson correlations. RESULTS: This dataset revealed that the set of metabolome and methylome signatures of birthweight have seven signals in common, including three metabolites [PC(34:2), plasmalogen PC(36:4)/PC(O-36:5), and a compound with m/z of 781.0545], two CpGs (on the DHCR24 and SC4MOL gene), and two proteins (periostin and CCL22). CCL22, a macrophage-derived chemokine has not been previously identified in relation to birthweight. Since the results of the omics integration indicated the central role of cholesterol metabolism, we explored the association of cholesterol levels in cord blood with birthweight in the ENVIRONAGE cohort (n = 1097), finding that higher birthweight was associated with increased high-density lipoprotein cholesterol and that high-density lipoprotein cholesterol was lower in small versus large for gestational age newborns. CONCLUSIONS: Our data suggests that an integration of different omic-layers in addition to single omics studies is a useful approach to generate new hypotheses regarding biological mechanisms. CCL22 and cholesterol metabolism in cord blood play a mechanistic role in birthweight.


Assuntos
Peso ao Nascer , Colesterol/metabolismo , Sangue Fetal/química , Quimiocina CCL22/metabolismo , Estudos Transversais , Feminino , Humanos , Recém-Nascido , Masculino , Metaboloma , Metilação
9.
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
10.
Mol Nutr Food Res ; 63(22): e1900659, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31483556

RESUMO

SCOPE: The goal of this work is to identify circulating biomarkers of habitual coffee intake using a metabolomic approach, and to investigate their associations with coffee intake in four European countries. METHODS AND RESULTS: Untargeted mass spectrometry-based metabolic profiling is performed on serum samples from 451 participants of the European Prospective Investigation on Cancer and Nutrition (EPIC) originating from France, Germany, Greece, and Italy. Eleven coffee metabolites are found to be associated with self-reported habitual coffee intake, including eight more strongly correlated (r = 0.25-0.51, p < 10E-07 ). Trigonelline shows the highest correlation, followed by caffeine, two caffeine metabolites (paraxanthine and 5-Acetylamino-6-amino-3-methyluracil), quinic acid, and three compounds derived from coffee roasting (cyclo(prolyl-valyl), cyclo(isoleucyl-prolyl), cyclo(leucyl-prolyl), and pyrocatechol sulfate). Differences in the magnitude of correlations are observed between countries, with trigonelline most highly correlated with coffee intake in France and Germany, quinic acid in Greece, and cyclo(isoleucyl-prolyl) in Italy. CONCLUSION: Several biomarkers of habitual coffee intake are identified. No unique biomarker is found to be optimal for all tested populations. Instead, optimal biomarkers are shown to depend on the population and on the type of coffee consumed. These biomarkers should help to further explore the role of coffee in disease risk.


Assuntos
Biomarcadores/sangue , Café , Metabolômica , Adulto , Idoso , Alcaloides/sangue , Cafeína/sangue , Café/metabolismo , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Teofilina/sangue
11.
Am J Clin Nutr ; 110(6): 1424-1433, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31559413

RESUMO

BACKGROUND: Processed meat intake is associated with a higher risk of colorectal and stomach cancers, coronary artery disease, and type 2 diabetes and with higher mortality, but the estimation of intake of different processed meat products in this heterogeneous food group in epidemiological studies remains challenging. OBJECTIVE: This work aimed at identifying novel biomarkers for processed meat intake using metabolomics. METHODS: An untargeted, multi-tiered metabolomics approach based on LC-MS was applied to 33 meat products digested in vitro and secondly to urine and plasma samples from a randomized crossover dietary intervention in which 12 volunteers consumed successively 3 processed meat products (bacon, salami, and hot dog) and 2 other foods used as controls, over 3 consecutive days. The putative biomarkers were then measured in urine from 474 subjects from the European Prospective Investigation into Cancer and Nutrition (EPIC) cross-sectional study for which detailed 24-h dietary recalls and FFQs were available. RESULTS: Syringol and 4 derivatives of syringol were found to be characteristic of in vitro digests of smoked meat products. The same compounds present as sulfate esters in urine increased at 2 and 12 h after consumption of smoked meat products (hot dog, bacon) in the intervention study. The same syringol sulfates were also positively associated with recent or habitual consumption of smoked meat products in urine samples from participants of the EPIC cross-sectional study. These compounds showed good discriminative ability for smoked meat intake with receiver operator characteristic areas under the curve ranging from 0.78 to 0.86 and 0.74 to 0.79 for short-term and habitual intake, respectively. CONCLUSIONS: Four novel syringol sulfates were identified as potential biomarkers of smoked meat intake and may be used to improve assessment of smoked meat intake in epidemiological studies. This trial was registered at clinicaltrials.gov as NCT03354130.


Assuntos
Biomarcadores/sangue , Produtos da Carne/análise , Pirogalol/análogos & derivados , Idoso , Estudos Transversais , Dieta/efeitos adversos , Feminino , Humanos , Masculino , Produtos da Carne/efeitos adversos , Metabolômica , Pessoa de Meia-Idade , Estudos Prospectivos , Pirogalol/sangue , Pirogalol/metabolismo
12.
Eur J Hum Genet ; 27(10): 1589-1598, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31231134

RESUMO

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (ORmale) = 0.83 [95% CI = 0.78-0.89], Pmale = 1.71 × 10-8 compared with female odds ratio (ORfemale) = 0.98 [95% CI = 0.90-1.07], Pfemale = 0.68) and 12q23.3 (intergenic, ORmale = 0.75 [95% CI = 0.68-0.83], Pmale = 1.59 × 10-8 compared with ORfemale = 0.93 [95% CI = 0.82-1.06], Pfemale = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.


Assuntos
Carcinoma de Células Renais/epidemiologia , Carcinoma de Células Renais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Renais/epidemiologia , Neoplasias Renais/genética , Biologia Computacional , Feminino , Humanos , Masculino , Razão de Chances , Polimorfismo de Nucleotídeo Único , Locos de Características Quantitativas , Fatores Sexuais
13.
Int J Cancer ; 145(5): 1221-1231, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30665271

RESUMO

Colorectal cancer is known to arise from multiple tumorigenic pathways; however, the underlying mechanisms remain not completely understood. Metabolomics is becoming an increasingly popular tool in assessing biological processes. Previous metabolomics research focusing on colorectal cancer is limited by sample size and did not replicate findings in independent study populations to verify robustness of reported findings. Here, we performed a ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) screening on EDTA plasma from 268 colorectal cancer patients and 353 controls using independent discovery and replication sets from two European cohorts (ColoCare Study: n = 180 patients/n = 153 controls; the Colorectal Cancer Study of Austria (CORSA) n = 88 patients/n = 200 controls), aiming to identify circulating plasma metabolites associated with colorectal cancer and to improve knowledge regarding colorectal cancer etiology. Multiple logistic regression models were used to test the association between disease state and metabolic features. Statistically significant associated features in the discovery set were taken forward and tested in the replication set to assure robustness of our findings. All models were adjusted for sex, age, BMI and smoking status and corrected for multiple testing using False Discovery Rate. Demographic and clinical data were abstracted from questionnaires and medical records.


Assuntos
Neoplasias Colorretais/sangue , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Humanos , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade
14.
Environ Int ; 123: 124-131, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30522001

RESUMO

Exposure to traffic-related air pollution (TRAP) has been associated with adverse health outcomes but underlying biological mechanisms remain poorly understood. Two randomized crossover trials were used here, the Oxford Street II (London) and the TAPAS II (Barcelona) studies, where volunteers were allocated to high or low air pollution exposures. The two locations represent different exposure scenarios, with Oxford Street characterized by diesel vehicles and Barcelona by normal mixed urban traffic. Levels of five and four pollutants were measured, respectively, using personal exposure monitoring devices. Serum samples were used for metabolomic profiling. The association between TRAP and levels of each metabolic feature was assessed. All pollutant levels were significantly higher at the high pollution sites. 29 and 77 metabolic features were associated with at least one pollutant in the Oxford Street II and TAPAS II studies, respectively, which related to 17 and 30 metabolic compounds. Little overlap was observed across pollutants for metabolic features, suggesting that different pollutants may affect levels of different metabolic features. After observing the annotated compounds, the main pathway suggested in Oxford Street II in association with NO2 was the acyl-carnitine pathway, previously found to be associated with cardio-respiratory disease. No overlap was found between the metabolic features identified in the two studies.


Assuntos
Poluentes Atmosféricos/toxicidade , Exposição Ambiental , Metaboloma , Poluição Relacionada com o Tráfego , Idoso , Estudos Cross-Over , Exposição Ambiental/análise , Monitoramento Ambiental/métodos , Feminino , Humanos , Londres , Masculino , Metabolômica , Pessoa de Meia-Idade , Espanha , Emissões de Veículos/análise
15.
Environ Int ; 119: 334-345, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29990954

RESUMO

BACKGROUND: Epidemiologic evidence indicates common risk factors, including air pollution exposure, for respiratory and cardiovascular diseases, suggesting the involvement of common altered molecular pathways. OBJECTIVES: The goal was to find intermediate metabolites or metabolic pathways that could be associated with both air pollutants and health outcomes ("meeting-in-the-middle"), thus shedding light on mechanisms and reinforcing causality. METHODS: We applied a statistical approach named 'meet-in-the-middle' to untargeted metabolomics in two independent case-control studies nested in cohorts on adult-onset asthma (AOA) and cardio-cerebrovascular diseases (CCVD). We compared the results to identify both common and disease-specific altered metabolic pathways. RESULTS: A novel finding was a strong association of AOA with ultrafine particles (UFP; odds ratio 1.80 [1.26, 2.55] per increase by 5000 particles/cm3). Further, we have identified several metabolic pathways that potentially mediate the effect of air pollution on health outcomes. Among those, perturbation of Linoleate metabolism pathway was associated with air pollution exposure, AOA and CCVD. CONCLUSIONS: Our results suggest common pathway perturbations may occur as a consequence of chronic exposure to air pollution leading to increased risk for both AOA and CCVD.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Asma/epidemiologia , Doenças Cardiovasculares/epidemiologia , Exposição Ambiental , Redes e Vias Metabólicas/efeitos dos fármacos , Adulto , Estudos de Casos e Controles , Exposição Ambiental/análise , Exposição Ambiental/estatística & dados numéricos , Humanos
16.
J Proteome Res ; 17(3): 1235-1247, 2018 03 02.
Artigo em Inglês | MEDLINE | ID: mdl-29401400

RESUMO

Birth weight is an important indicator of maternal and fetal health and a predictor of health in later life. However, the determinants of variance in birth weight are still poorly understood. We aimed to identify the biological pathways, which may be perturbed by environmental exposures, that are important in determining birth weight. We applied untargeted mass-spectrometry-based metabolomics to 481 cord blood samples collected at delivery in four birth cohorts from across Europe: ENVIRONAGE (Belgium), INMA (Spain), Piccolipiu (Italy), and Rhea (Greece). We performed a metabolome-wide association scan for birth weight on over 4000 metabolic features, controlling the false discovery rate at 5%. Annotation of compounds was conducted through reference to authentic standards. We identified 68 metabolites significantly associated with birth weight, including vitamin A, progesterone, docosahexaenoic acid, indolelactic acid, and multiple acylcarnitines and phosphatidylcholines. We observed enrichment (p < 0.05) of the tryptophan metabolism, prostaglandin formation, C21-steroid hormone signaling, carnitine shuttle, and glycerophospholipid metabolism pathways. Vitamin A was associated with both maternal smoking and birth weight, suggesting a mediation pathway. Our findings shed new light on the pathways central to fetal growth and will have implications for antenatal and perinatal care and potentially for health in later life.


Assuntos
Peso ao Nascer/fisiologia , Sangue Fetal/química , Desenvolvimento Fetal/fisiologia , Metaboloma , Carnitina/análogos & derivados , Carnitina/sangue , Cromatografia Líquida de Alta Pressão , Estudos de Coortes , Ácidos Docosa-Hexaenoicos/sangue , Exposição Ambiental/análise , Europa (Continente) , Feminino , Feto , Humanos , Indóis/sangue , Recém-Nascido , Masculino , Espectrometria de Massas/métodos , Material Particulado/análise , Fosfatidilcolinas/sangue , Gravidez , Progesterona/sangue , Prostaglandinas/sangue , Padrões de Referência , Triptofano/sangue , Vitamina A/sangue
17.
Nat Commun ; 8: 15724, 2017 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-28598434

RESUMO

Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10-10), 3p22.1 (rs67311347, P=2.5 × 10-8), 3q26.2 (rs10936602, P=8.8 × 10-9), 8p21.3 (rs2241261, P=5.8 × 10-9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10-8), 11q22.3 (rs74911261, P=2.1 × 10-10) and 14q24.2 (rs4903064, P=2.2 × 10-24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.


Assuntos
Carcinoma de Células Renais/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Neoplasias Renais/genética , Adolescente , Adulto , Idoso , Grupo com Ancestrais do Continente Europeu/genética , Feminino , Loci Gênicos , Mutação em Linhagem Germinativa , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único , Adulto Jovem
18.
J Med Genet ; 53(5): 298-309, 2016 05.
Artigo em Inglês | MEDLINE | ID: mdl-26921362

RESUMO

BACKGROUND: BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. METHODS: We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. RESULTS: The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). CONCLUSIONS: These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas de Ligação a DNA/genética , Predisposição Genética para Doença , Mutação , RNA Helicases/genética , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Proteínas de Grupos de Complementação da Anemia de Fanconi , Feminino , Estudos de Associação Genética , Humanos , Pessoa de Meia-Idade , Risco
19.
PLoS One ; 10(4): e0123700, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25849217

RESUMO

BACKGROUND: French Polynesia has one of the highest incidence rates of thyroid cancer worldwide. Relationships with the atmospheric nuclear weapons tests and other environmental, biological, or behavioral factors have already been reported, but genetic susceptibility has yet to be investigated. We assessed the contribution of polymorphisms at the 9q22.33 and 14q13.3 loci identified by GWAS, and within the DNA repair gene ATM, to the risk of differentiated thyroid cancer (DTC) in 177 cases and 275 matched controls from the native population. PRINCIPAL FINDINGS: For the GWAS SNP rs965513 near FOXE1, an association was found between genotypes G/A and A/A, and risk of DTC. A multiplicative effect of allele A was even noted. An excess risk was also observed in individuals carrying two long alleles of the poly-alanine tract expansion in FOXE1, while no association was observed with rs1867277 falling in the promoter region of the gene. In contrast, the GWAS SNP rs944289 (NKX2-1) did not show any significant association. Although the missense substitution D1853N (rs1801516) in ATM was rare in the population, carriers of the minor allele (A) also showed an excess risk. The relationships between these five polymorphisms and the risk of DTC were not contingent on the body surface area, body mass index, ethnicity or dietary iodine intake. However, an interaction was evidenced between the thyroid radiation dose and rs944289. SIGNIFICANCE: A clear link could not be established between the high incidence in French Polynesia and the studied polymorphisms, involved in susceptibility to DTC in other populations. Important variation in allele frequencies was observed in the Polynesian population as compared to the European populations. For FOXE1 rs965513, the direction of association and the effect size was similar to that observed in other populations, whereas for ATM rs1801516, the minor allele was associated to an increased risk in the Polynesian population and with a decreased risk in the European population.


Assuntos
Adenocarcinoma Folicular/genética , Proteínas Mutadas de Ataxia Telangiectasia/genética , Carcinoma Papilar/genética , Cromossomos Humanos Par 14/genética , Cromossomos Humanos Par 9/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias da Glândula Tireoide/genética , Adenocarcinoma Folicular/epidemiologia , Adulto , Carcinoma Papilar/epidemiologia , Estudos de Casos e Controles , Diferenciação Celular , Feminino , Fatores de Transcrição Forkhead/genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Polinésia/epidemiologia , Fatores de Risco , Neoplasias da Glândula Tireoide/epidemiologia , Fator Nuclear 1 de Tireoide , Fatores de Transcrição/genética
20.
BMC Genet ; 16: 22, 2015 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-25879635

RESUMO

BACKGROUND: The incidence of differentiated thyroid carcinoma (DTC) in Cuba is low and the contribution of host genetic factors to DTC in this population has not been investigated so far. Our goal was to assess the role of known risk polymorphisms in DTC cases living in Havana. We genotyped five polymorphisms located at the DTC susceptibility loci on chromosome 14q13.3 near NK2 homeobox 1 (NKX2-1), on chromosome 9q22.33 near Forkhead factor E1 (FOXE1) and within the DNA repair gene Ataxia-Telangiectasia Mutated (ATM) in 203 cases and 212 age- and sex- matched controls. Potential interactions between these polymorphisms and other DTC risk factors such as body surface area, body mass index, size, ethnicity, and, for women, the parity were also examined. RESULTS: Significant association with DTC risk was found for rs944289 near NKX2-1 (OR per A allele = 1.6, 95% CI: 1.2-2.1), and three polymorphisms near or within FOXE1, namely rs965513 (OR per A allele = 1.7, 95% CI: 1.2-2.3), rs1867277 in the promoter region of the gene (OR per A allele = 1.5, 95% CI: 1.1-1.9) and the poly-alanine tract expansion polymorphism rs71369530 (OR per Long Allele = 1.8, 95% CI: 1.3-2.5), only the 2 latter remaining significant when correcting for multiple tests. Overall, no association between DTC and the coding SNP D1853N (rs1801516) in ATM (OR per A Allele = 1.1, 95% CI: 0.7-1.7) was seen. Nevertheless women who had 2 or more pregnancies had a 3.5-fold increase in risk of DTC if they carried the A allele (OR 3.5, 95% CI: 3.2-9.8) as compared to 0.8 (OR 0.8, 95% CI: 0.4-1.6) in those who had fewer than 2. CONCLUSIONS: We confirmed in the Cuban population the role of the loci previously associated with DTC susceptibility in European and Japanese populations through genome-wide association studies. Our results on ATM and the number of pregnancies raise interesting questions on the mechanisms by which oestrogens, or other hormones, alter the DNA damage response and DNA repair through the regulation of key effector proteins such as ATM. Due to the small size of our study and to multiple tests, all these results warrant further investigation.


Assuntos
Proteínas Mutadas de Ataxia Telangiectasia/genética , Cromossomos Humanos Par 14 , Cromossomos Humanos Par 9 , Variação Genética , Locos de Características Quantitativas , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Alelos , Cuba/epidemiologia , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Gradação de Tumores , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único , Risco , Neoplasias da Glândula Tireoide/epidemiologia
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