RESUMO
MicroRNAs (miRNAs) are post-transcriptional gene regulators involved in a wide range of biological processes including tumorigenesis. Deregulation of miRNA pathways has been associated with cancer but the contribution of their genetic variability to this disorder is poorly known. We analyzed the genetic association of gastric cancer (GC) and its anatomical and histological subtypes, with 133 single-nucleotide polymorphisms (SNPs) tagging 15 isolated miRNAs and 24 miRNA clusters potentially involved in cancer, in 365 GC cases and 1,284 matched controls within the European Prospective Investigation into Cancer and Nutrition cohort. Various SNPs were associated with GC under the log-additive model. Furthermore, several of these miRNAs passed the gene-based permutation test when analyzed according to GC subtypes: three tagSNPs of the miR-29a/miR-29b-1 cluster were associated with diffuse subtype (minimum p-value = 1.7 × 10(-4) ; odds ratio, OR = 1.72; 95% confidence interval, CI = 1.30-2.28), two tagSNPs of the miR-25/miR-93/miR-106b cluster were associated with cardia GC (minimum p-value = 5.38 × 10(-3) ; OR = 0.56, 95% CI = 0.37-0.86) and one tagSNP of the miR-363/miR-92a-2/miR-19b-2/miR-20b/miR-18b/miR-106a cluster was associated with noncardia GC (minimum p-value = 5.40 × 10(-3) ; OR = 1.41, 95% CI = 1.12-1.78). Some functionally validated target genes of these miRNAs are implicated in cancer-related processes such as methylation (DNMT3A, DNMT3B), cell cycle (E2F1, CDKN1A, CDKN1C), apoptosis (BCL2L11, MCL1), angiogenesis (VEGFA) and progression (PIK3R1, MYCN). Furthermore, we identified genetic interactions between variants tagging these miRNAs and variants in their validated target genes. Deregulation of the expression of these miRNAs in GC also supports our findings, altogether suggesting for the fist time that genetic variation in MIR29, MIR25, MIR93 and MIR106b may have a critical role in genetic susceptibility to GC and could contribute to the molecular mechanisms of gastric carcinogenesis.
Assuntos
Adenocarcinoma/genética , MicroRNAs/genética , Polimorfismo de Nucleotídeo Único/genética , Neoplasias Gástricas/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Estudos de Casos e Controles , Cromossomos Humanos Par 7/genética , Cromossomos Humanos X/genética , Feminino , Seguimentos , Predisposição Genética para Doença , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , População BrancaRESUMO
CONTEXT: Bone mineral metabolism may play a role in the development of heart failure (HF). OBJECTIVE: The aim of the study was to investigate the relationships of plasma fibroblast growth factor (FGF) 23, PTH, and 25-hydroxyvitamin D3 [25(OH)D3] with incident congestive HF in a population-based cohort of men and women aged 40-65 and 35-65 years, respectively, at baseline. DESIGN: We conducted a prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort, including a randomly drawn sample of the total cohort free of HF and all incident HF cases that occurred during a mean follow-up of 8.2 ± 1.6 years. PARTICIPANTS AND SETTING: A total of 221 incident congestive HF cases and 1228 individuals free of HF were included in the study. MAIN OUTCOME MEASURES: Incident congestive HF was measured. RESULTS: In a multivariable model, each doubling of FGF23 [ie, per log (base 2) unit higher FGF23] was associated with a 29% higher HF risk (hazard ratio, 1.29 [95% confidence interval (CI), 1.07-1.56]). After multivariable adjustment, including estimated glomerular filtration rate, PTH was not related to HF risk (hazard ratio per doubling of PTH, 1.21 [95% CI, 0.99-1.48]). However, an interaction was observed between PTH and obesity, suggesting a relationship with HF risk in obese, but not in nonobese individuals. The hazard ratio for HF per doubling of 25(OH)D3 was 1.02 (95% CI, 0.73-1.41). CONCLUSIONS: Our findings provide epidemiological evidence for a positive relationship between FGF23 and risk of HF. The role of PTH in the development of HF remains unclear, in particular in obese individuals, until further confirmation in other studies. 25(OH)D3 was not related to HF.
Assuntos
Calcifediol/sangue , Fatores de Crescimento de Fibroblastos/sangue , Insuficiência Cardíaca/epidemiologia , Hormônio Paratireóideo/sangue , Adulto , Idoso , Osso e Ossos/metabolismo , Estudos de Casos e Controles , Estudos de Coortes , Feminino , Fator de Crescimento de Fibroblastos 23 , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
BACKGROUND: Several countries are discussing new legislation regarding the ban on smoking in public places, based on the growing evidence of the hazards of secondhand smoke (SHS) exposure. The objective of the present study is to quantitatively assess the relationship between smoking, SHS, and serum cotinine levels in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. METHODS: From a study on lung cancer in the EPIC cohort, questionnaire information on smoking was collected at enrolment, and cotinine was measured in serum. Three statistical models were applied by using samples available in a cross-section design: (i) cotinine levels by categories combining smoking and SHS (n = 859); (ii) the effect of hours of passive smoking exposure in nonsmokers only (n = 107); (iii) the effect of the number of cigarettes consumed per day in current smokers only (n = 832). All models were adjusted for country, sex, age, and body mass index. RESULTS: Among nonsmokers, passive smokers presented significant differences in cotinine compared with nonexposed, with a marked (but not significant) difference among former-smokers. A one hour per day increment of SHS gave rise to a significant 2.58 nmol/L (0.45 ng/mL) increase in mean serum cotinine (P < 0.001). In current smokers, a one cigarette per day increment gave rise to a significant 22.44 nmol/L (3.95 ng/mL) increase in cotinine mean (P < 0.001). CONCLUSIONS: There is clear evidence that not only tobacco smoking but also involuntary exposure increases cotinine levels. IMPACT: This study strengthens the evidence for the benefits of a smoking ban in public places.
Assuntos
Cotinina/sangue , Neoplasias Pulmonares/etiologia , Fumar/efeitos adversos , Poluição por Fumaça de Tabaco/efeitos adversos , Adulto , Idoso , Estudos de Casos e Controles , Estudos de Coortes , Estudos Transversais , Europa (Continente)/epidemiologia , Feminino , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/epidemiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , População BrancaRESUMO
Our objective was to analyze detailed anthropometric characterization for risk of breast cancer in Uruguayan women. The design was a case-control study. The setting was Pereira Rossell Women's Hospital, Montevideo, Uruguay. Subjects were 343 incident breast cancer cases and 1,042 frequency-matched healthy controls who were interviewed on menstrual and reproductive story; and a series of skin folds, circumferences, and diameters were measured to calculate fat and muscle fractions and the derived fat-to-muscle ratio (FMR). Odds ratio (ORs) coefficients were taken as estimates of relative risk derived from unconditional logistic regression. Muscle fraction was negatively associated with risk [OR for highest quartile = 0.23, 95% confidence interval (CI) = 0.15-0.34], fat fraction was positively associated (OR = 3.90, 95% CI = 2.62-5.80), and FMR was positively associated (OR = 4.45, 95% CI = 2.99-6.62). Stratified analyses by body mass index levels also showed risk increases for the highest tertiles of FMR, always displaying significant linear trends. Since increases of risk were found in overweight and in normal weight women, results suggest that fractions and amount of muscle and fat components might be risk factors for breast cancer on the basis of currently existing metabolic and immune interrelationships between adipose and muscular tissue given by glutamine, exercise-derived myokines, and other cytokines produced by these tissues.