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
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
BACKGROUND: Earlier, a G/T single nucleotide polymorphism (SNP) in the HMGCR gene was shown to significantly reduce the overall serum lipids response to pravastatin. This study aimed to investigate the relationship of the rs17238540 SNP with coronary heart disease, stroke and cardiovascular disease risk. DESIGN: Cross-sectional study from the European Prospective Investigation into Cancer and Nutrition-Norfolk cohort. METHODS: Genotype was determined by pyrosequencing 23,011 participants, for whom clinical and biochemical data were available. Baseline risk factors according to genotype were evaluated, and the risk for fatal and nonfatal stroke, ischaemic heart disease and all types of cardiovascular diseases were assessed by logistic regression after approximately 11 years of follow-up. RESULTS: The G allele carriers presented 1.4 mmHg higher systolic blood pressure and 0.8 mmHg higher diastolic blood pressure than those who were TT carriers. They also presented higher risk of prevalent total (odds ratio: 1.44, 95% confidence interval: 1.05-1.97, P = 0.025) and nonfatal (odds ratio: 1.56, 95% confidence interval: 1.12-2.17, P = 0.009) stroke events compared with the TT individuals in the multivariate models. CONCLUSION: An association between the rs17238540 SNP and stroke risk was observed, independent of the effect of the SNP on the blood pressure. The possible mechanisms involved, besides the effect on blood pressure, might be related to pleiotropic functions of the HMGCR, and remain to be explored.