Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 26
Filtrar
Filtros adicionais











País/Região como assunto
Intervalo de ano
1.
Eur Urol Oncol ; 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31378665

RESUMO

BACKGROUND: Little is known about the underlying molecular mechanisms of prostate cancer, especially advanced and fatal prostate cancer. OBJECTIVE: To examine associations of prediagnostic plasma metabolomic profiles with advanced and fatal prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: In a case-cohort study of the Cancer Prevention Study-II Nutrition Cohort, of 14 210 cancer-free men with a blood sample in 1998-2001, 129 were diagnosed with advanced prostate cancer (T3-T4 or N1 or M1) through June 2013 and 112 died from prostate cancer through December 2014. Plasma samples from advanced and fatal cases, and a randomly selected subcohort of 347 men were metabolically profiled using untargeted mass spectroscopy-based platforms. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prentice-weighted Cox proportional hazards regression models were used to assess associations of 699 known metabolites with advanced and fatal prostate cancer. RESULTS AND LIMITATIONS: Two metabolites derived from fatty acid metabolism (ethylmalonate and butyrylcarnitine), aspartate, sphingomyelin (d18:1/18:0), and two γ-glutamyl amino acids (γ-glutamylmethionine and γ-glutamylglutamine) were statistically significantly associated (false discovery rate <0.2) with fatal prostate cancer. One standard deviation (SD) increase in each γ-glutamyl amino acid was associated with 34-38% decreased risk, whereas one SD increase in each of the other metabolites was associated with 45-53% increased risk. A metabolic risk score based on four of these metabolites (excluding butyrylcarnitine and γ-glutamylglutamine, which were not independent predictors) was strongly associated with fatal prostate cancer (relative risk per SD: 2.72, 95% confidence interval: 2.05-3.60). No metabolites were statistically significantly associated with advanced prostate cancer. These results were observational and may not be causal. CONCLUSIONS: These findings identified metabolic pathways that are altered in the development of fatal prostate cancer. Further research into these pathways may provide insights into the etiology of fatal prostate cancer. PATIENT SUMMARY: In a large follow-up study of cancer-free men, those with a certain metabolomic profile had a higher risk of dying from prostate cancer.

2.
Am J Clin Nutr ; 109(5): 1439-1451, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31051511

RESUMO

BACKGROUND: Healthy diet patterns are associated with lower risk of cancer and other chronic diseases. Metabolomics has the potential to expand dietary biomarker development to include dietary patterns, which may provide a complement or alternative to self-reported diet. OBJECTIVE: This study examined the correlation of serum untargeted metabolomic markers with 4 diet pattern scores-the alternate Mediterranean diet score (aMED), alternate Healthy Eating Index (AHEI)-2010, the Dietary Approaches to Stop Hypertension (DASH) diet, and the Healthy Eating Index (HEI)-2015-and used multivariate methods to identify discriminatory metabolites for each pattern. METHODS: Among 1367 US postmenopausal women with serum metabolomic data in the Cancer Prevention Study-II Nutrition Cohort, we conducted partial correlation analysis, adjusted for demographic and lifestyle variables, to examine cross-sectional correlations between serum metabolomic markers and healthy diet pattern scores. In a randomly selected "training" set (50%), we conducted orthogonal partial least-squares discriminant analysis to identify metabolites that discriminated the top from bottom diet score quintiles. Combinations of metabolites with a variable importance in projection (VIP) score ≥2.5 were tested for predictability in the "testing" set based on the use of receiver operating characteristic curves. RESULTS: Out of 1186 metabolites, 32 unique metabolites were considered discriminatory based on a VIP score ≥2.5 in the training dataset with some overlap across scores (aMED = 16; AHEI = 17; DASH = 13; HEI = 12). Spearman partial correlation analyses, applying a cut-point (|r| ≥ 0.15) and Bonferroni correction (P < 1.05 × 10-5), identified similar key metabolites. The top 5 metabolites for each pattern mostly distinguished high compared with low scores; 4 of the 5 (fish-derived) metabolites were the same for aMED and AHEI, 2 of which were identified for HEI; 4 DASH metabolites were unique. CONCLUSIONS: Metabolomic methods that used a split-sample approach identified potential biomarkers for 4 healthy diet patterns. Similar metabolites across scores reflect fish consumption in healthy dietary patterns. These findings should be replicated in independent populations.

3.
Nat Commun ; 10(1): 1741, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30988301

RESUMO

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.


Assuntos
Neoplasias da Mama/genética , Predisposição Genética para Doença , Feminino , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Locos de Características Quantitativas
4.
Br J Haematol ; 186(2): 243-254, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30977126

RESUMO

There is insufficient evidence linking excess body weight to risk of myeloid malignancies. We investigated this association using data from the Cancer Prevention Study-II (CPS-II), and a meta-analysis of published cohort studies. Among 152 090 CPS-II participants, 387 acute myeloid leukaemias (AML), 100 chronic myeloid leukaemias (CML) and 170 MDS were identified over 21 years of follow-up. In CPS-II, body mass index (BMI) was weakly associated with risk of CML (hazard ratio [HR] = 1·04, 95% confidence interval [CI]: 0·99-1·09 per 1 unit increase in BMI), AML (HR = 1·01, 95% CI: 0·98-1·03) and MDS (HR = 1·03, 95% CI: 0·99-1·07). After controlling for other anthropometric factors, no clear association was observed for height, BMI at age 18 years or weight change. In the meta-analysis (n = 7117 myeloid leukaemias), BMI 25-29·9 kg/m2 (HRpooled  = 1·36, 95% CI: 1·12-1·59) and BMI ≥30 kg/m2 (HRpooled  = 1·43, 95% CI: 1·18-1·69) were associated with higher risk of myeloid leukaemia overall, compared to a BMI <25 kg/m2 . Likewise, BMI ≥25 kg/m2 was positively associated with both AML and CML risk individually in the meta-analysis. These results underscore the need for large studies to detect associations with rare cancers, and show a modest, but positive association between excess body weight and myeloid malignancy risk.

5.
Br J Cancer ; 120(6): 647-657, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30787463

RESUMO

BACKGROUND: We examined the associations between germline variants and breast cancer mortality using a large meta-analysis of women of European ancestry. METHODS: Meta-analyses included summary estimates based on Cox models of twelve datasets using ~10.4 million variants for 96,661 women with breast cancer and 7697 events (breast cancer-specific deaths). Oestrogen receptor (ER)-specific analyses were based on 64,171 ER-positive (4116) and 16,172 ER-negative (2125) patients. We evaluated the probability of a signal to be a true positive using the Bayesian false discovery probability (BFDP). RESULTS: We did not find any variant associated with breast cancer-specific mortality at P < 5 × 10-8. For ER-positive disease, the most significantly associated variant was chr7:rs4717568 (BFDP = 7%, P = 1.28 × 10-7, hazard ratio [HR] = 0.88, 95% confidence interval [CI] = 0.84-0.92); the closest gene is AUTS2. For ER-negative disease, the most significant variant was chr7:rs67918676 (BFDP = 11%, P = 1.38 × 10-7, HR = 1.27, 95% CI = 1.16-1.39); located within a long intergenic non-coding RNA gene (AC004009.3), close to the HOXA gene cluster. CONCLUSIONS: We uncovered germline variants on chromosome 7 at BFDP < 15% close to genes for which there is biological evidence related to breast cancer outcome. However, the paucity of variants associated with mortality at genome-wide significance underpins the challenge in providing genetic-based individualised prognostic information for breast cancer patients.

7.
Am J Hum Genet ; 104(1): 21-34, 2019 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-30554720

RESUMO

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

8.
Metabolites ; 8(4)2018 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-30248901

RESUMO

Over-the-counter analgesic use is common and is typically assessed through self-report; therefore, it is subject to misclassification. Detection of drug metabolites in biofluids offers a viable tool for validating self-reported analgesic use. Thus, the aim of this study was to determine the utility of a metabolomics approach for the validation of acetaminophen and ibuprofen use in blood samples. Untargeted mass spectrometry-based metabolomics analysis was conducted in serum samples from 1547 women and plasma samples from 556 men. The presence of two metabolites each for acetaminophen and ibuprofen at levels at or above a defined cutoff value was used to determine concordance with self-reported use. For acetaminophen use based on the presence of both acetaminophen and acetamidophenylglucuronide, concordance was 98.5⁻100% among individuals reporting use today, and 79.8⁻91.4% for those reporting never or rare use. Ibuprofen use based on the presence of both carboxyibuprofen and hydroxyibuprofen resulted in concordance of 51.3⁻52.5% for individuals reporting use today and 99.4⁻100% for those reporting never or rare use. Our findings suggest that an untargeted metabolomics approach in blood samples may be useful for validating self-reported acetaminophen use. However, this approach appears unlikely to be suitable for validating ibuprofen use.

9.
Cancer Res ; 78(20): 6011-6021, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30185547

RESUMO

Various subtypes of breast cancer defined by estrogen receptor (ER), progesterone receptor (PR), and HER2 exhibit etiologic differences in reproductive factors, but associations with other risk factors are inconsistent. To clarify etiologic heterogeneity, we pooled data from nine cohort studies. Multivariable, joint Cox proportional hazards regression models were used to estimate HRs and 95% confidence intervals (CI) for molecular subtypes. Of 606,025 women, 11,741 invasive breast cancers with complete tissue markers developed during follow-up: 8,700 luminal A-like (ER+ or PR+/HER2-), 1,368 luminal B-like (ER+ or PR+/HER2+), 521 HER2-enriched (ER-/PR-/HER2+), and 1,152 triple-negative (ER-/PR-/HER2-) disease. Ever parous compared with never was associated with lower risk of luminal A-like (HR, 0.78; 95% CI, 0.73-0.83) and luminal B-like (HR, 0.74; 95% CI, 0.64-0.87) as well as a higher risk of triple-negative disease (HR, 1.23; 95% CI, 1.02-1.50; P value for overall tumor heterogeneity < 0.001). Direct associations with luminal-like, but not HER2-enriched or triple-negative, tumors were found for age at first birth, years between menarche and first birth, and age at menopause (P value for overall tumor heterogeneity < 0.001). Age-specific associations with baseline body mass index differed for risk of luminal A-like and triple-negative breast cancer (P value for tumor heterogeneity = 0.02). These results provide the strongest evidence for etiologic heterogeneity of breast cancer to date from prospective studies.Significance: These findings comprise the largest study of prospective data to date and contribute to the accumulating evidence that etiological heterogeneity exists in breast carcinogenesis. Cancer Res; 78(20); 6011-21. ©2018 AACR.

10.
Nat Genet ; 50(7): 968-978, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29915430

RESUMO

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology.

11.
Nat Genet ; 50(7): 928-936, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29892016

RESUMO

Genome-wide association studies (GWAS) and fine-mapping efforts to date have identified more than 100 prostate cancer (PrCa)-susceptibility loci. We meta-analyzed genotype data from a custom high-density array of 46,939 PrCa cases and 27,910 controls of European ancestry with previously genotyped data of 32,255 PrCa cases and 33,202 controls of European ancestry. Our analysis identified 62 novel loci associated (P < 5.0 × 10-8) with PrCa and one locus significantly associated with early-onset PrCa (≤55 years). Our findings include missense variants rs1800057 (odds ratio (OR) = 1.16; P = 8.2 × 10-9; G>C, p.Pro1054Arg) in ATM and rs2066827 (OR = 1.06; P = 2.3 × 10-9; T>G, p.Val109Gly) in CDKN1B. The combination of all loci captured 28.4% of the PrCa familial relative risk, and a polygenic risk score conferred an elevated PrCa risk for men in the ninetieth to ninety-ninth percentiles (relative risk = 2.69; 95% confidence interval (CI): 2.55-2.82) and first percentile (relative risk = 5.71; 95% CI: 5.04-6.48) risk stratum compared with the population average. These findings improve risk prediction, enhance fine-mapping, and provide insight into the underlying biology of PrCa1.

12.
Nat Commun ; 9(1): 2256, 2018 06 11.
Artigo em Inglês | MEDLINE | ID: mdl-29892050

RESUMO

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling.

13.
J Nutr ; 148(6): 932-943, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29767735

RESUMO

Background: Recent studies suggest that untargeted metabolomics is a promising tool to identify novel biomarkers of individual foods. However, few large cross-sectional studies with comprehensive data on habitual diet and circulating metabolites have been conducted. Objective: We aimed to identify potential food biomarkers and evaluate their predictive accuracy. Methods: We conducted a cross-sectional analysis of consumption of 91 food groups or items, assessed by a 152-item food-frequency questionnaire, in relation to 1186 serum metabolites measured by mass spectrometry-based platforms from 1369 nonsmoking postmenopausal women (mean age = 68.3 y). Diet-metabolite associations were selected by Pearson's partial correlation analysis (P < 4.63 × 10-7, |r| > 0.2). The predictive accuracy of the selected food metabolites was evaluated from the area under the curve (AUC) calculated from receiver operating characteristic analysis conducted among women in the top and bottom quintiles of dietary intake. Results: We identified 379 diet-metabolite associations. Forty-two food groups or items were correlated with 199 serum metabolites. We replicated 63 metabolites as biomarkers of habitual food intake reported in previous cross-sectional studies. Among those not previously shown to be associated with habitual diet, several are biologically plausible and were reported in acute feeding studies including: banana and dopamine 3-O-sulfate (r = 0.34, AUC = 76%) and dopamine 4-O-sulfate (r = 0.33, AUC = 74%), garlic and alliin (r = 0.24, AUC = 69%), N-acetylalliin (r = 0.27, AUC = 70%), and S-allylcysteine (r = 0.23, AUC = 69). Two unannotated metabolites were the strongest predictors for dark fish (X-02269, r = 0.51, AUC = 94%) and coffee intake (X-21442, r = 0.62, AUC = 98%). Conclusion: In this comprehensive, cross-sectional analysis of habitual food intake and serum metabolites among postmenopausal women, we identified several potentially novel food biomarkers and replicated others. Our findings contribute to the limited literature on food-based biomarkers and highlight the significant and promising role that large cohort studies with archived blood samples could play in this field. This study was registered at clinicaltrials.gov as NCT03282812.

14.
Metabolomics ; 14(10): 129, 2018 09 25.
Artigo em Inglês | MEDLINE | ID: mdl-30830406

RESUMO

INTRODUCTION: Processing delays after blood collection is a common pre-analytical condition in large epidemiologic studies. It is critical to evaluate the suitability of blood samples with processing delays for metabolomics analysis as it is a potential source of variation that could attenuate associations between metabolites and disease outcomes. OBJECTIVES: We aimed to evaluate the reproducibility of metabolites over extended processing delays up to 48 h. We also aimed to test the reproducibility of the metabolomics platform. METHODS: Blood samples were collected from 18 healthy volunteers. Blood was stored in the refrigerator and processed for plasma at 0, 15, 30, and 48 h after collection. Plasma samples were metabolically profiled using an untargeted, ultrahigh performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) platform. Reproducibility of 1012 metabolites over processing delays and reproducibility of the platform were determined by intraclass correlation coefficients (ICCs) with variance components estimated from mixed-effects models. RESULTS: The majority of metabolites (approximately 70% of 1012) were highly reproducible (ICCs ≥ 0.75) over 15-, 30- or 48-h processing delays. Nucleotides, energy-related metabolites, peptides, and carbohydrates were most affected by processing delays. The platform was highly reproducible with a median technical ICC of 0.84 (interquartile range 0.68-0.93). CONCLUSION: Most metabolites measured by the UPLC-MS/MS platform show acceptable reproducibility up to 48-h processing delays. Metabolites of certain pathways need to be interpreted cautiously in relation to outcomes in epidemiologic studies with prolonged processing delays.

15.
Metabolomics ; 14(7): 97, 2018 07 06.
Artigo em Inglês | MEDLINE | ID: mdl-30830410

RESUMO

INTRODUCTION: Postmenopausal hormone use is linked to several health outcomes and the risk associated with some may differ depending on whether estrogen is used alone or in combination with progestin. OBJECTIVE: Metabolomic analyses of postmenopausal hormone use and differences between hormone regimes was done to identify metabolites associated with each type of hormone treatment. METHODS: Untargeted metabolomics analysis was done on serum from 1336 women enrolled in the Cancer Prevention II Nutrition Cohort. Levels of 781 named metabolites were compared between 667 nonusers with 332 estrogen-only and with 337 estrogen plus progestin users using linear regression. Metabolite levels were also compared between estrogen-only and estrogen plus progestin users. RESULTS: Compared to nonusers, 276 metabolites were statistically significantly (P < 6.40 × 10- 5) associated with estrogen-only use and 222 were associated with estrogen plus progestin use. The metabolites associated with both types of hormones included numerous lipids, acyl carnitines, and amino acids as well as the thyroid hormone thyroxine and the oncometabolite fumarate. The 65 metabolites that differed significantly between estrogen-only and estrogen plus progestin users included 19 steroids and 12 lipids that contained the bioactive fatty acid arachidonic acid. CONCLUSIONS: These findings suggest that postmenopausal hormone use influences metabolic pathways linked to a variety of cellular processes, including the regulation of metabolism and stress responses, energy production, and inflammation. The differential association of numerous lipids which influence cellular signaling suggests that differences in signal transduction may contribute to the disparate risks for some diseases between estrogen-only and estrogen plus progestin users.

16.
Cancer Causes Control ; 28(12): 1357-1368, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-28940119

RESUMO

Physical activity has been associated with lower lung cancer risk in numerous studies with estimates ranging from 20 to 50% lower risk in the most versus the least active study participants. Underweight and obesity have also been associated with lower lung cancer risk, with a nonlinear, inverted U-shaped relationship. However, associations of physical activity and obesity with lung cancer are likely significantly confounded by smoking since individuals who smoke are generally less active and leaner than non-smokers, but few studies have examined these associations stratified by smoking status. Using data from 162,679 men and women who were cancer-free at enrollment (1992-1993) in the American Cancer Society Cancer Prevention Study-II Nutrition Cohort, we examined associations of baseline recreational physical activity (MET-hours per week; none, 0.1 to <8.75 (reference), 8.75-17.4, 17.5+ MET-hours/week), baseline body mass index (BMI, weight (kg)/height (m2); <18.5, 18.5-22.0 (reference), 22.1-24.9, 25.0-29.9, 30.0+ kg/m2), and waist circumference (measured in 1997; sex-specific quartiles) in relation to lung cancer risk stratified by smoking status and years since quitting among former smokers (never, current, former <10 years, former, 10-19 years, former 20+ years). Cox proportional hazards modeling computed hazard rate ratios (RR) and 95% confidence intervals (CI) while adjusting for potential confounders. During 2,384,546 person years of follow-up time, 4,669 men and women were diagnosed with lung cancer (453 among never smokers; 1,452 among current smokers; 1,194 among former smokers <10 years since quitting; 725 among former 10-19 years; and 845 among former 20+ years). Physical activity was not associated with lung cancer risk within any of the smoking strata except in former smokers less than 10 years since quitting (RR = 0.77; 95% CI 0.67-0.90 for 17.5+ MET-hours/week). Similarly, BMI was inversely associated with lung cancer in former smokers less than 10 years since quitting (RR = 0.68; 95% CI 0.55-0.84 for 30+ kg/m2) and more modestly in former smokers who quit 10-19 and 20+ years ago. Waist circumference was not associated with lung cancer risk in any smoking category. While being physically active and maintaining a healthy body weight are important for prevention of various chronic diseases, including several types of cancer, our results suggest that physical activity, BMI, and waist circumference are not associated with lung cancer risk, regardless of smoking status.


Assuntos
Exercício , Neoplasias Pulmonares/epidemiologia , Obesidade/epidemiologia , Fumar/epidemiologia , Idoso , Índice de Massa Corporal , Peso Corporal , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Fatores de Risco , Circunferência da Cintura
17.
Fertil Steril ; 107(1): 179-188.e6, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27816232

RESUMO

OBJECTIVE: To evaluate the association of parity, number of live births, and age at first birth with mortality using multivariable-adjusted Cox proportional hazards regression models. DESIGN: Observational cohort. SETTING: Not applicable. PATIENT(S): A total of 424,797 women. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): All-cause and cause-specific mortality. RESULT(S): During median follow-up of 24.93 years, 238,324 deaths occurred. Parous, compared with nulliparous, women had lower rates of all-cause (hazards ratio [HR] = 0.94, 95% confidence interval [CI] 0.93-0.96) mortality, driven by heart disease and overall cancer mortality. A linear trend was found for more births and diabetes mortality (P<.001) with having ≥6 births, compared with 2, associated with an HR of 1.28 (95% CI 1.15-1.43). Compared with age at first birth from 20-22 years, age at first birth <20 years was associated with higher mortality rates overall (HR = 1.04, 95% CI 1.02-1.06), driven by heart disease and chronic obstructive pulmonary disease mortality; whereas, ≥35 years was associated with higher overall cancer mortality (HR = 1.13, 95% CI 1.06-1.20). CONCLUSION(S): Although parity was associated with a slight reduction in rates of all-cause mortality resulting in a minimal impact on average lifespan, the higher diabetes mortality in grand multiparous women might warrant continuous monitoring, particularly for abnormal glucose metabolism, among these women.


Assuntos
Diabetes Mellitus/mortalidade , Idade Materna , Neoplasias/mortalidade , Paridade , Adulto , Idoso , Idoso de 80 Anos ou mais , Causas de Morte , Distribuição de Qui-Quadrado , Diabetes Mellitus/diagnóstico , Feminino , Humanos , Modelos Lineares , Nascimento Vivo , Pessoa de Meia-Idade , Análise Multivariada , Neoplasias/diagnóstico , Neoplasias/prevenção & controle , Gravidez , Modelos de Riscos Proporcionais , Fatores de Proteção , Medição de Risco , Fatores de Risco , Fatores de Tempo , Estados Unidos/epidemiologia
18.
Int J Epidemiol ; 46(3): 881-893, 2017 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-28031315

RESUMO

Background: The 2014 US Surgeon General's report noted research gaps necessary to determine a causal relationship between active cigarette smoking and invasive breast cancer risk, including the role of alcohol consumption, timing of exposure, modification by menopausal status and heterogeneity by oestrogen receptor (ER) status. Methods: To address these issues, we pooled data from 14 cohort studies contributing 934 681 participants (36 060 invasive breast cancer cases). Cox proportional hazard regression models were used to calculate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Smoking duration before first birth was positively associated with risk ( P -value for trend = 2 × 10 -7 ) with the highest HR for initiation >10 years before first birth (HR = 1.18, CI 1.12-1.24). Effect modification by current alcohol consumption was evident for the association with smoking duration before first birth ( P -value=2×10 -4 ); compared with never-smoking non-drinkers, initiation >10 years before first birth was associated with risk in every category of alcohol intake, including non-drinkers (HR = 1.15, CI 1.04-1.28) and those who consumed at least three drinks per day (1.85, 1.55-2.21). Associations with smoking before first birth were limited to risk of ER+ breast cancer ( P -value for homogeneity=3×10 -3 ). Other smoking timing and duration characteristics were associated with risk even after controlling for alcohol, but were not associated with risk in non-drinkers. Effect modification by menopause was not evident. Conclusions: Smoking, particularly if initiated before first birth, was modestly associated with ER+ breast cancer risk that was not confounded by amount of adult alcohol intake. Possible links with breast cancer provide additional motivation for young women to not initiate smoking.


Assuntos
Consumo de Bebidas Alcoólicas/epidemiologia , Neoplasias da Mama/epidemiologia , Fumar Cigarros/epidemiologia , Adulto , Idoso , Fumar Cigarros/efeitos adversos , Estudos de Coortes , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , National Cancer Institute (U.S.) , Modelos de Riscos Proporcionais , Receptores Estrogênicos/genética , Fatores de Risco , Estados Unidos
19.
Nicotine Tob Res ; 19(4): 435-441, 2017 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-27629278

RESUMO

Background: Numerous studies have sought to identify genes that influence the ability to quit smoking, but none found any that are consistently associated with smoking cessation. Methods: We developed a novel difficulty of quitting smoking phenotype based on the extremes of the number of quit attempts needed to achieve successful abstinence: Easy quitters were defined as having achieved long-term (>1 year) abstinence after their first quit attempt and difficult quitters as having reported 10 or more quit attempts. We conducted a two-stage study to determine if this phenotype could be useful for identifying single nucleotide polymorphisms (SNPs) that influence smoking cessation. In stage 1, 82 SNPs in 26 genes involved in nicotine signaling and metabolism were genotyped in 1357 easy quitters and 1321 difficult quitters from Cancer Prevention Study 3 (CPS-3). In stage 2, the 11 SNPs associated with difficult quitting in stage 1 (p < .1) were genotyped in an independent sample of 1300 easy quitters and 1299 difficult quitters from CPS-3. Results: Three of 11 SNPs (HTR1B rs6298, NR4A2 rs834829, and CYP2A65 rs8192729) were significantly associated with the difficult quitting phenotype in stage 2 (p < .05). In addition, a polygenic risk score based on the 11 SNPs identified in stage 1 was significantly associated with the difficult quitting phenotype in stage 2 (odds ratio = 1.08, 95% confidence interval: 1.03-1.14 per quintile, p trend = 4.5×10-3). Conclusions: Using a novel difficulty of quitting phenotype, three gene variants and a polygenic risk score based on 11 SNPs were found to be significantly associated with smoking cessation. Implications: Our results provide evidence that a difficulty of quitting smoking phenotype based on the extremes of number of quit attempts could be a useful tool for identifying genetic variants that influence difficulty of smoking cessation. Knowledge of these genetic variants will indicate biological pathways that could be targeted for the development of novel smoking cessation aids and could be used to determine which smokers are most likely to benefit from such smoking cessation aids.


Assuntos
Abandono do Hábito de Fumar/estatística & dados numéricos , Fumar , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fumar/epidemiologia , Fumar/genética , Fumar/terapia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA