Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 22
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-33653810

RESUMO

BACKGROUND: Observational evidence has shown that smoking is a risk factor for breast and colorectal cancer. We used Mendelian randomization (MR) to examine causal associations between smoking and risks of breast and colorectal cancer. METHODS: Genome-wide association study summary data were used to identify genetic variants associated with lifetime amount of smoking (n=126 variants) and ever having smoked regularly (n=112 variants). Using two-sample MR, we examined these variants in relation to incident breast (122,977 cases/105,974 controls) and colorectal cancer (52,775 cases/45,940 controls). RESULTS: In inverse-variance weighted models, a genetic predisposition to higher lifetime amount of smoking was positively associated with breast cancer risk [odds ratio [OR] per 1-standard deviation (SD) increment: 1.13 (95% confidence interval [CI]: 1.00-1.26); P: 0.04]; although heterogeneity was observed. Similar associations were found for estrogen receptor-positive and estrogen receptor-negative tumors. Higher lifetime amount of smoking was positively associated with colorectal cancer [OR per 1-SD increment: 1.21 (95% CI: 1.04-1.40); P: 0.01], colon cancer [OR: 1.31 (95% CI: 1.11-1.55); P: <0.01], and rectal cancer [OR: 1.36 (95% CI: 1.07-1.73); P: 0.01]. Ever having smoked regularly was not associated with risks of breast [OR: 1.01 (95% CI: 0.90-1.14); P: 0.85] or colorectal cancer [OR: 0.97 (95% CI: 0.86-1.10); P: 0.68]. CONCLUSIONS: These findings are consistent with prior observational evidence and support a causal role of higher lifetime smoking amount in the development of breast and colorectal cancer. IMPACT: The results from this comprehensive MR analysis indicate that lifetime smoking is a causal risk factor for these common malignancies.

2.
Curr Oncol Rep ; 23(3): 29, 2021 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-33582975

RESUMO

PURPOSE OF REVIEW: Repurposing established medicines for a new therapeutic indication potentially has important global and societal impact. The high costs and slow pace of new drug development have increased interest in more cost-effective repurposed drugs, particularly in the cancer arena. The conventional drug development pathway and evidence framework are not designed for drug repurposing and there is currently no consensus on establishing the evidence base before embarking on a large, resource intensive, potential practice changing phase III randomised controlled trial (RCT). Numerous observational studies have suggested a potential role for statins as a repurposed drug for cancer chemoprevention and therapy, and we review the strength of the cumulative evidence here. RECENT FINDINGS: In the setting of cancer, a potential repurposed drug, like statins, typically goes through a cyclical history, with initial use for several years in another disease setting, prior to epidemiological research identifying a possible chemo-protective effect. However, further information is required, including review of RCT data in the initial disease setting with exploration of cancer outcomes. Additionally, more contemporary methods should be considered, such as Mendelian randomization and pharmaco-epidemiological research with "target" trial design emulation using electronic health records. Pre-clinical and traditional observational data potentially support the role of statins in the treatment of cancer; however, randomised trial evidence is not supportive. Evaluation of contemporary methods provides little added support for the use of statin therapy in cancer. We provide complementary evidence of alternative study designs to enable a robust critical appraisal from a number of sources of the go/no-go decision for a prospective phase III RCT of statins in the treatment of cancer.

3.
Nat Genet ; 52(10): 1122-1131, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32895551

RESUMO

The human proteome is a major source of therapeutic targets. Recent genetic association analyses of the plasma proteome enable systematic evaluation of the causal consequences of variation in plasma protein levels. Here we estimated the effects of 1,002 proteins on 225 phenotypes using two-sample Mendelian randomization (MR) and colocalization. Of 413 associations supported by evidence from MR, 130 (31.5%) were not supported by results of colocalization analyses, suggesting that genetic confounding due to linkage disequilibrium is widespread in naïve phenome-wide association studies of proteins. Combining MR and colocalization evidence in cis-only analyses, we identified 111 putatively causal effects between 65 proteins and 52 disease-related phenotypes ( https://www.epigraphdb.org/pqtl/ ). Evaluation of data from historic drug development programs showed that target-indication pairs with MR and colocalization support were more likely to be approved, evidencing the value of this approach in identifying and prioritizing potential therapeutic targets.


Assuntos
Proteínas Sanguíneas/genética , Predisposição Genética para Doença , Análise da Randomização Mendeliana , Proteoma/genética , Estudo de Associação Genômica Ampla , Humanos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
5.
Int J Cancer ; 147(6): 1597-1603, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32134113

RESUMO

Circulating adipokines and C-reactive protein (CRP) have been linked to breast cancer risk in observational epidemiological studies. The causal nature of these associations is unclear because of the susceptibility of conventional observational designs to residual confounding, reverse causation and other forms of bias. Mendelian randomisation (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational settings. We performed a MR analysis to evaluate the causal relevance of six previously reported circulating adipokines [adiponectin, hepatocyte growth factor (HGF), interleukin-6, leptin receptor, plasminogen activator inhibitor-1 and resistin] and CRP in risk of overall and oestrogen receptor-stratified breast cancer in up to 122,977 cases and 105,974 controls of European ancestry. Genetic instruments were constructed from single-nucleotide polymorphisms robustly (p < 5 × 10-8 ) associated with risk factors in genome-wide association studies. Colocalisation was performed as a sensitivity analysis to examine whether findings reflected shared causal variants or genomic confounding. In MR analyses, there was evidence for an association of HGF with oestrogen receptor-negative cancer (odds ratio per standard deviation increase: 1.17, 95% confidence interval: 1.01-1.35; p = 0.035) but little evidence for associations of other adipokines or CRP with overall or oestrogen receptor-stratified breast cancer. Colocalisation analysis suggested that the association of HGF with oestrogen receptor-negative breast cancer was unlikely to reflect a causal association. Collectively, these findings do not support an important aetiological role of various adipokines or CRP in overall or oestrogen receptor-specific breast cancer risk.

6.
JAMA ; 323(7): 646-655, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32068819

RESUMO

Importance: Preclinical and epidemiological studies indicate a potential chemopreventive role of statins in epithelial ovarian cancer risk. Objective: To evaluate the association of genetically proxied inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (ie, genetic variants related to lower function of HMG-CoA reductase, target of statins) with epithelial ovarian cancer among the general population and in BRCA1/2 mutation carriers. Design, Setting, and Participants: Single-nucleotide polymorphisms (SNPs) in HMGCR, NPC1L1, and PCSK9 associated with low-density lipoprotein (LDL) cholesterol in a genome-wide association study (GWAS) meta-analysis (N ≤196 475) were used to proxy therapeutic inhibition of HMG-CoA reductase, Niemann-Pick C1-Like 1 (NPC1L1) and proprotein convertase subtilisin/kexin type 9 (PCSK9), respectively. Summary statistics were obtained for these SNPs from a GWAS meta-analysis of case-control analyses of invasive epithelial ovarian cancer in the Ovarian Cancer Association Consortium (OCAC; N = 63 347) and from a GWAS meta-analysis of retrospective cohort analyses of epithelial ovarian cancer among BRCA1/2 mutation carriers in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA; N = 31 448). Across the 2 consortia, participants were enrolled between 1973 and 2014 and followed up through 2015. OCAC participants came from 14 countries and CIMBA participants came from 25 countries. SNPs were combined into multi-allelic models and mendelian randomization estimates representing lifelong inhibition of targets were generated using inverse-variance weighted random-effects models. Exposures: Primary exposure was genetically proxied inhibition of HMG-CoA reductase and secondary exposures were genetically proxied inhibition of NPC1L1 and PCSK9 and genetically proxied circulating LDL cholesterol levels. Main Outcomes and Measures: Overall and histotype-specific invasive epithelial ovarian cancer (general population) and epithelial ovarian cancer (BRCA1/2 mutation carriers), measured as ovarian cancer odds (general population) and hazard ratio (BRCA1/2 mutation carriers). Results: The OCAC sample included 22 406 women with invasive epithelial ovarian cancer and 40 941 control individuals and the CIMBA sample included 3887 women with epithelial ovarian cancer and 27 561 control individuals. Median ages for the cohorts ranged from 41.5 to 59.0 years and all participants were of European ancestry. In the primary analysis, genetically proxied HMG-CoA reductase inhibition equivalent to a 1-mmol/L (38.7-mg/dL) reduction in LDL cholesterol was associated with lower odds of epithelial ovarian cancer (odds ratio [OR], 0.60 [95% CI, 0.43-0.83]; P = .002). In BRCA1/2 mutation carriers, genetically proxied HMG-CoA reductase inhibition was associated with lower ovarian cancer risk (hazard ratio, 0.69 [95% CI, 0.51-0.93]; P = .01). In secondary analyses, there were no significant associations of genetically proxied inhibition of NPC1L1 (OR, 0.97 [95% CI, 0.53-1.75]; P = .91), PCSK9 (OR, 0.98 [95% CI, 0.85-1.13]; P = .80), or circulating LDL cholesterol (OR, 0.98 [95% CI, 0.91-1.05]; P = .55) with epithelial ovarian cancer. Conclusions and Relevance: Genetically proxied inhibition of HMG-CoA reductase was significantly associated with lower odds of epithelial ovarian cancer. However, these findings do not indicate risk reduction from medications that inhibit HMG-CoA reductase; further research is needed to understand whether there is a similar association with such medications.


Assuntos
Carcinoma Epitelial do Ovário/prevenção & controle , Hidroximetilglutaril-CoA Redutases/genética , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Neoplasias Ovarianas/prevenção & controle , Polimorfismo de Nucleotídeo Único , Adulto , Carcinoma Epitelial do Ovário/genética , Estudos de Casos e Controles , LDL-Colesterol/sangue , Feminino , Genes BRCA1 , Genes BRCA2 , Humanos , Proteínas de Membrana Transportadoras/genética , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Mutação , Razão de Chances , Neoplasias Ovarianas/genética , Pró-Proteína Convertase 9/genética , Estudos Retrospectivos , Risco
7.
PLoS Med ; 16(8): e1002893, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31390370

RESUMO

BACKGROUND: Various risk factors have been associated with epithelial ovarian cancer risk in observational epidemiological studies. However, the causal nature of the risk factors reported, and thus their suitability as effective intervention targets, is unclear given the susceptibility of conventional observational designs to residual confounding and reverse causation. Mendelian randomization (MR) uses genetic variants as proxies for risk factors to strengthen causal inference in observational studies. We used MR to evaluate the association of 12 previously reported risk factors (reproductive, anthropometric, clinical, lifestyle, and molecular factors) with risk of invasive epithelial ovarian cancer, invasive epithelial ovarian cancer histotypes, and low malignant potential tumours. METHODS AND FINDINGS: Genetic instruments to proxy 12 risk factors were constructed by identifying single nucleotide polymorphisms (SNPs) that were robustly (P < 5 × 10-8) and independently associated with each respective risk factor in previously reported genome-wide association studies. These risk factors included genetic liability to 3 factors (endometriosis, polycystic ovary syndrome, type 2 diabetes) scaled to reflect a 50% higher odds liability to disease. We obtained summary statistics for the association of these SNPs with risk of overall and histotype-specific invasive epithelial ovarian cancer (22,406 cases; 40,941 controls) and low malignant potential tumours (3,103 cases; 40,941 controls) from the Ovarian Cancer Association Consortium (OCAC). The OCAC dataset comprises 63 genotyping project/case-control sets with participants of European ancestry recruited from 14 countries (US, Australia, Belarus, Germany, Belgium, Denmark, Finland, Norway, Canada, Poland, UK, Spain, Netherlands, and Sweden). SNPs were combined into multi-allelic inverse-variance-weighted fixed or random effects models to generate effect estimates and 95% confidence intervals (CIs). Three complementary sensitivity analyses were performed to examine violations of MR assumptions: MR-Egger regression and weighted median and mode estimators. A Bonferroni-corrected P value threshold was used to establish strong evidence (P < 0.0042) and suggestive evidence (0.0042 < P < 0.05) for associations. In MR analyses, there was strong or suggestive evidence that 2 of the 12 risk factors were associated with invasive epithelial ovarian cancer and 8 of the 12 were associated with 1 or more invasive epithelial ovarian cancer histotypes. There was strong evidence that genetic liability to endometriosis was associated with an increased risk of invasive epithelial ovarian cancer (odds ratio [OR] per 50% higher odds liability: 1.10, 95% CI 1.06-1.15; P = 6.94 × 10-7) and suggestive evidence that lifetime smoking exposure was associated with an increased risk of invasive epithelial ovarian cancer (OR per unit increase in smoking score: 1.36, 95% CI 1.04-1.78; P = 0.02). In analyses examining histotypes and low malignant potential tumours, the strongest associations found were between height and clear cell carcinoma (OR per SD increase: 1.36, 95% CI 1.15-1.61; P = 0.0003); age at natural menopause and endometrioid carcinoma (OR per year later onset: 1.09, 95% CI 1.02-1.16; P = 0.007); and genetic liability to polycystic ovary syndrome and endometrioid carcinoma (OR per 50% higher odds liability: 0.89, 95% CI 0.82-0.96; P = 0.002). There was little evidence for an association of genetic liability to type 2 diabetes, parity, or circulating levels of 25-hydroxyvitamin D and sex hormone binding globulin with ovarian cancer or its subtypes. The primary limitations of this analysis include the modest statistical power for analyses of risk factors in relation to some less common ovarian cancer histotypes (low grade serous, mucinous, and clear cell carcinomas), the inability to directly examine the association of some ovarian cancer risk factors that did not have robust genetic variants available to serve as proxies (e.g., oral contraceptive use, hormone replacement therapy), and the assumption of linear relationships between risk factors and ovarian cancer risk. CONCLUSIONS: Our comprehensive examination of possible aetiological drivers of ovarian carcinogenesis using germline genetic variants to proxy risk factors supports a role for few of these factors in invasive epithelial ovarian cancer overall and suggests distinct aetiologies across histotypes. The identification of novel risk factors remains an important priority for the prevention of epithelial ovarian cancer.


Assuntos
Carcinoma Epitelial do Ovário/etiologia , Neoplasias Ovarianas/etiologia , Fatores Etários , Índice de Massa Corporal , Carcinoma Epitelial do Ovário/genética , Feminino , Predisposição Genética para Doença/genética , Humanos , Menarca , Análise da Randomização Mendeliana , Menopausa , Neoplasias Ovarianas/genética , Paridade , Fatores de Risco , Fumar/efeitos adversos
8.
Thorax ; 74(7): 633-642, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-30936389

RESUMO

INTRODUCTION: Males have a higher prevalence of asthma in childhood, whereas females have a higher prevalence in adolescence and adulthood. The 'adolescent switch' observed between sexes during puberty has been hypothesised to be due to fluctuating sex hormones. Robust evidence of the involvement of sex hormones in asthma could lead to development of therapeutic interventions. METHODS: We combine observational evidence using longitudinal data on sex hormone-binding globulin (SHBG), total and bioavailable testosterone and asthma from a subset of males (n=512) in the Avon Longitudinal Study of Parents and Children, and genetic evidence of SHBG and asthma using two-sample Mendelian randomisation (MR), a method of causal inference. We meta-analysed two-sample MR results across two large data sets, the Trans-National Asthma Genetics Consortium genome-wide association study of asthma and UK Biobank (over 460 000 individuals combined). RESULTS: Observational evidence indicated weak evidence of a protective effect of increased circulating testosterone on asthma in males in adolescence, but no strong pattern of association with SHBG. Genetic evidence using two-sample MR indicated a protective effect of increased SHBG, with an OR for asthma of 0.86 (95% CI 0.74 to 1.00) for the inverse-variance weighted approach and an OR of 0.83 (95% CI 0.72 to 0.96) for the weighted median estimator, per unit increase in natural log SHBG. A sex-stratified sensitivity analysis suggested the protective effect of SHBG was mostly evident in females. CONCLUSION: We report the first suggestive evidence of a protective effect of genetically elevated SHBG on asthma, which may provide a biological explanation behind the observed asthma sex discordance. Further work is required to disentangle the downstream effects of SHBG on asthma and the molecular pathways involved.


Assuntos
Asma/genética , Hormônios Esteroides Gonadais/fisiologia , Asma/sangue , Asma/fisiopatologia , Medicina Baseada em Evidências/métodos , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Estudos Observacionais como Assunto , Fatores Sexuais , Globulina de Ligação a Hormônio Sexual/metabolismo , Testosterona/sangue , Testosterona/fisiologia , Bancos de Tecidos
10.
Cancer Causes Control ; 29(11): 1073-1080, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30306355

RESUMO

PURPOSE: Observational studies suggest that dietary and serum calcium are risk factors for prostate cancer. However, such studies suffer from residual confounding (due to unmeasured or imprecisely measured confounders), undermining causal inference. Mendelian randomization uses randomly assigned (hence unconfounded and pre-disease onset) germline genetic variation to proxy for phenotypes and strengthen causal inference in observational studies. We tested the hypothesis that serum calcium is associated with an increased risk of overall and advanced prostate cancer. METHODS: A genetic instrument was constructed using five single-nucleotide polymorphisms robustly associated with serum calcium in a genome-wide association study (n ≤ 61,079). This instrument was then used to test the effect of a 0.5 mg/dL increase (1 standard deviation, SD) in serum calcium on risk of prostate cancer in 72,729 men in the PRACTICAL (Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome) Consortium (44,825 cases, 27,904 controls) and risk of advanced prostate cancer in 33,498 men (6,263 cases, 27,235 controls). RESULTS: We found weak evidence for a protective effect of serum calcium on prostate cancer risk (odds ratio [OR] per 0.5 mg/dL increase in calcium: 0.83, 95% CI 0.63-1.08; p = 0.12). We did not find strong evidence for an effect of serum calcium on advanced prostate cancer (OR per 0.5 mg/dL increase in calcium: 0.98, 95% CI 0.57-1.70; p = 0.93). CONCLUSIONS: Our Mendelian randomization analysis does not support the hypothesis that serum calcium increases risk of overall or advanced prostate cancer.


Assuntos
Cálcio na Dieta/sangue , Cálcio/sangue , Análise da Randomização Mendeliana , Neoplasias da Próstata/sangue , Neoplasias da Próstata/epidemiologia , Cálcio na Dieta/efeitos adversos , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Razão de Chances , Fenótipo , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/etiologia , Neoplasias da Próstata/genética , Fatores de Risco
11.
Cancer Epidemiol Biomarkers Prev ; 27(9): 995-1010, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29941659

RESUMO

Observational epidemiologic studies are prone to confounding, measurement error, and reverse causation, undermining robust causal inference. Mendelian randomization (MR) uses genetic variants to proxy modifiable exposures to generate more reliable estimates of the causal effects of these exposures on diseases and their outcomes. MR has seen widespread adoption within cardio-metabolic epidemiology, but also holds much promise for identifying possible interventions for cancer prevention and treatment. However, some methodologic challenges in the implementation of MR are particularly pertinent when applying this method to cancer etiology and prognosis, including reverse causation arising from disease latency and selection bias in studies of cancer progression. These issues must be carefully considered to ensure appropriate design, analysis, and interpretation of such studies. In this review, we provide an overview of the key principles and assumptions of MR, focusing on applications of this method to the study of cancer etiology and prognosis. We summarize recent studies in the cancer literature that have adopted a MR framework to highlight strengths of this approach compared with conventional epidemiological studies. Finally, limitations of MR and recent methodologic developments to address them are discussed, along with the translational opportunities they present to inform public health and clinical interventions in cancer. Cancer Epidemiol Biomarkers Prev; 27(9); 995-1010. ©2018 AACR.


Assuntos
Análise da Randomização Mendeliana/métodos , Neoplasias/epidemiologia , Neoplasias/genética , Causalidade , Estudos Epidemiológicos , Humanos , Prognóstico
12.
Elife ; 72018 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-29846171

RESUMO

Results from genome-wide association studies (GWAS) can be used to infer causal relationships between phenotypes, using a strategy known as 2-sample Mendelian randomization (2SMR) and bypassing the need for individual-level data. However, 2SMR methods are evolving rapidly and GWAS results are often insufficiently curated, undermining efficient implementation of the approach. We therefore developed MR-Base (http://www.mrbase.org): a platform that integrates a curated database of complete GWAS results (no restrictions according to statistical significance) with an application programming interface, web app and R packages that automate 2SMR. The software includes several sensitivity analyses for assessing the impact of horizontal pleiotropy and other violations of assumptions. The database currently comprises 11 billion single nucleotide polymorphism-trait associations from 1673 GWAS and is updated on a regular basis. Integrating data with software ensures more rigorous application of hypothesis-driven analyses and allows millions of potential causal relationships to be efficiently evaluated in phenome-wide association studies.


Assuntos
Análise da Randomização Mendeliana , LDL-Colesterol/metabolismo , Doença das Coronárias/etiologia , Bases de Dados Genéticas , Pleiotropia Genética , Estudo de Associação Genômica Ampla , Humanos , Modelos Genéticos , Fenótipo , Polimorfismo de Nucleotídeo Único/genética
13.
J Natl Cancer Inst ; 110(9): 1035-1038, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-29788239

RESUMO

In the Selenium and Vitamin E Cancer Prevention Trial (SELECT), selenium supplementation (causing a median 114 µg/L increase in circulating selenium) did not lower overall prostate cancer risk, but increased risk of high-grade prostate cancer and type 2 diabetes. Mendelian randomization analysis uses genetic variants to proxy modifiable risk factors and can strengthen causal inference in observational studies. We constructed a genetic instrument comprising 11 single nucleotide polymorphisms robustly (P < 5 × 10-8) associated with circulating selenium in genome-wide association studies. In a Mendelian randomization analysis of 72 729 men in the PRACTICAL Consortium (44 825 case subjects, 27 904 control subjects), 114 µg/L higher genetically elevated circulating selenium was not associated with prostate cancer (odds ratio [OR] = 1.01, 95% confidence interval [CI] = 0.89 to 1.13). In concordance with findings from SELECT, selenium was weakly associated with advanced (including high-grade) prostate cancer (OR = 1.21, 95% CI = 0.98 to 1.49) and type 2 diabetes (OR = 1.18, 95% CI = 0.97 to 1.43; in a type 2 diabetes genome-wide association study meta-analysis with up to 49 266 case subjects and 249 906 control subjects). Our Mendelian randomization analyses do not support a role for selenium supplementation in prostate cancer prevention and suggest that supplementation could have adverse effects on risks of advanced prostate cancer and type 2 diabetes.


Assuntos
Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/etiologia , Selênio/efeitos adversos , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/etiologia , Predisposição Genética para Doença , Humanos , Masculino , Análise da Randomização Mendeliana , Razão de Chances , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/patologia , Medição de Risco , Fatores de Risco , Selênio/sangue
14.
Sao Paulo Med J ; 135(3): 266-269, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28746662

RESUMO

CONTEXT AND OBJECTIVE:: It has been reported that earlier age at first childbirth may increase the risk of adult-onset diabetes among postmenopausal women, a novel finding with important public health implications. To date, however, no known studies have attempted to replicate this finding. We aimed to test the hypothesis that age at first childbirth is associated with the risk of adult-onset diabetes among postmenopausal women. DESIGN AND SETTING:: Cross-sectional analysis using baseline data from 2919 middle-aged and elderly postmenopausal women in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). METHODS:: Age at first childbirth was determined from self-reporting and newly diagnosed diabetes through a 2-hour 75-g oral glucose tolerance test and/or glycated hemoglobin. Logistic regression was performed to examine associations between age at first childbirth and newly diagnosed diabetes among postmenopausal women. RESULTS:: We did not find any association between age at first childbirth and diabetes, either when minimally adjusted for age, race and study center (odds ratio, OR [95% confidence interval, CI]: ≤ 19 years: 1.15 [0.82-1.59], 20-24 years: 0.90 [0.66-1.23] and ≥ 30 years: 0.86 [0.63-1.17] versus 25-29 years; P = 0.36) or when fully adjusted for childhood and adult factors (OR [95% CI]: ≤ 19 years: 0.95 [0.67-1.34], 20-24 years: 0.78 [0.56-1.07] and ≥ 30 years: 0.84 [0.61-1.16] versus 25-29 years; P = 0.40). CONCLUSION:: Our current analysis does not support the existence of an association between age at first childbirth and adult-onset diabetes among postmenopausal women, which had been reported previously.


Assuntos
Diabetes Mellitus/fisiopatologia , Idade Materna , Pós-Menopausa/fisiologia , Adulto , Idade de Início , Idoso , Glicemia/análise , Brasil , Estudos Transversais , Diabetes Mellitus/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Prospectivos , Fatores de Risco , Estatísticas não Paramétricas , Fatores de Tempo
15.
Säo Paulo med. j ; 135(3): 266-269, May-June 2017. tab
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1043427

RESUMO

ABSTRACT CONTEXT AND OBJECTIVE: It has been reported that earlier age at first childbirth may increase the risk of adult-onset diabetes among postmenopausal women, a novel finding with important public health implications. To date, however, no known studies have attempted to replicate this finding. We aimed to test the hypothesis that age at first childbirth is associated with the risk of adult-onset diabetes among postmenopausal women. DESIGN AND SETTING: Cross-sectional analysis using baseline data from 2919 middle-aged and elderly postmenopausal women in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). METHODS: Age at first childbirth was determined from self-reporting and newly diagnosed diabetes through a 2-hour 75-g oral glucose tolerance test and/or glycated hemoglobin. Logistic regression was performed to examine associations between age at first childbirth and newly diagnosed diabetes among postmenopausal women. RESULTS: We did not find any association between age at first childbirth and diabetes, either when minimally adjusted for age, race and study center (odds ratio, OR [95% confidence interval, CI]: ≤ 19 years: 1.15 [0.82-1.59], 20-24 years: 0.90 [0.66-1.23] and ≥ 30 years: 0.86 [0.63-1.17] versus 25-29 years; P = 0.36) or when fully adjusted for childhood and adult factors (OR [95% CI]: ≤ 19 years: 0.95 [0.67-1.34], 20-24 years: 0.78 [0.56-1.07] and ≥ 30 years: 0.84 [0.61-1.16] versus 25-29 years; P = 0.40). CONCLUSION: Our current analysis does not support the existence of an association between age at first childbirth and adult-onset diabetes among postmenopausal women, which had been reported previously.


RESUMO CONTEXTO E OBJETIVO: Foi relatado que idade mais precoce no primeiro parto pode aumentar o risco do diabetes de início adulto entre mulheres na menopausa, um novo achado com implicações de saúde pública importantes. Até então, no entanto, nenhum estudo conhecido tentou replicar esta descoberta. Objetivou-se testar a hipótese de que a idade no primeiro parto está associada ao risco de diabetes de início na vida adulta em mulheres pós-menopáusicas. DESENHO DE ESTUDO E LOCAL: Análise transversal utilizando dados de base de 2.919 mulheres pós-menopáusicas de meia-idade e idosas no Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil). MÉTODOS: A idade no primeiro parto foi determinada por autorrelato e diabetes recentemente diagnosticado por um teste de tolerância à glicose oral de 2 horas com 75 g e/ou hemoglobina glicada. A regressão logística foi realizada para examinar associações entre idade no primeiro parto e diabetes recentemente diagnosticada entre mulheres pós-menopáusicas. RESULTADOS: Não encontramos associação entre idade no primeiro parto e diabetes, quando ajustados minimamente para idade, raça e centro de estudo (odds ratio, OR [intervalo de confiança, IC 95%]: ≤ 19 anos: 1,15 [0,82-1,59], 20-24 anos: 0,90 [0,66-1,23], ≥ 30 anos: 0,86 [0,63-1,17] versus 25-29 anos, P = 0,36) ou quando totalmente ajustados para fatores infantis e adultos (OR [IC 95%]: ≤ 19 anos: 0,95 [0,67-1,34], 20-24 anos: 0,78 [0,56-1,07], ≥ 30 anos: 0,84 [0,61-1,16] versus 25-29 anos, P = 0,40). CONCLUSÃO: Nossa análise atual não apoia uma associação entre a idade no primeiro parto e o diabetes de início na vida adulta entre mulheres pós-menopáusicas, como relatado anteriormente.

16.
Sci Rep ; 6: 37032, 2016 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-27845438

RESUMO

Emerging evidence suggests sex differences in the early origins of adult metabolic disease, but this has been little investigated in developing countries. We investigated sex-specific associations between low birth weight (LBW; <2.5 kg) and adult-onset diabetes in 12,525 participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Diabetes was defined by self-reported information and laboratory measurements. In confounder-adjusted analyses, LBW (vs. 2.5-4 kg) was associated with higher prevalence of diabetes in women (Prevalence Ratio (PR) 1.54, 95% CI: 1.32-1.79), not in men (PR 1.06, 95% CI: 0.91-1.25; Pheterogeneity = 0.003). The association was stronger among participants with maternal diabetes (PR 1.60, 95% CI: 1.35-1.91), than those without (PR 1.15, 95% CI: 0.99-1.32; Pheterogeneity = 0.03). When jointly stratified by sex and maternal diabetes, the association was observed for women with (PR 1.77, 95% CI: 1.37-2.29) and without (PR 1.45, 95% CI: 1.20-1.75) maternal diabetes. In contrast, in men, LBW was associated with diabetes in participants with maternal diabetes (PR 1.45, 95% CI: 1.15-1.83), but not in those without (PR 0.92, 95% CI: 0.74-1.14). These sex-specific findings extended to continuous measures of glucose homeostasis. LBW was associated with higher diabetes prevalence in Brazilian women, and in men with maternal diabetes, suggesting sex-specific intrauterine effects on adult metabolic health.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus/sangue , Diabetes Mellitus/epidemiologia , Homeostase , Recém-Nascido de Baixo Peso/sangue , Caracteres Sexuais , Adulto , Idade de Início , Idoso , Brasil/epidemiologia , Feminino , Humanos , Recém-Nascido , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prevalência
18.
Sci Rep ; 6: 17714, 2016 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-26813008

RESUMO

An emerging body of evidence has implicated plasminogen activator inhibitor-1 (PAI-1) in the development of type 2 diabetes (T2D), though findings have not always been consistent. We systematically reviewed epidemiological studies examining the association of PAI-1 with T2D. EMBASE, PubMed, Web of Science, and the Cochrane Library were searched to identify studies for inclusion. Fifty-two studies (44 cross-sectional with 47 unique analytical comparisons and 8 prospective) were included. In pooled random-effects analyses of prospective studies, a comparison of the top third vs. bottom third of baseline PAI-1 values generated a RR of T2D of 1.67 (95% CI 1.28-2.18) with moderate heterogeneity (I(2) = 38%). Additionally, of 47 cross-sectional comparisons, 34(72%) reported significantly elevated PAI-1 among diabetes cases versus controls, 2(4%) reported significantly elevated PAI-1 among controls, and 11(24%) reported null effects. Results from pooled analyses of prospective studies did not differ substantially by study design, length of follow-up, adjustment for various putative confounding factors, or study quality, and were robust to sensitivity analyses. Findings from this systematic review of the available epidemiological literature support a link between PAI-1 and T2D, independent of established diabetes risk factors. Given the moderate size of the association and heterogeneity across studies, future prospective studies are warranted.


Assuntos
Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/metabolismo , Inibidor 1 de Ativador de Plasminogênio/metabolismo , Estudos Transversais , Diabetes Mellitus Tipo 2/epidemiologia , Humanos , Razão de Chances , Estudos Prospectivos
19.
J Nutr ; 146(2): 290-7, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26661840

RESUMO

BACKGROUND: Recent animal studies suggest that artificially sweetened beverage (ASB) consumption increases diabetes risk. OBJECTIVE: We examined the relation of ASB intake with newly diagnosed diabetes and measures of glucose homeostasis in a large Brazilian cohort of adults. METHODS: We used cross-sectional data from 12,884 participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). ASB use was assessed by questionnaire and newly diagnosed diabetes by a 2-h 75-g oral glucose tolerance test and/or glycated hemoglobin. Logistic and linear regression analyses were performed to examine the association of ASB consumption with diabetes and continuous measures of glucose homeostasis, respectively. RESULTS: Although ASB consumption was not associated with diabetes in logistic regression analyses after adjustment for body mass index (BMI; in kg/m(2)) overall, the association varied across BMI categories (P-interaction = 0.04). Among those with a BMI <25, we found a 15% increase in the adjusted odds of diabetes for each increase in the frequency of ASB consumption per day (P = 0.001); compared with nonusers, ASB users presented monotonic increases in the adjusted ORs (95% CIs) of diabetes with increased frequency of consumption: 1.03 (0.60, 1.77), 1.43 (0.93, 2.20), 1.62 (1.08, 2.44), and 2.51 (1.40, 4.50) for infrequent, 1-2, 3-4, and >4 times/d, respectively. In linear regression analyses, among normal-weight individuals, greater ASB consumption was also associated with increased fasting glucose concentrations (P = 0.01) and poorer ß-cell function (P = 0.009). No such associations were seen for those with BMI ≥25. In fact, in overweight or obese participants, greater ASB consumption was significantly associated with improved indexes of insulin resistance and 2-h postload glucose. CONCLUSIONS: Normal-weight, but not excess-weight, individuals with greater ASB consumption presented diabetes more frequently and had higher fasting glucose and poorer ß-cell function.


Assuntos
Bebidas/efeitos adversos , Glicemia/metabolismo , Índice de Massa Corporal , Diabetes Mellitus Tipo 2/etiologia , Comportamento Alimentar , Obesidade/complicações , Edulcorantes/efeitos adversos , Adulto , Idoso , Brasil , Estudos Transversais , Diabetes Mellitus Tipo 2/sangue , Dieta , Feminino , Teste de Tolerância a Glucose , Hemoglobina A Glicada/metabolismo , Humanos , Resistência à Insulina , Modelos Logísticos , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Sobrepeso , Valores de Referência , Ganho de Peso
20.
Nutr Rev ; 73(4): 236-46, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26024546

RESUMO

CONTEXT: Tea has been proposed as an antihypertensive agent for individuals with elevated blood pressure, yet the evidence for this has not been systematically reviewed to date. OBJECTIVE: The aim of this review was to evaluate the effects of tea on blood pressure in individuals within the prehypertensive and hypertensive blood pressure ranges. DATA SOURCES: The CENTRAL, PubMed, Embase, and Web of Science databases were searched for all relevant studies published from 1946 to September 27, 2013. STUDY SELECTION: The selection criteria included randomized controlled trials of adults whose blood pressure was within hypertensive or prehypertensive ranges and in which the applied intervention was green or black tea; controls consisting of placebo, minimal tea intervention, or no intervention; and a follow-up period of at least 2 months. DATA EXTRACTION: Two reviewers independently extracted data on participants, interventions, comparators, outcomes, and study design. Mean differences (MDs) and 95% confidence intervals (95%CIs) were pooled to generate summary effect estimates. RESULTS: Meta-analyses of 10 trials (834 participants) showed statistically significant reductions in systolic blood pressure (MD -2.36 mmHg, 95%CI -4.20 to -0.52) and diastolic blood pressure (MD -1.77 mmHg, 95%CI -3.03 to -0.52) with tea consumption. CONCLUSIONS: Consumption of green or black tea can reduce blood pressure in individuals within prehypertensive and hypertensive ranges, although further investigation with studies of longer duration and stronger methodological quality is warranted to confirm these findings.


Assuntos
Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Camellia sinensis , Hipertensão/prevenção & controle , Fitoterapia , Extratos Vegetais/uso terapêutico , Prevenção Secundária , Anti-Hipertensivos/farmacologia , Humanos , Extratos Vegetais/farmacologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Chá
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...