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2.
Diabetes Care ; 43(7): 1537-1545, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32345654

RESUMO

OBJECTIVE: Type 2 diabetes develops for many years before diagnosis. We aimed to reveal early metabolic features characterizing liability to adult disease by examining genetic liability to adult type 2 diabetes in relation to metabolomic traits across early life. RESEARCH DESIGN AND METHODS: Up to 4,761 offspring from the Avon Longitudinal Study of Parents and Children were studied. Linear models were used to examine effects of a genetic risk score (162 variants) for adult type 2 diabetes on 229 metabolomic traits (lipoprotein subclass-specific cholesterol and triglycerides, amino acids, glycoprotein acetyls, and others) measured at age 8 years, 16 years, 18 years, and 25 years. Two-sample Mendelian randomization (MR) was also conducted using genome-wide association study data on metabolomic traits in an independent sample of 24,925 adults. RESULTS: At age 8 years, associations were most evident for type 2 diabetes liability (per SD higher) with lower lipids in HDL subtypes (e.g., -0.03 SD [95% CI -0.06, -0.003] for total lipids in very large HDL). At 16 years, associations were stronger with preglycemic traits, including citrate and with glycoprotein acetyls (0.05 SD; 95% CI 0.01, 0.08), and at 18 years, associations were stronger with branched-chain amino acids. At 25 years, associations had strengthened with VLDL lipids and remained consistent with previously altered traits, including HDL lipids. Two-sample MR estimates among adults indicated persistent patterns of effect of disease liability. CONCLUSIONS: Our results support perturbed HDL lipid metabolism as one of the earliest features of type 2 diabetes liability, alongside higher branched-chain amino acid and inflammatory levels. Several features are apparent in childhood as early as age 8 years, decades before the clinical onset of disease.

3.
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
5.
Eur J Cancer Prev ; 28(6): 569-575, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30921005

RESUMO

Whether prostate cancer (PCa) may be preventable by dietary interventions can be assessed in randomized trials using intermediate biomarkers of cancer risk or progression. We investigated whether lycopene or green tea modify circulating insulin-like growth factor (IGF) peptides in men at increased risk of PCa. Participants (aged 50-69 years) in one centre in the UK wide PCa testing and treatment trial (ProtecT) with prostate specific antigen between 2.0 and 2.95 ng/ml or negative biopsies, were randomized to daily lycopene (n = 44 assigned 15 mg capsules/day; 44 assigned a lycopene-rich diet; 45 assigned placebo) and green tea (n = 45 assigned 600 mg/day epigallocatechin gallate; 45 assigned green tea drink; 43 assigned placebo) for 6 months. The interventions significantly elevated the primary outcomes, serum epigallocatechin gallate and lycopene at 6 months of follow-up. We report here an exploratory analysis in which serum IGF-I, IGF-II, IGF binding protein (BP)-2 and IGFBP-3 were measured at baseline and 6 months of postintervention. A total of 133 men were randomized (34% of eligible men approached) and 130 had follow-up IGF peptides (98%). In intention-to-treat analyses, there was only weak evidence that lycopene or green tea influenced some aspects of serum IGF-I, IGF-II, IGFBP-2 or IGFBP-3. In men randomized to lycopene supplements, IGFBP-2 was nonsignificantly (50.9 ng/ml; 95% confidence interval: -51.2-152.9, P = 0.3) higher in comparison to placebo, whereas in men randomized to green tea supplements, IGFBP-3 was nonsignificantly (205.2 ng/ml; 95% confidence interval: -583.3-172.9, P = 0.3) lower than with placebo. In this small, pilot randomized controlled trial, there was little evidence that lycopene or green tea interventions influenced serum levels of IGF-I, IGF-II, IGFBBP-3 and IGFBP-2. However, the effects were imprecisely estimates and some observed trends may justify larger trials.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Fator de Crescimento Insulin-Like II/metabolismo , Fator de Crescimento Insulin-Like I/metabolismo , Licopeno/farmacologia , Neoplasias da Próstata/dietoterapia , Chá/química , Idoso , Suplementos Nutricionais , Seguimentos , Humanos , Licopeno/administração & dosagem , Masculino , Pessoa de Meia-Idade , Projetos Piloto
6.
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
8.
Public Health Nutr ; 19(18): 3369-3377, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27339189

RESUMO

OBJECTIVE: To investigate the prospective associations between dietary patterns in childhood and CVD risk in adolescence. DESIGN: Prospective cohort study. Exposures were dietary patterns at age 7, 10 and 13 years derived by cluster analysis. Outcomes were physiological and biochemical cardiovascular risk markers. SETTING: Avon Longitudinal Study of Parents and Children (ALSPAC), UK. SUBJECTS: Children (n 2311, 44.1 % male) with complete data available. RESULTS: After adjustment for known confounders, we observed an association between being in the 'Processed' and 'Packed lunch' dietary pattern clusters at age 7 and BMI at age 17. Compared with the 'healthy' cluster, the OR (95 % CI) for being in the top 10 % for BMI was 1·60 (1·01, 2·55; P=0·05) for the 'Processed' cluster and 1·96 (1·22, 3·13; P=0·005) for the 'Packed lunch' cluster. However, no association was observed between BMI and dietary patterns at age 10 and 13. Longitudinal analyses showed that being in either the 'Processed' or 'Packed lunch' cluster at age 7 was associated with increased risk of being in the top 10 % for BMI regardless of subsequent cluster membership. No associations between other cardiovascular risk measures and dietary patterns were robust to adjustment for confounders. CONCLUSIONS: We did not find any consistent evidence to support an association between dietary patterns in childhood and cardiovascular risk factors in adolescence, with the exception of BMI and dietary pattern at age 7 only. However, the importance of dietary intake in childhood upon health later in life requires further investigation and we would encourage the adoption of a healthy diet as early in life as possible.


Assuntos
Índice de Massa Corporal , Doenças Cardiovasculares/epidemiologia , Dieta , Adolescente , Criança , Feminino , Humanos , Estudos Longitudinais , Masculino , Estudos Prospectivos , Fatores de Risco , Reino Unido
9.
Cancer Med ; 5(6): 1125-36, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26992435

RESUMO

Genetic risk scores were used as unconfounded instruments for specific lipid traits (Mendelian randomization) to assess whether circulating lipids causally influence prostate cancer risk. Data from 22,249 prostate cancer cases and 22,133 controls from 22 studies within the international PRACTICAL consortium were analyzed. Allele scores based on single nucleotide polymorphisms (SNPs) previously reported to be uniquely associated with each of low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels, were first validated in an independent dataset, and then entered into logistic regression models to estimate the presence (and direction) of any causal effect of each lipid trait on prostate cancer risk. There was weak evidence for an association between the LDL genetic score and cancer grade: the odds ratio (OR) per genetically instrumented standard deviation (SD) in LDL, comparing high- (≥7 Gleason score) versus low-grade (<7 Gleason score) cancers was 1.50 (95% CI: 0.92, 2.46; P = 0.11). A genetically instrumented SD increase in TGs was weakly associated with stage: the OR for advanced versus localized cancer per unit increase in genetic risk score was 1.68 (95% CI: 0.95, 3.00; P = 0.08). The rs12916-T variant in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) was inversely associated with prostate cancer (OR: 0.97; 95% CI: 0.94, 1.00; P = 0.03). In conclusion, circulating lipids, instrumented by our genetic risk scores, did not appear to alter prostate cancer risk. We found weak evidence that higher LDL and TG levels increase aggressive prostate cancer risk, and that a variant in HMGCR (that mimics the LDL lowering effect of statin drugs) reduces risk. However, inferences are limited by sample size and evidence of pleiotropy.


Assuntos
Lipídeos/sangue , Análise da Randomização Mendeliana , Neoplasias da Próstata/sangue , Neoplasias da Próstata/genética , Estudos de Casos e Controles , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Masculino , Metanálise como Assunto , Gradação de Tumores , Estadiamento de Neoplasias , Razão de Chances , Polimorfismo de Nucleotídeo Único , Vigilância da População , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/patologia , Característica Quantitativa Herdável
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