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2.
PLoS One ; 16(1): e0236904, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33465101

RESUMO

BACKGROUND: Observational studies have reported either null or weak protective associations for coffee consumption and risk of breast cancer. METHODS: We conducted a two-sample Mendelian randomization (MR) analysis to evaluate the relationship between coffee consumption and breast cancer risk using 33 single-nucleotide polymorphisms (SNPs) associated with coffee consumption from a genome-wide association (GWA) study on 212,119 female UK Biobank participants of White British ancestry. Risk estimates for breast cancer were retrieved from publicly available GWA summary statistics from the Breast Cancer Association Consortium (BCAC) on 122,977 cases (of which 69,501 were estrogen receptor (ER)-positive, 21,468 ER-negative) and 105,974 controls of European ancestry. Random-effects inverse variance weighted (IVW) MR analyses were performed along with several sensitivity analyses to assess the impact of potential MR assumption violations. RESULTS: One cup per day increase in genetically predicted coffee consumption in women was not associated with risk of total (IVW random-effects; odds ratio (OR): 0.91, 95% confidence intervals (CI): 0.80-1.02, P: 0.12, P for instrument heterogeneity: 7.17e-13), ER-positive (OR = 0.90, 95% CI: 0.79-1.02, P: 0.09) and ER-negative breast cancer (OR: 0.88, 95% CI: 0.75-1.03, P: 0.12). Null associations were also found in the sensitivity analyses using MR-Egger (total breast cancer; OR: 1.00, 95% CI: 0.80-1.25), weighted median (OR: 0.97, 95% CI: 0.89-1.05) and weighted mode (OR: 1.00, CI: 0.93-1.07). CONCLUSIONS: The results of this large MR study do not support an association of genetically predicted coffee consumption on breast cancer risk, but we cannot rule out existence of a weak association.

3.
Int J Cancer ; 2020 Aug 05.
Artigo em Inglês | MEDLINE | ID: mdl-32761610

RESUMO

The epidemiological literature reports inconsistent associations between consumption or circulating concentrations of micronutrients and breast cancer risk. We investigated associations between genetically predicted concentrations of 11 micronutrients (beta-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B6 , vitamin B12 and zinc) and breast cancer risk using Mendelian randomization (MR). A two-sample MR study was conducted using 122 977 women with breast cancer and 105 974 controls from the Breast Cancer Association Consortium. MR analyses were conducted using the inverse variance-weighted approach, and sensitivity analyses were conducted to assess the impact of potential violations of MR assumptions. A value of 1 SD (SD: 0.08 mmol/L) higher genetically predicted concentration of magnesium was associated with a 17% (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.10-1.25, P value = 9.1 × 10-7 ) and 20% (OR: 1.20, 95% CI: 1.08-1.34, P value = 3.2 × 10-6 ) higher risk of overall and ER+ve breast cancer, respectively. An inverse association was observed for a SD (0.5 mg/dL) higher genetically predicted phosphorus concentration and ER-ve breast cancer (OR: 0.84, 95% CI: 0.72-0.98, P value = .03). There was little evidence that any other nutrient was associated with breast cancer. The results for magnesium were robust under all sensitivity analyses and survived correction for multiple comparisons. Higher circulating concentrations of magnesium and potentially phosphorus may affect breast cancer risk. Further work is required to replicate these findings and investigate underlying mechanisms.

4.
Br J Radiol ; 93(1114): 20200363, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-32730088

RESUMO

OBJECTIVES: This study aims to explore the reading performances of radiologists in detecting cancers on mammograms using Tabar Breast Imaging Reporting and Data System (BIRADS) classification and identify factors related to breast imaging reporting scores. METHODS: 117 readings of five different mammogram test sets with each set containing 20 cancer and 40 normal cases were performed by Australian radiologists. Each radiologist evaluated the mammograms using the BIRADS lexicon with category 1 - negative, category 2 - benign findings, category 3 - equivocal findings (Recall), category 4 - suspicious findings (Recall), and category 5 - highly suggestive of malignant findings (Recall). Performance metrics (true positive, false positive, true negative, and false negative) were calculated for each radiologist and the distribution of reporting categories was analyzed in reader-based and case-based groups. The association of reader characteristics and case features among categories was examined using Mann-Whitney U and Kruskal-Wallis tests. RESULTS: 38% of cancer-containing mammograms were reported with category 3 which decreased to 32.3% with category 4 and 16.2% with category 5 while 16.6 and 10.3% of cancer cases were marked with categories 1 and 2. Female readers had less false-negative rates when using categories 1 and 2 for cancer cases than male readers (p < 0.01). A similar pattern as gender category was also found in Breast Screen readers and readers completed breast reading fellowships compared with non-Breast Screen and non-fellowship readers (p < 0.05). Radiologists with low number of cases read per week were more likely to record the cancer cases with category 4 while the ones with high number of cases were with category 3 (p < 0.01). Discrete mass and asymmetric density were the two types of abnormalities reported mostly as equivocal findings with category 3 (47-50%; p = 0.005) while spiculated mass or stellate lesions were mostly selected as highly suggestive of malignancy with category 5 (26%, p = 0.001). CONCLUSIONS: Most radiologists used category 3 when reporting cancer mammograms. Gender, working for BreastScreen, fellowship completion, and number of cases read per week were factors associated with scoring selection. Radiologists reported higher Tabar BIRADS category for specific types of abnormalities on mammograms than others. ADVANCES IN KNOWLEDGE: The study identified factors associated with the decision of radiologists in assigning a BIRADS Tabar score for mammograms with abnormality. These findings will be useful for individual training programs to improve the confidence of radiologists in recognizing abnormal lesions on screening mammograms.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Competência Clínica , Radiologistas , Austrália , Tomada de Decisões , Diagnóstico Diferencial , Feminino , Humanos , Mamografia , Variações Dependentes do Observador
5.
Genet Epidemiol ; 44(8): 924-933, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32710482

RESUMO

It has been hypothesised that nonsyndromic cleft lip/palate (nsCL/P) and cancer may share aetiological risk factors. Population studies have found inconsistent evidence for increased incidence of cancer in nsCL/P cases, but several genes (e.g., CDH1, AXIN2) have been implicated in the aetiologies of both phenotypes. We aimed to evaluate shared genetic aetiology between nsCL/P and oral cavity/oropharyngeal cancers (OC/OPC), which affect similar anatomical regions. Using a primary sample of 5,048 OC/OPC cases and 5,450 controls of European ancestry and a replication sample of 750 cases and 336,319 controls from UK Biobank, we estimate genetic overlap using nsCL/P polygenic risk scores (PRS) with Mendelian randomization analyses performed to evaluate potential causal mechanisms. In the primary sample, we found strong evidence for an association between a nsCL/P PRS and increased odds of OC/OPC (per standard deviation increase in score, odds ratio [OR]: 1.09; 95% confidence interval [CI]: 1.04, 1.13; p = .000053). Although confidence intervals overlapped with the primary estimate, we did not find confirmatory evidence of an association between the PRS and OC/OPC in UK Biobank (OR 1.02; 95% CI: 0.95, 1.10; p = .55). Mendelian randomization analyses provided evidence that major nsCL/P risk variants are unlikely to influence OC/OPC. Our findings suggest possible shared genetic influences on nsCL/P and OC/OPC.

6.
Am J Med Genet B Neuropsychiatr Genet ; 183(6): 360-369, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32578352

RESUMO

Schizophrenia shows a genetic correlation with both anxiety disorder and neuroticism, a trait strongly associated with anxiety. However, genetic correlations do not discern causality from genetic confounding. We therefore aimed to investigate whether anxiety-related phenotypes lie on the causal pathway to schizophrenia using Mendelian randomization (MR). Four MR methods, each with different assumptions regarding instrument validity, were used to investigate casual associations of anxiety and neuroticism related phenotypes on schizophrenia, and vice versa: inverse variance weighted (IVW), weighted median, weighted mode, and, when appropriate, MR Egger regression. MR provided evidence of a causal effect of neuroticism on schizophrenia (IVW odds ratio [OR]: 1.33, 95% confidence interval [CI]: 1.12-1.59), but only weak evidence of a causal effect of anxiety on schizophrenia (IVW OR: 1.10, 95% CI: 1.01-1.19). There was also evidence of a causal association from schizophrenia liability to anxiety disorder (IVW OR: 1.28, 95% CI: 1.18-1.39) and worry (IVW beta: 0.05, 95% CI: 0.03-0.07), but effect estimates from schizophrenia to neuroticism were inconsistent in the main analysis. The evidence of neuroticism increasing schizophrenia risk provided by our results supports future efforts to evaluate neuroticism- or anxiety-based therapies to prevent onset of psychotic disorders.

7.
Int J Epidemiol ; 49(4): 1282-1293, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32373937

RESUMO

BACKGROUND: Previous studies have found that children born with a non-syndromic orofacial cleft have lower-than-average educational attainment. Differences could be due to a genetic predisposition to low intelligence and academic performance, factors arising due to the cleft phenotype (such as social stigmatization, impaired speech/language development) or confounding by the prenatal environment. A clearer understanding of this mechanism will inform interventions to improve educational attainment in individuals born with a cleft, which could substantially improve their quality of life. We assessed evidence for the hypothesis that common variant genetic liability to non-syndromic cleft lip with or without cleft palate (nsCL/P) influences educational attainment. METHODS: We performed a genome-wide association study (GWAS) meta-analysis of nsCL/P with 1692 nsCL/P cases and 4259 parental and unrelated controls. Using GWAS summary statistics, we performed Linkage Disequilibrium (LD)-score regression to estimate the genetic correlation between nsCL/P, educational attainment (GWAS n = 766 345) and intelligence (GWAS n = 257 828). We used two-sample Mendelian randomization to evaluate the causal effects of genetic liability to nsCL/P on educational attainment and intelligence. RESULTS: There was limited evidence for shared genetic aetiology or causal relationships between nsCL/P and educational attainment [genetic correlation (rg) -0.05, 95% confidence interval (CI) -0.12 to 0.01, P 0.13; MR estimate (ßMR) -0.002, 95% CI -0.009 to 0.006, P 0.679) or intelligence (rg -0.04, 95% CI -0.13 to 0.04, P 0.34; ßMR -0.009, 95% CI -0.02 to 0.002, P 0.11). CONCLUSIONS: Common variants are unlikely to predispose individuals born with nsCL/P to low educational attainment or intelligence. This is an important first step towards understanding the aetiology of low educational attainment in this group.

8.
Nat Commun ; 11(1): 597, 2020 01 30.
Artigo em Inglês | MEDLINE | ID: mdl-32001714

RESUMO

Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER+ve) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.


Assuntos
Neoplasias da Mama/genética , Neoplasias Colorretais/genética , Exercício Físico , Predisposição Genética para Doença , Análise da Randomização Mendeliana , Acelerometria , Feminino , Humanos , Razão de Chances , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco
9.
Cancer Causes Control ; 31(3): 273-282, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32006205

RESUMO

PURPOSE: The relationship of allergic diseases, such as asthma, hay fever, and eczema, with cancer is under debate. Observational studies have reported conflicting findings, but such studies are susceptible to confounding and reverse causation. Understanding the potential role of allergy in carcinogenesis may shed new light on the biological mechanisms underpinning intrinsic immunity and cancer. METHODS: We conducted a Mendelian randomization study, using germline genetic variants as instrumental variables, to determine the causal relevance of allergic disease and on two most common malignancies: breast cancer and prostate cancer. We used the summary statistics from the largest ever genome-wide association studies conducted on allergic disease (ncase = 180,129), asthma (ncase = 14,085), breast (ncase = 122,977), and prostate cancer (ncase = 79,148) and calculated odds ratios (ORs) and 95% confidence intervals (CIs) of cancer for allergic disease. RESULTS: We did not observe any evidence to support a causal association between allergic disease and risk of breast cancer overall [OR 1.00 (95% CI 0.96-1.04), p = 0.95] or by subtype (estrogen receptor (ER)+ [0.99 (0.95-1.04), p = 0.71], ER- [1.05 (0.99-1.10), p = 0.11]). We also did not find any evidence for an association with prostate cancer [1.00 (0.94-1.05), p = 0.93] or advanced subtype [0.97 (0.90-1.05), p = 0.46]. Sensitivity analyses did not reveal directional pleiotropy. CONCLUSION: Our study does not support a causal effect of allergic disease on the risk of breast or prostate cancer. Future studies may be conducted to focus on understanding the causal role of allergic disease in cancer prognosis or drug responses (e.g., immunotherapy).


Assuntos
Asma/complicações , Neoplasias da Mama/imunologia , Neoplasias da Próstata/imunologia , Asma/genética , Neoplasias da Mama/genética , Estudos de Casos e Controles , Suscetibilidade a Doenças , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Razão de Chances , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética
10.
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
11.
Int J Epidemiol ; 2020 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-31993631

RESUMO

BACKGROUND: Systematic reviews of prenatal alcohol exposure effects generally only include conventional observational studies. However, estimates from such studies are prone to confounding and other biases. OBJECTIVES: To systematically review the evidence on the effects of prenatal alcohol exposure from randomized controlled trials (RCTs) and observational designs using alternative analytical approaches to improve causal inference. SEARCH STRATEGY: Medline, Embase, Web of Science, PsychINFO from inception to 21 June 2018. Manual searches of reference lists of retrieved papers. SELECTION CRITERIA: RCTs of interventions to stop/reduce drinking in pregnancy and observational studies using alternative analytical methods (quasi-experimental studies e.g. Mendelian randomization and natural experiments, negative control comparisons) to determine the causal effects of prenatal alcohol exposure on pregnancy and longer-term offspring outcomes in human studies. DATA COLLECTION AND ANALYSIS: One reviewer extracted data and another checked extracted data. Risk of bias was assessed using customized risk of bias tools. A narrative synthesis of findings was carried out and a meta-analysis for one outcome. MAIN RESULTS: Twenty-three studies were included, representing five types of study design, including 1 RCT, 9 Mendelian randomization and 7 natural experiment studies, and reporting on over 30 outcomes. One study design-outcome combination included enough independent results to meta-analyse. Based on evidence from several studies, we found a likely causal detrimental role of prenatal alcohol exposure on cognitive outcomes, and weaker evidence for a role in low birthweight. CONCLUSION: None of the included studies was judged to be at low risk of bias in all domains, results should therefore be interpreted with caution. SYSTEMATIC REVIEW REGISTRATION: This study is registered with PROSPERO, registration number CRD42015015941.

12.
Int J Epidemiol ; 49(2): 587-596, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31802111

RESUMO

BACKGROUND: Prostate cancer is the second most common male cancer worldwide, but there is substantial geographical variation, suggesting a potential role for modifiable risk factors in prostate carcinogenesis. METHODS: We identified previously reported prostate cancer risk factors from the World Cancer Research Fund (WCRF)'s systematic appraisal of the global evidence (2018). We assessed whether each identified risk factor was causally associated with risk of overall (79 148 cases and 61 106 controls) or aggressive (15 167 cases and 58 308 controls) prostate cancer using Mendelian randomization (MR) based on genome-wide association-study summary statistics from the PRACTICAL and GAME-ON/ELLIPSE consortia. We assessed evidence for replication in UK Biobank (7844 prostate-cancer cases and 204 001 controls). RESULTS: WCRF identified 57 potential risk factors, of which 22 could be instrumented for MR analyses using single nucleotide polymorphisms. For overall prostate cancer, we identified evidence compatible with causality for the following risk factors (odds ratio [OR] per standard deviation increase; 95% confidence interval): accelerometer-measured physical activity, OR = 0.49 (0.33-0.72; P = 0.0003); serum iron, OR = 0.92 (0.86-0.98; P = 0.007); body mass index (BMI), OR = 0.90 (0.84-0.97; P = 0.003); and monounsaturated fat, OR = 1.11 (1.02-1.20; P = 0.02). Findings in our replication analyses in UK Biobank were compatible with our main analyses (albeit with wide confidence intervals). In MR analysis, height was positively associated with aggressive-prostate-cancer risk: OR = 1.07 (1.01-1.15; P = 0.03). CONCLUSIONS: The results for physical activity, serum iron, BMI, monounsaturated fat and height are compatible with causality for prostate cancer. The results suggest that interventions aimed at increasing physical activity may reduce prostate-cancer risk, although interventions to change other risk factors may have negative consequences on other diseases.

13.
J Med Radiat Sci ; 66(4): 292-295, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31709775

RESUMO

Artificial intelligence (AI) is heralded as the most disruptive technology to health services in the 21st century. Many commentary articles published in the general public and health domains recognise that medical imaging is at the forefront of these changes due to our large digital data footprint. Radiomics is transforming medical images into mineable high-dimensional data to optimise clinical decision-making; however, some would argue that AI could infiltrate workplaces with very few ethical checks and balances. In this commentary article, we describe how AI is beginning to change medical imaging services and the innovations that are on the horizon. We explore how AI and its various forms, including machine learning, will challenge the way medical imaging is delivered from workflow, image acquisition, image registration to interpretation. Diagnostic radiographers will need to learn to work alongside our 'virtual colleagues', and we argue that there are vital changes to entry and advanced curricula together with national professional capabilities to ensure machine-learning tools are used in the safest and most effective manner for our patients.


Assuntos
Inteligência Artificial , Diagnóstico por Imagem , Processamento de Imagem Assistida por Computador
14.
Nat Commun ; 10(1): 5039, 2019 11 19.
Artigo em Inglês | MEDLINE | ID: mdl-31745073

RESUMO

Alcohol use is correlated within spouse-pairs, but it is difficult to disentangle effects of alcohol consumption on mate-selection from social factors or the shared spousal environment. We hypothesised that genetic variants related to alcohol consumption may, via their effect on alcohol behaviour, influence mate selection. Here, we find strong evidence that an individual's self-reported alcohol consumption and their genotype at rs1229984, a missense variant in ADH1B, are associated with their partner's self-reported alcohol use. Applying Mendelian randomization, we estimate that a unit increase in an individual's weekly alcohol consumption increases partner's alcohol consumption by 0.26 units (95% C.I. 0.15, 0.38; P = 8.20 × 10-6). Furthermore, we find evidence of spousal genotypic concordance for rs1229984, suggesting that spousal concordance for alcohol consumption existed prior to cohabitation. Although the SNP is strongly associated with ancestry, our results suggest some concordance independent of population stratification. Our findings suggest that alcohol behaviour directly influences mate selection.


Assuntos
Álcool Desidrogenase/genética , Consumo de Bebidas Alcoólicas/genética , Alcoolismo/genética , Bancos de Espécimes Biológicos/estatística & dados numéricos , Casamento , Polimorfismo de Nucleotídeo Único , Adulto , Feminino , Genótipo , Humanos , Masculino , Fenótipo , Reprodução/genética , Autorrelato , Reino Unido
15.
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
16.
Int J Epidemiol ; 48(3): 807-816, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31143958

RESUMO

BACKGROUND: There are observational data suggesting an inverse association between circulating concentrations of sex hormone binding globulin (SHBG) and risk of postmenopausal breast cancer. However, causality is uncertain and few studies have investigated this association by tumour receptor status. We aimed to investigate these associations under the causal framework of Mendelian randomization (MR). METHODS: We used summary association estimates extracted from published genome-wide association study (GWAS) meta-analyses for SHBG and breast cancer, to perform two-sample MR analyses. Summary statistics were available for 122 977 overall breast cancer cases, of which 69 501 were estrogen receptor positive (ER+ve) and 21 468 were ER-ve, and 105 974 controls. To control for potential horizontal pleiotropy acting via body mass index (BMI), we performed multivariable inverse-variance weighted (IVW) MR as the main analysis, with the robustness of this approach further tested in sensitivity analyses. RESULTS: The multivariable IVW MR analysis indicated a lower risk of overall (odds ratio [OR]: 0.94; 95% confidence interval [CI]: 0.90, 0.98; P: 0.006) and ER+ve (OR: 0.92; 95% CI: 0.87, 0.97; P: 0.003) breast cancer, and a higher risk of ER-ve disease (OR: 1.09; 95% CI: 1.00, 1.18; P: 0.047) per 25 nmol/L higher SHBG levels. Sensitivity analyses were consistent with the findings of the main analysis. CONCLUSIONS: We corroborated the previous literature evidence coming from observational studies for a potentially causal inverse association between SHBG concentrations and risk of ER+ve breast cancer, but our findings also suggested a potential novel positive association with ER-ve disease that warrants further investigation, given the low prior probability of being true.


Assuntos
Neoplasias da Mama/epidemiologia , Globulina de Ligação a Hormônio Sexual/metabolismo , Índice de Massa Corporal , Neoplasias da Mama/metabolismo , Feminino , Humanos , Análise da Randomização Mendeliana , Razão de Chances , Receptores Estrogênicos/metabolismo , Globulina de Ligação a Hormônio Sexual/genética
17.
Drug Alcohol Depend ; 197: 42-47, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30772781

RESUMO

BACKGROUND: High levels of prenatal alcohol exposure are known to cause an array of adverse outcomes including fetal alcohol syndrome (FAS); however, the effects of low to moderate exposure are less-well characterized. Previous findings suggest that differences in normal-range facial morphology may be a marker for alcohol exposure and related adverse effects. METHODS: In the Avon Longitudinal Study of Parents and Children, we tested for an association between maternal alcohol consumption and six FAS-related facial phenotypes in their offspring, using both self-report questionnaires and the maternal genotype at rs1229984 in ADH1B as measures of maternal alcohol consumption. RESULTS: In both self-reported alcohol consumption (N = 4233) and rs1229984 genotype (N = 3139) analyses, we found no strong statistical evidence for an association between maternal alcohol consumption and facial phenotypes tested. The directions of effect estimates were compatible with the known effects of heavy alcohol exposure, but confidence intervals were largely centered around zero. CONCLUSIONS: There is no strong evidence, in a sample representative of the general population, for an effect of prenatal alcohol exposure on normal-range variation in facial morphology.


Assuntos
Face/anormalidades , Transtornos do Espectro Alcoólico Fetal/etiologia , Exposição Materna/efeitos adversos , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Adulto , Álcool Desidrogenase/análise , Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/genética , Biomarcadores/análise , Criança , Face/patologia , Feminino , Transtornos do Espectro Alcoólico Fetal/patologia , Genótipo , Humanos , Estudos Longitudinais , Masculino , Fenótipo , Gravidez , Complicações na Gravidez/genética , Complicações na Gravidez/psicologia , Reino Unido
18.
Syst Rev ; 8(1): 52, 2019 02 12.
Artigo em Inglês | MEDLINE | ID: mdl-30755270

RESUMO

BACKGROUND: Evidence from studies on prostate cancer progression have identified vitamin D to be a potentially important nutrient. However, the World Cancer Research Fund and American Institute for Cancer Research have reported the quality of this evidence to be limited and warrant further investigation. We plan to use the recently developed WCRF International/University of Bristol mechanistic systematic review framework to determine whether the observed association between vitamin D and prostate cancer exists through a plausible biological pathway. METHODS: This protocol sets out how we will perform a systematic review of the literature in human and animal studies. We will search the electronic databases MEDLINE, EMBASE, PubMed, and BIOSIS Citation Index without restrictions on year of publication or language. We will extract data from observational and experimental studies examining two inter-linked pathways in the relationship between vitamin D and prostate cancer progression: (1) vitamin D and testosterone, and (2) testosterone and prostate cancer progression. We focus on testosterone as its actions form a potentially novel intermediate mechanism that was identified via our online literature mining tools. The outcomes of interest include incidence or prevalence of prostate cancer, measures of prostate cancer progression (including biochemical recurrence, local, or distal metastases), and prostate cancer-specific mortality. We will assess study quality and the level of certainty of the evidence. We will analyse data where possible, using meta-analysis with forest plots or albatross plots; otherwise, a narrative synthesis will be performed. DISCUSSION: To our knowledge, this will be the first systematic synthesis of the evidence underpinning the vitamin D-testosterone-prostate cancer mechanistic pathway. The results of the review may inform future research, intervention trials, and public health messages.


Assuntos
Metanálise como Assunto , Neoplasias da Próstata/metabolismo , Revisões Sistemáticas como Assunto , Testosterona/fisiologia , Vitamina D/fisiologia , Animais , Progressão da Doença , Interações Medicamentosas/fisiologia , Humanos , Masculino , Estudos Observacionais como Assunto
19.
Int J Epidemiol ; 48(5): 1416-1424, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30597039

RESUMO

BACKGROUND: Observational studies have suggested an association between circulating vitamin D concentrations [25(OH)D] and risk of breast and prostate cancer, which was not supported by a recent Mendelian randomization (MR) analysis comprising 15 748 breast and 22 898 prostate-cancer cases. Demonstrating causality has proven challenging and one common limitation of MR studies is insufficient power. METHODS: We aimed to determine whether circulating concentrations of vitamin D are causally associated with the risk of breast and prostate cancer, by using summary-level data from the largest ever genome-wide association studies conducted on vitamin D (N = 73 699), breast cancer (Ncase = 122 977) and prostate cancer (Ncase = 79 148). We constructed a stronger instrument using six common genetic variants (compared with the previous four variants) and applied several two-sample MR methods. RESULTS: We found no evidence to support a causal association between 25(OH)D and risk of breast cancer [OR per 25 nmol/L increase, 1.02 (95% confidence interval: 0.97-1.08), P = 0.47], oestrogen receptor (ER)+ [1.00 (0.94-1.07), P = 0.99] or ER- [1.02 (0.90-1.16), P = 0.75] subsets, prostate cancer [1.00 (0.93-1.07), P = 0.99] or the advanced subtype [1.02 (0.90-1.16), P = 0.72] using the inverse-variance-weighted method. Sensitivity analyses did not reveal any sign of directional pleiotropy. CONCLUSIONS: Despite its almost five-fold augmented sample size and substantially improved statistical power, our MR analysis does not support a causal effect of circulating 25(OH)D concentrations on breast- or prostate-cancer risk. However, we can still not exclude a modest or non-linear effect of vitamin D. Future studies may be designed to understand the effect of vitamin D in subpopulations with a profound deficiency.


Assuntos
Neoplasias da Mama/epidemiologia , Neoplasias da Próstata/epidemiologia , Vitamina D/sangue , Idoso , Neoplasias da Mama/genética , Causalidade , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Análise da Randomização Mendeliana , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Neoplasias da Próstata/genética , Receptores Estrogênicos/biossíntese , Fatores de Risco
20.
Epigenomics ; 11(2): 133-145, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30638414

RESUMO

AIM: To determine if nonsyndromic cleft lip with or without cleft palate (nsCL/P) genetic risk variants influence liability to nsCL/P through gene regulation pathways, such as those involving DNA methylation. MATERIALS & METHODS: nsCL/P genetic summary data and methylation data from four studies were used in conjunction with Mendelian randomization and joint likelihood mapping to investigate potential mediation of nsCL/P genetic variants. RESULTS & CONCLUSION: Evidence was found at VAX1 (10q25.3), LOC146880 (17q23.3) and NTN1 (17p13.1), that liability to nsCL/P and variation in DNA methylation might be driven by the same genetic variant, suggesting that genetic variation at these loci may increase liability to nsCL/P by influencing DNA methylation. Follow-up analyses using different tissues and gene expression data provided further insight into possible biological mechanisms.


Assuntos
Fenda Labial/genética , Fissura Palatina/genética , Metilação de DNA , Variação Genética , Criança , Fenda Labial/patologia , Fissura Palatina/patologia , Epigênese Genética , Feminino , Proteínas de Homeodomínio/genética , Humanos , Masculino , Análise da Randomização Mendeliana , Netrina-1/genética , Fatores de Transcrição/genética
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