Publications
363 results found
Breeur M, Ferrari P, Dossus L, et al., 2022, Pan-cancer analysis of pre-diagnostic blood metabolite concentrations in the European Prospective Investigation into Cancer and Nutrition, Publisher: Cold Spring Harbor Laboratory
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Epidemiological studies of associations between metabolites and cancer risk have typically focused on specific cancer types separately. Here, we designed a multivariate pan-cancer analysis to identify metabolites potentially associated with multiple cancer types, while also allowing the investigation of cancer type-specific associations.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>We analyzed targeted metabolomics data available for 5,828 matched case-control pairs from cancer-specific case-control studies on breast, colorectal, endometrial, gallbladder, kidney, localized and advanced prostate cancer, and hepatocellular carcinoma nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. From pre-diagnostic blood levels of an initial set of 117 metabolites, 33 cluster representatives of strongly correlated metabolites, and 17 single metabolites were derived by hierarchical clustering. The mutually adjusted associations of the resulting 50 metabolites with cancer risk were examined in penalized conditional logistic regression models adjusted for body mass index, using the data shared lasso penalty.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Out of the 50 studied metabolites, <jats:italic>(i)</jats:italic> six were inversely associated with risk of most cancer types: glutamine, butyrylcarnitine, lysophosphatidylcholine a C18:2 and three clusters of phosphatidylcholines (PCs); <jats:italic>(ii)</jats:italic> three were positively associated with most cancer types: proline, decanoylcarnitine and one cluster of PCs; and <jats:italic>(iii)</jats:italic> 10 were specifically associated with particular cancer types, including histidine that was inversely associate
Christakoudi S, Riboli E, Evangelou E, et al., 2022, Associations of body shape phenotypes with sex steroids and their binding proteins in the UK Biobank cohort, Scientific Reports, Vol: 12, ISSN: 2045-2322
Associations of sex steroids and their binding proteins with body shape are unclear, because waist and hip circumference are correlated strongly with body size. We defined body shape using “a body shape index” (ABSI) and hip index (HI), which are independent of weight and height by design, and examined associations in multivariable generalised linear models for the UK Biobank cohort (179,902 men, 207,444 women). Total testosterone was associated inversely with ABSI, especially in men. Free testosterone was lowest for large-ABSI-large-HI (“wide”) and highest for small-ABSI-small-HI (“slim”) in men, but lowest for small-ABSI-large-HI (“pear”) and highest for large-ABSI-small-HI (“apple”) in women. Oestradiol was associated inversely with ABSI in obese pre-menopausal women but positively with HI in obese men and post-menopausal women not using hormone replacement therapy. Sex-hormone binding globulin (SHBG) was associated inversely with ABSI but positively with HI and was lowest for “apple” and highest for “pear” phenotype in both sexes. Albumin was associated inversely with HI in women, but matched the pattern of free testosterone in obese men (lowest for “wide”, highest for “slim” phenotype). In conclusion, sex steroids and their binding proteins are associated with body shape, including hip as well as waist size, independent of body size.
Watts EL, Perez-Cornago A, Fensom GK, et al., 2022, Circulating insulin-like growth factors and risks of overall, aggressive and early-onset prostate cancer: a collaborative analysis of 20 prospective studies and Mendelian randomization analysis, INTERNATIONAL JOURNAL OF EPIDEMIOLOGY, ISSN: 0300-5771
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Watts EL, Perez-Cornago A, Fensom GK, et al., 2022, Circulating free testosterone and risk of aggressive prostate cancer: Prospective and Mendelian randomisation analyses in international consortia, International Journal of Cancer, Vol: 151, Pages: 1033-1046, ISSN: 0020-7136
Previous studies had limited power to assess the associations of testosterone with aggressive disease as a primary endpoint. Further, the association of genetically predicted testosterone with aggressive disease is not known. We investigated the associations of calculated free and measured total testosterone and sex hormone-binding globulin (SHBG) with aggressive, overall and early-onset prostate cancer. In blood-based analyses, odds ratios (OR) and 95% confidence intervals (CI) for prostate cancer were estimated using conditional logistic regression from prospective analysis of biomarker concentrations in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group (up to 25 studies, 14 944 cases and 36 752 controls, including 1870 aggressive prostate cancers). In Mendelian randomisation (MR) analyses, using instruments identified using UK Biobank (up to 194 453 men) and outcome data from PRACTICAL (up to 79 148 cases and 61 106 controls, including 15 167 aggressive cancers), ORs were estimated using the inverse-variance weighted method. Free testosterone was associated with aggressive disease in MR analyses (OR per 1 SD = 1.23, 95% CI = 1.08-1.40). In blood-based analyses there was no association with aggressive disease overall, but there was heterogeneity by age at blood collection (OR for men aged <60 years 1.14, CI = 1.02-1.28; Phet = .0003: inverse association for older ages). Associations for free testosterone were positive for overall prostate cancer (MR: 1.20, 1.08-1.34; blood-based: 1.03, 1.01-1.05) and early-onset prostate cancer (MR: 1.37, 1.09-1.73; blood-based: 1.08, 0.98-1.19). SHBG and total testosterone were inversely associated with overall prostate cancer in blood-based analyses, with null associations in MR analysis. Our results support free testosterone, rather than total testosterone, in the development of prostate cancer, including aggressive subgroups.
Whelan E, Kalliala I, Semertzidou A, et al., 2022, Risk Factors for Ovarian Cancer: An Umbrella Review of the Literature, Cancers, Vol: 14, Pages: 2708-2708
<jats:p>Several non-genetic factors have been associated with ovarian cancer incidence or mortality. To evaluate the strength and validity of the evidence we conducted an umbrella review of the literature that included systematic reviews/meta-analyses that evaluated the link between non-genetic risk factors and ovarian cancer incidence and mortality. We searched PubMed, EMBASE, Cochrane Database of Systematic Reviews and performed a manual screening of references. Evidence was graded into strong, highly suggestive, suggestive or weak based on statistical significance of the random effects summary estimate and the largest study in a meta-analysis, the number of cases, between-study heterogeneity, 95% prediction intervals, small study effects, and presence of excess significance bias. We identified 212 meta-analyses, investigating 55 non-genetic risk factors for ovarian cancer. Risk factors were grouped in eight broad categories: anthropometric indices, dietary intake, physical activity, pre-existing medical conditions, past drug history, biochemical markers, past gynaecological history and smoking. Of the 174 meta-analyses of cohort studies assessing 44 factors, six associations were graded with strong evidence. Greater height (RR per 10 cm 1.16, 95% confidence interval (CI) 1.11–1.20), body mass index (BMI) (RR ≥ 30 kg/m2 versus normal 1.27, 95% CI 1.17–1.38) and three exposures of varying preparations and usage related to hormone replacement therapy (HRT) use increased the risk of developing ovarian cancer. Use of oral contraceptive pill reduced the risk (RR 0.74, 95% CI 0.69–0.80). Refining the significance of genuine risk factors for the development of ovarian cancer may potentially increase awareness in women at risk, aid prevention and early detection.</jats:p>
Christakoudi S, Riboli E, Evangelou E, et al., 2022, Associations of body shape index (ABSI) and hip index with liver, metabolic, and inflammatory biomarkers in the UK Biobank cohort, Scientific Reports, Vol: 12, ISSN: 2045-2322
Associations of liver, metabolic, and inflammatory biomarkers in blood with body shape are unclear, because waist circumference (WC) and hip circumference (HC) are dependent on overall body size, resulting in bias. We have used the allometric “a body shape index” (ABSI = WC(mm)∗Weight(kg)-2/3∗Height(m)5/6) and hip index (HIwomen = HC(cm)∗Weight(kg)-0.482∗Height(cm)0.310, HImen = HC(cm)∗Weight(kg)-2/5∗Height(cm)1/5), which are independent of body mass index (BMI) by design, in multivariable linear regression models for 121,879 UK Biobank men and 135,559 women. Glucose, glycated haemoglobin (HbA1c), triglycerides, low-density-lipoprotein cholesterol, apolipoprotein-B, alanine aminotransferase (ALT), gamma-glutamyltransferase, and lymphocytes were associated positively with BMI and ABSI but inversely with HI. High-density-lipoprotein cholesterol and apolipoprotein-A1 were associated inversely with BMI and ABSI but positively with HI. Lipid-related biomarkers and ALT were associated only with HI in obese men. C-reactive protein, neutrophils, monocytes, and alkaline phosphatase were associated positively, while bilirubin was associated inversely, with BMI and ABSI but not with HI. Associations were consistent within the clinical reference ranges but were lost or changed direction for low or high biomarker levels. Our study confirms associations with waist and hip size, independent of BMI, for metabolic biomarkers but only with waist size for inflammatory biomarkers, suggesting different contribution of the mechanistic pathways related to body shape.
Hermelink R, Leitzmann MF, Markozannes G, et al., 2022, Sedentary behavior and cancer-an umbrella review and meta-analysis, European Journal of Epidemiology, Vol: 37, Pages: 1-14, ISSN: 0393-2990
Several systematic reviews and meta-analyses have summarized the association between sedentary behavior (SB) and cancer. However, the level of evidence and the potential for risk of bias remains unclear. This umbrella review summarized the current data on SB in relation to cancer incidence and mortality, with a particular emphasis on assessing the risk of bias. We searched PubMed, Web of Science and Cochrane Database for systematic reviews and meta-analyses on the association between SB and cancer incidence and mortality. We also searched for recent observational studies not yet included in existing meta-analyses. We re-calculated summary risk estimates for cancer incidence and mortality using random effects models. We included 14 meta-analyses covering 17 different cancer sites from 77 original studies. We found that high SB levels increase the risk for developing ovarian, endometrial, colon, breast, prostate, and rectal cancers, with relative risks of 1.29 (95% confidence interval (CI) = 1.08–1.56), 1.29 (95% CI = 1.16–1.45), 1.25 (95% CI = 1.16–1.33), 1.08 (95% CI = 1.04–1.11), 1.08 (95% CI = 1.00–1.17), and 1.07 (95% CI = 1.01–1.12), respectively. Also, we found an increased risk of cancer mortality of 1.18 (95% CI = 1.09–1.26). Most associations between SB and specific cancer sites were supported by a “suggestive” level of evidence. High levels of SB are associated with increased risk of several types of cancer and increased cancer mortality risk.
Derdemezis C, Rontogianni M, Trigki M, et al., 2022, Parental hesitancy towards the established childhood vaccination programmes in the COVID-19 era: assessing the drivers of a challenging public health concern, Vaccines, Vol: 10, ISSN: 2076-393X
1) Background: Vaccine hesitancy remains a major public health concern. The reasons behind this attitude are complex and warrant careful consideration, especially in the context of the COVID-19 era. The purpose of this study was to estimate vaccine hesitancy towards the established childhood immunization programmes in a non-random sample of Greek parents and explore possible links with important drivers of this phenomenon. 2) Methods: An online self-administered questionnaire was used from October 2020 to April 2021 to collect socio-demographic, lifestyle and health status data and evaluate knowledge, views and attitudes of the Greek population on COVID-19 pandemic-related issues. Parents were further asked to complete the Parent Attitudes about Childhood Vaccines (PACV) questionnaire. 3) Results: A total of 1,095 parents participated in the study with a mean age of 50 years (SD 9.5 years). The hesitancy against the established childhood vaccinations was estimated at 8.9% (95% CI, 7.3-10.8%). Married status, higher education and income were negatively correlated with hesitancy, whereas positive correlations were found for stress and depressive symptoms and current smoking. Variables related to proper awareness, sound knowledge and trust to authorities regarding the COVID-19 pandemic were strongly associated with being less hesitant against the established childhood vaccination programmes. 4) Conclusion: The estimated parental hesitancy against the established childhood vaccinations is worrying. Variables related to good awareness and knowledge towards COVID-19 pandemic were strongly associated with being less hesitant against childhood vaccinations. Since controversy surrounding COVID-19 vaccinations may decrease parents’ confidence in routine childhood vaccinations, appreciating the complex reasons behind vaccine hesitancy may inform public health policies to overcome barriers and increase vaccine acceptance.
Kohls M, Freisling H, Charvat H, et al., 2022, Impact of cumulative body mass index and cardiometabolic diseases on survival among patients with colorectal and breast cancer: a multi-centre cohort study, BMC Cancer, Vol: 22, ISSN: 1471-2407
BACKGROUND: Body mass index (BMI) and cardiometabolic comorbidities such as cardiovascular disease and type 2 diabetes have been studied as negative prognostic factors in cancer survival, but possible dependencies in the mechanisms underlying these associations remain largely unexplored. We analysed these associations in colorectal and breast cancer patients. METHODS: Based on repeated BMI assessments of cancer-free participants from four European countries in the European Prospective Investigation into Cancer and nutrition (EPIC) study, individual BMI-trajectories reflecting predicted mean BMI between ages 20 to 50 years were estimated using a growth curve model. Participants with incident colorectal or breast cancer after the age of 50 years were included in the survival analysis to study the prognostic effect of mean BMI and cardiometabolic diseases (CMD) prior to cancer. CMD were defined as one or more chronic conditions among stroke, myocardial infarction, and type 2 diabetes. Hazard ratios (HRs) and confidence intervals (CIs) of mean BMI and CMD were derived using multivariable-adjusted Cox proportional hazard regression for mean BMI and CMD separately and both exposures combined, in subgroups of localised and advanced disease. RESULTS: In the total cohort of 159,045 participants, there were 1,045 and 1,620 eligible patients of colorectal and breast cancer. In colorectal cancer patients, a higher BMI (by 1 kg/m2) was associated with a 6% increase in risk of death (95% CI of HR: 1.02-1.10). The HR for CMD was 1.25 (95% CI: 0.97-1.61). The associations for both exposures were stronger in patients with localised colorectal cancer. In breast cancer patients, a higher BMI was associated with a 4% increase in risk of death (95% CI: 1.00-1.08). CMDs were associated with a 46% increase in risk of death (95% CI: 1.01-2.09). The estimates and CIs for BMI remained similar after adjustment for CMD and vice versa. CONCLUSIONS: Our results suggest that cumula
Murphy N, Song M, Papadimitriou N, et al., 2022, Associations Between Glycemic Traits and Colorectal Cancer: A Mendelian Randomization Analysis, JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE, Vol: 114, Pages: 740-752, ISSN: 0027-8874
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- Citations: 17
Rothwell JA, Murphy N, Bešević J, et al., 2022, Metabolic signatures of healthy lifestyle patterns and colorectal cancer risk in a European cohort, Clinical Gastroenterology and Hepatology, Vol: 20, Pages: e1061-e1082, ISSN: 1542-3565
Background & AimsColorectal cancer risk can be lowered by adherence to the World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) guidelines. We derived metabolic signatures of adherence to these guidelines and tested their associations with colorectal cancer risk in the European Prospective Investigation into Cancer cohort.MethodsScores reflecting adherence to the WCRF/AICR recommendations (scale, 1–5) were calculated from participant data on weight maintenance, physical activity, diet, and alcohol among a discovery set of 5738 cancer-free European Prospective Investigation into Cancer participants with metabolomics data. Partial least-squares regression was used to derive fatty acid and endogenous metabolite signatures of the WCRF/AICR score in this group. In an independent set of 1608 colorectal cancer cases and matched controls, odds ratios (ORs) and 95% CIs were calculated for colorectal cancer risk per unit increase in WCRF/AICR score and per the corresponding change in metabolic signatures using multivariable conditional logistic regression.ResultsHigher WCRF/AICR scores were characterized by metabolic signatures of increased odd-chain fatty acids, serine, glycine, and specific phosphatidylcholines. Signatures were inversely associated more strongly with colorectal cancer risk (fatty acids: OR, 0.51 per unit increase; 95% CI, 0.29–0.90; endogenous metabolites: OR, 0.62 per unit change; 95% CI, 0.50–0.78) than the WCRF/AICR score (OR, 0.93 per unit change; 95% CI, 0.86–1.00) overall. Signature associations were stronger in male compared with female participants.ConclusionsMetabolite profiles reflecting adherence to WCRF/AICR guidelines and additional lifestyle or biological risk factors were associated with colorectal cancer. Measuring a specific panel of metabolites representative of a healthy or unhealthy lifestyle may identify strata of the population at higher risk of colorectal cancer.
Jordahl KM, Shcherbina A, Kim AE, et al., 2022, Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region, CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION, Vol: 31, Pages: 1077-1089, ISSN: 1055-9965
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- Citations: 3
Morales Berstein F, McCartney DL, Lu AT, et al., 2022, Assessing the causal role of epigenetic clocks in the development of multiple cancers: a Mendelian randomization study, eLife, Vol: 11, Pages: 1-46, ISSN: 2050-084X
Background: Epigenetic clocks have been associated with cancer risk in several observational studies. Nevertheless, it is unclear whether they play a causal role in cancer risk or if they act as a non-causal biomarker. Methods: We conducted a two-sample Mendelian randomization (MR) study to examine the genetically predicted effects of epigenetic age acceleration as measured by HannumAge (nine single-nucleotide polymorphisms (SNPs)), Horvath Intrinsic Age (24 SNPs), PhenoAge (11 SNPs), and GrimAge (4 SNPs) on multiple cancers (i.e. breast, prostate, colorectal, ovarian and lung cancer). We obtained genome-wide association data for biological ageing from a meta-analysis (N = 34,710), and for cancer from the UK Biobank (N cases = 2671-13,879; N controls = 173,493-372,016), FinnGen (N cases = 719-8401; N controls = 74,685-174,006) and several international cancer genetic consortia (N cases = 11,348-122,977; N controls = 15,861-105,974). Main analyses were performed using multiplicative random effects inverse variance weighted (IVW) MR. Individual study estimates were pooled using fixed effect meta-analysis. Sensitivity analyses included MR-Egger, weighted median, weighted mode and Causal Analysis using Summary Effect Estimates (CAUSE) methods, which are robust to some of the assumptions of the IVW approach. Results: Meta-analysed IVW MR findings suggested that higher GrimAge acceleration increased the risk of colorectal cancer (OR = 1.12 per year increase in GrimAge acceleration, 95% CI 1.04-1.20, p = 0.002). The direction of the genetically predicted effects was consistent across main and sensitivity MR analyses. Among subtypes, the genetically predicted effect of GrimAge acceleration was greater for colon cancer (IVW OR = 1.15, 95% CI 1.09-1.21, p = 0.006), than rectal cancer (IVW OR = 1.05, 95% CI 0.97-1.13, p = 0.24). Results were less consistent for associations between other epigenetic clocks and cancers. Conclusions: GrimAge acceleration may increase the risk of
Daniel N, Bouras E, Tsilidis K, et al., 2022, Genetically predicted circulating concentrations of micronutrients and COVID-19 Susceptibility and Severity: a Mendelian Randomization Study, Frontiers in Nutrition, Vol: 9, ISSN: 2296-861X
Background: Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 which since 2019 has caused over 5 million deaths to date. The pathogenicity of the virus is highly variable ranging from asymptomatic to fatal. Evidence from experimental and observational studies suggests that circulating micronutrients may affect COVID-19 outcome. Objectives: To complement and inform observational studies, we investigated associations of genetically predicted concentrations of 12 micronutrients (β-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B-6, vitamin B-12, vitamin D and zinc) with SARS-CoV-2 infection risk and COVID-19 severity using Mendelian randomization (MR).Methods: Two-sample MR was conducted using 87,870 individuals of European descent with COVID-19 diagnosis and 2,210,804 controls from the COVID-19 host genetics initiative. Inverse variance-weighted MR analyses were performed with sensitivity analyses to assess the impact of potential violations of MR assumptions. Results: Compared to the general population, nominally significant associations were noted for higher genetically predicted vitamin B-6 (Odds ratio per standard deviation [ORSD]: 1.06; 95% confidence interval [CI]: 1.00, 1.13; p-value = 0.036) and lower magnesium concentrations (ORSD: 0.33; 95%CI: 0.11, 0.96; P = 0.042) with COVID-19 infection risk. However, the association for magnesium was not consistent in some sensitivity analyses, and sensitivity analyses could not be performed for vitamin B-6 as only two genetic instruments were available. Genetically predicted levels of calcium, folate, β-carotene, copper, iron, vitamin B-12, vitamin D, selenium, phosphorus or zinc were not associated with outcomes from COVID-19 disease.Conclusions: These results provide little evidence for possible associations of circulating concentrations of micronutrients with COVID-19 outcomes.
Bouras E, Tsilidis KK, Triggi M, et al., 2022, Diet and risk of gastric cancer: an umbrella review, Nutrients, Vol: 14, ISSN: 2072-6643
Several dietary exposures have been associated with gastric cancer (GC), but the associations are often heterogenous and may be afflicted by inherent biases. In the context of an Umbrella Review (UR), we provide an overview and a critical evaluation of the strength and quality, and evidence classification of the associations of diet-related exposures in relation to the risk of GC. We searched PubMed and Scopus for eligible meta-analyses of observational studies published in English from inception to 12 December 2021, and for any identified association, we applied robust epidemiological validity evaluation criteria and individual study quality assessment using AMSTAR. We screened 3846 titles/abstracts and assessed 501 full articles for eligibility, of which 49 were included in the analysis, investigating 147 unique exposures in relation to GC, cardia (GCC) or non-cardia (GNCC) cancer. Supported by suggestive evidence, positive associations were found comparing the highest vs. lowest categories for: heavy (>42 g/day) alcohol consumption (Relative Risk (RR) = 1.42, 95% Confidence Interval (CI): 1.20–1.67), salted fish consumption (RR = 1.56, 95% CI:1.30–1.87) and waist circumference (RR = 1.48, 95% CI:1.24–1.78) and an inverse association for the healthy lifestyle index (RR = 0.60, 95% CI:0.48–0.74) in relation to GC. Additionally, a positive association was found comparing obese individuals (Body Mass Index (BMI) ≥ 30) to normal-weight individuals (BMI: 18.5–25) (RR = 1.82, 95% CI:1.32–2.49) in relation to GCC. Most of the meta-analyses were of medium-to-high quality (median items: 7.0, interquartile range: 6–9). Maintaining a normal body weight and adopting healthy dietary choices, in particular, limiting the consumption of salt-preserved foods and alcohol, can reduce the risk of gastric cancer.
Mariosa D, Smith-Byrne K, Richardson TG, et al., 2022, Body size at different ages and risk of six cancers: a Mendelian randomization and prospective cohort study, JNCI: Journal of the National Cancer Institute, Vol: 114, Pages: 1296-1300, ISSN: 0027-8874
It is unclear if body weight in early life affects cancer risk independently of adult body weight. To investigate this question for six obesity-related cancers, we performed univariable and multivariable analyses using i) Mendelian randomization (MR) analysis and ii) longitudinal analyses in prospective cohorts. Both the MR and longitudinal analyses indicated that larger body size at age 10 was associated with higher risk of endometrial (ORMR=1.61, 95%CI = 1.23–2.11) and kidney cancer (ORMR=1.40, 95%CI = 1.09–1.80). These associations were attenuated after accounting for adult body size in both the MR and cohort analyses. Early life BMI was not consistently associated with the other investigated cancers. The lack of clear independent risk associations suggests that early life BMI influences endometrial and kidney cancer risk mainly through pathways that are common with adult BMI.
Papadimitriou N, Bouras E, van den Brandt PA, et al., 2022, A prospective diet-wide association study for risk of colorectal cancer in EPIC, Clinical Gastroenterology and Hepatology, Vol: 20, Pages: 864-873.e13, ISSN: 1542-3565
BACKGROUND & AIMS: Evidence regarding the association of dietary exposures with colorectal cancer (CRC) risk is not consistent with a few exceptions. Therefore, we conducted a diet-wide association study (DWAS) in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the associations between several dietary exposures with CRC risk. METHODS: The association of 92 food and nutrient intakes with CRC risk was assessed in 386,792 participants, 5,069 of whom developed incident CRC. Correction for multiple comparisons was performed using the false discovery rate, and emerging associations were examined in the Netherlands Cohort Study (NLCS). Multiplicative gene-nutrient interactions were also tested in EPIC based on known CRC-associated loci. RESULTS: In EPIC, alcohol, liquor/spirits, wine, beer/cider, soft drinks, and pork were positively associated with CRC, whereas milk, cheese, calcium, phosphorus, magnesium, potassium, riboflavin, vitamin B6, beta-carotene, fruit, fibre, non-white bread, banana, and total protein intakes were inversely associated. Of these 20 associations, 13 were replicated in NLCS, for which a meta-analysis was performed, namely alcohol (summary HR per 1 SD increment in intake: 1.07; 95%CI:1.04-1.09), liquor/spirits (1.04; 1.02-1.06), wine (1.04;1.02-1.07), beer/cider (1.06;1.04-1.08), milk (0.95;0.93-0.98), cheese (0.96;0.94-0.99), calcium (0.93;0.90-0.95), phosphorus (0.92;0.90-0.95), magnesium (0.95;0.92-0.98), potassium (0.96;0.94-0.99), riboflavin (0.94;0.92-0.97), beta-carotene (0.96;0.93-0.98), and total protein (0.94;0.92-0.97). None of the gene-nutrient interactions were significant after adjustment for multiple comparisons. CONCLUSIONS: Our findings confirm a positive association for alcohol and an inverse association for dairy products and calcium with CRC risk, and also suggest a lower risk at higher dietary intakes of phosphorus, magnesium, potassium, riboflavin, beta-carotene and total protein.
Li D, Lu Y, Yuan S, et al., 2022, Gut microbiota-derived metabolite Trimethylamine-N-oxide (TMAO) and multiple health outcomes: an umbrella review and updated meta-analysis., American Journal of Clinical Nutrition, Vol: 116, Pages: 230-243, ISSN: 0002-9165
BACKGROUND: Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite produced from dietary nutrients. Many studies have discovered that circulating TMAO levels are linked to a wide range of health outcomes. OBJECTIVES: This study aimed to summarize health outcomes related to circulating TMAO levels. METHODS: We searched Embase, Medline, Web of Science and Scopus databases from inception to 15 February 2022 to identify and update meta-analyses examining the associations between TMAO and multiple health outcomes. For each health outcome, we estimated the summary effect size, 95% prediction confidence interval (CI), between-study heterogeneity, evidence of small-study effects, and evidence of excess-significance bias. These metrics were used to evaluate the evidence credibility of the identified associations. RESULTS: This umbrella review identified 24 meta-analyses that investigated the association between circulating TMAO levels and health outcomes including all-cause mortality, cardiovascular diseases, diabetes mellitus, cancer, and renal function. We updated these meta-analyses by including a total of 82 individual studies in 18 unique health outcomes. Among them, 14 associations were nominally significant. After evidence credibility assessment, we found six (33%) associations (i.e., all-cause mortality, cardiovascular disease mortality, major adverse cardiovascular events, hypertension, diabetes mellitus, and glomerular filtration rate) to present highly suggestive evidence. CONCLUSIONS: TMAO might be a novel biomarker related to human health conditions including all-cause mortality, hypertension, cardiovascular disease, diabetes, cancer and kidney function. Further studies are needed to investigate whether circulating TMAO levels could be an intervention target for chronic disease.
Lopez DS, Liu L, Smith-Warner SA, et al., 2022, Association of Prudent, Western, and Alternate Healthy Eating Index (AHEI-2010) dietary patterns with serum testosterone and sex hormone binding globulin levels in men, HORMONES-INTERNATIONAL JOURNAL OF ENDOCRINOLOGY AND METABOLISM, Vol: 21, Pages: 113-125, ISSN: 1109-3099
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Markozannes G, Kanellopoulou A, Dimopoulou O, et al., 2022, Systematic review of Mendelian randomization studies on risk of cancer, BMC Medicine, Vol: 20, ISSN: 1741-7015
BackgroundWe aimed to map and describe the current state of Mendelian randomization (MR) literature on cancer risk and to identify associations supported by robust evidence.MethodsWe searched PubMed and Scopus up to 06/10/2020 for MR studies investigating the association of any genetically predicted risk factor with cancer risk. We categorized the reported associations based on a priori designed levels of evidence supporting a causal association into four categories, namely robust, probable, suggestive, and insufficient, based on the significance and concordance of the main MR analysis results and at least one of the MR-Egger, weighed median, MRPRESSO, and multivariable MR analyses. Associations not presenting any of the aforementioned sensitivity analyses were not graded.ResultsWe included 190 publications reporting on 4667 MR analyses. Most analyses (3200; 68.6%) were not accompanied by any of the assessed sensitivity analyses. Of the 1467 evaluable analyses, 87 (5.9%) were supported by robust, 275 (18.7%) by probable, and 89 (6.1%) by suggestive evidence. The most prominent robust associations were observed for anthropometric indices with risk of breast, kidney, and endometrial cancers; circulating telomere length with risk of kidney, lung, osteosarcoma, skin, thyroid, and hematological cancers; sex steroid hormones and risk of breast and endometrial cancer; and lipids with risk of breast, endometrial, and ovarian cancer.ConclusionsDespite the large amount of research on genetically predicted risk factors for cancer risk, limited associations are supported by robust evidence for causality. Most associations did not present a MR sensitivity analysis and were thus non-evaluable. Future research should focus on more thorough assessment of sensitivity MR analyses and on more transparent reporting.
Ioannidou A, Watts EL, Perez-Cornago A, et al., 2022, The relationship between lipoprotein A and other lipids with prostate cancer risk: A multivariable Mendelian randomisation study, PLoS Medicine, Vol: 19, ISSN: 1549-1277
BACKGROUND: Numerous epidemiological studies have investigated the role of blood lipids in prostate cancer (PCa) risk, though findings remain inconclusive to date. The ongoing research has mainly involved observational studies, which are often prone to confounding. This study aimed to identify the relationship between genetically predicted blood lipid concentrations and PCa. METHODS AND FINDINGS: Data for low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides (TG), apolipoprotein A (apoA) and B (apoB), lipoprotein A (Lp(a)), and PCa were acquired from genome-wide association studies in UK Biobank and the PRACTICAL consortium, respectively. We used a two-sample summary-level Mendelian randomisation (MR) approach with both univariable and multivariable (MVMR) models and utilised a variety of robust methods and sensitivity analyses to assess the possibility of MR assumptions violation. No association was observed between genetically predicted concentrations of HDL, TG, apoA and apoB, and PCa risk. Genetically predicted LDL concentration was positively associated with total PCa in the univariable analysis, but adjustment for HDL, TG, and Lp(a) led to a null association. Genetically predicted concentration of Lp(a) was associated with higher total PCa risk in the univariable (ORweighted median per standard deviation (SD) = 1.091; 95% CI 1.028 to 1.157; P = 0.004) and MVMR analyses after adjustment for the other lipid traits (ORIVW per SD = 1.068; 95% CI 1.005 to 1.134; P = 0.034). Genetically predicted Lp(a) was also associated with advanced (MVMR ORIVW per SD = 1.078; 95% CI 0.999 to 1.163; P = 0.055) and early age onset PCa (MVMR ORIVW per SD = 1.150; 95% CI 1.015,1.303; P = 0.028). Although multiple estimation methods were utilised to minimise the effect of pleiotropy, the presence of any unmeasured pleiotropy cannot be excluded and may limit our findings. CONCLUSIONS: We observed that genetically predicted Lp(a) concentra
Harbs J, Rinaldi S, Gicquiau A, et al., 2022, Circulating sex hormone levels and colon cancer risk in men: a nested case-control study and meta-analysis, Cancer Epidemiology, Biomarkers and Prevention, Vol: 31, Pages: 793-803, ISSN: 1055-9965
BACKGROUND: Endogenous sex hormones may contribute to higher colorectal cancer incidence rates in men compared to women, but despite an increased number of studies, clear evidence is lacking. METHODS: We conducted a comprehensive nested case-control study of circulating concentrations of sex hormones, sex hormone precursors and sex hormone binding globulin (SHBG) in relation to subsequent colon cancer risk in European men. Concentrations were measured using liquid chromatography-tandem mass spectrometry in prospectively collected plasma samples from 690 cases and 690 matched controls from the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Northern Sweden Health and Disease Study (NSHDS) cohorts. Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CI). In addition, we conducted a meta-analysis of previous studies on men. RESULTS: Circulating levels of testosterone (OR = 0.68, 95% CI = 0.51-0.89) and SHBG (OR = 0.77, 95% CI = 0.62-0.96) were inversely associated with colon cancer risk. For free testosterone, there was a nonsignificant inverse association (OR = 0.83, 95% CI = 0.58-1.18). In a dose-response meta-analysis of endogenous sex hormone levels, inverse associations with colorectal/colon cancer risk were found for testosterone (RR per 100 ng/dL = 0.98, 95% CI = 0.96-1.00, I2 = 22%) and free testosterone (RR per 10 ng/mL = 0.98, 95% CI = 0.95-1.00, I2 = 0%). CONCLUSIONS: Our results provide suggestive evidence for the association between testosterone, SHBG and male colon cancer development. IMPACT: Additional support for the involvement of sex hormones in male colon cancer.
Koureas M, Bogogiannidou Z, Vontas A, et al., 2022, SARS-CoV-2 sero-surveillance in Greece: evolution over time and epidemiological attributes during the pre-vaccination pandemic era, Diagnostics (Basel), Vol: 12, ISSN: 2075-4418
BACKGROUND: Nation-wide SARS-CoV-2 seroprevalence surveys provide valuable insights into the course of the pandemic, including information often not captured by routine surveillance of reported cases. METHODS: A serosurvey of IgG antibodies against SARS-CoV-2 was conducted in Greece between March and December 2020. It was designed as a cross-sectional survey repeated at monthly intervals. The leftover sampling methodology was used and a geographically stratified sampling plan was applied. RESULTS: Of 55,947 serum samples collected, 705 (1.26%) were found positive for anti-SARS-CoV-2 antibodies, with higher seroprevalence (9.09%) observed in December 2020. Highest seropositivity levels were observed in the "0-29" and "30-49" year age groups. Seroprevalence increased with age in the "0-29" age group. Highly populated metropolitan areas were characterized with elevated seroprevalence levels (11.92% in Attica, 12.76% in Thessaloniki) compared to the rest of the country (5.90%). The infection fatality rate (IFR) was estimated at 0.451% (95% CI: 0.382-0.549%) using aggregate data until December 2020, and the ratio of actual to reported cases was 9.59 (7.88-11.33). CONCLUSIONS: The evolution of seroprevalence estimates aligned with the course of the pandemic and varied widely by region and age group. Young and middle-aged adults appeared to be drivers of the pandemic during a severe epidemic wave under strict policy measures.
Hayes BL, Robinson T, Kar S, et al., 2022, Do sex hormones confound or mediate the effect of chronotype on breast and prostate cancer? A Mendelian randomization study, PLoS Genetics, Vol: 18, ISSN: 1553-7390
Morning-preference chronotype has been found to be protective against breast and prostate cancer. Sex hormones have been implicated in relation to chronotype and the development of both cancers. This study aimed to assess whether sex hormones confound or mediate the effect of chronotype on breast and prostate cancer using a Mendelian Randomization (MR) framework. Genetic variants associated with chronotype and sex hormones (total testosterone, bioavailable testosterone, sex hormone binding globulin, and oestradiol) (p<5×10-8) were obtained from published genome-wide association studies (n≤244,207 females and n≤205,527 males). These variants were used to investigate causal relationships with breast (nCases/nControls = 133,384/113,789) and prostate (nCases/nControls = 79,148/61,106) cancer using univariable, bidirectional and multivariable MR. In females, we found evidence for: I) Reduced risk of breast cancer per category increase in morning-preference (OR = 0.93, 95% CI:0. 88, 1.00); II) Increased risk of breast cancer per SD increase in bioavailable testosterone (OR = 1.10, 95% CI: 1.01, 1.19) and total testosterone (OR = 1.15, 95% CI:1.07, 1.23); III) Bidirectional effects between morning-preference and both bioavailable and total testosterone (e.g. mean SD difference in bioavailable testosterone = -0.08, 95% CI:-0.12, -0.05 per category increase in morning-preference vs difference in morning-preference category = -0.04, 95% CI: -0.08, 0.00 per SD increase in bioavailable testosterone). In males, we found evidence for: I) Reduced risk of prostate cancer per category increase in morning-preference (OR = 0.90, 95% CI: 0.83, 0.97) and II) Increased risk of prostate cancer per SD increase in bioavailable testosterone (OR = 1.22, 95% CI: 1.08, 1.37). No bidirectional effects were found between morning-preference and testosterone in males. While testosterone levels were causally implicated with both chronotype and cancer, there was inconsistent evidence f
Tsilidis K, 2022, Circulating inflammatory cytokines and risk of five cancers: a mendelian randomization analysis, BMC Medicine, Vol: 20, ISSN: 1741-7015
Background: Epidemiological and experimental evidence has linked chronic inflammation to cancer etiology. It is unclear whether associations for specific inflammatory biomarkers are causal or due to bias. In order to examine whether altered genetically-predicted concentration of circulating cytokines are associated with cancer development, we performed a two-sample Mendelian randomization (MR) analysis.Methods: Up to 31,112 individuals of European descent were included in genome-wide association study (GWAS) meta-analyses of 47 circulating cytokines. Single nucleotide polymorphisms (SNPs) robustly associated with the cytokines, located in or close to their coding gene (cis), were used as instrumental variables. Inverse-variance weighted MR was used as the primary analysis, and the MR assumptions were evaluated in sensitivity and colocalization analyses and a false discovery rate (FDR) correction for multiple comparisons was applied. Corresponding germline GWAS summary data for five cancer outcomes (breast, endometrial, lung, ovarian and prostate) and their subtypes were selected from the largest cancer-specific GWASs available (cases ranging from 12 906 for endometrial to 133 384 for breast cancer). Results: There was evidence of inverse associations of macrophage migration inhibitory factor with breast cancer (OR per SD = 0.88, 95%CI: 0.83 to 0.94), interleukin-1 receptor antagonist with endometrial cancer (0.86, 0.80 to 0.93), interleukin-18 with lung cancer (0.87, 0.81 to 0.93), and beta-chemokine-RANTES with ovarian cancer (0.70, 0.57 to 0.85); and positive associations of monokine induced by gamma interferon with endometrial cancer (3.73, 1.86 to 7.47) and cutaneous T-cell attracting chemokine with lung cancer (1.51, 1.22 to 1.87). These associations were similar in sensitivity analyses and supported in colocalization analyses. Conclusions: Our study adds to current knowledge on the role of specific inflammatory biomarker pathways in cancer etiology. Further va
Ellingjord-Dale M, Christakoudi S, Weiderpass E, et al., 2021, Long-term weight change and risk of breast cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, International Journal of Epidemiology, Vol: 50, Pages: 1914-1926, ISSN: 0300-5771
BACKGROUND: The role of obesity and weight change in breast-cancer development is complex and incompletely understood. We investigated long-term weight change and breast-cancer risk by body mass index (BMI) at age 20 years, menopausal status, hormone replacement therapy (HRT) and hormone-receptor status. METHODS: Using data on weight collected at three different time points from women who participated in the European Prospective Investigation into Cancer and Nutrition (EPIC) study, we investigated the association between weight change from age 20 years until middle adulthood and risk of breast cancer. RESULTS: In total, 150 257 women with a median age of 51 years at cohort entry were followed for an average of 14 years (standard deviation = 3.9) during which 6532 breast-cancer cases occurred. Compared with women with stable weight (±2.5 kg), long-term weight gain >10 kg was positively associated with postmenopausal breast-cancer risk in women who were lean at age 20 [hazard ratio (HR) = 1.42; 95% confidence interval 1.22-1.65] in ever HRT users (HR = 1.23; 1.04-1.44), in never HRT users (HR = 1.40; 1.16-1.68) and in oestrogen-and-progesterone-receptor-positive (ER+PR+) breast cancer (HR = 1.46; 1.15-1.85). CONCLUSION: Long-term weight gain was positively associated with postmenopausal breast cancer in women who were lean at age 20, both in HRT ever users and non-users, and hormone-receptor-positive breast cancer.
Bouras E, Papandreou C, Tzoulaki I, et al., 2021, Endogenous sex steroid hormones and colorectal cancer risk: a systematic review and meta-analysis, Discover Oncology, Vol: 12, Pages: 1-1, ISSN: 2730-6011
Preclinical data suggest that endogenous sex steroid hormones may be implicated in colorectal cancer (CRC) development, however, findings from epidemiological studies are conflicting. The aim of this systematic review and meta-analysis was to investigate the associations between endogenous concentrations of sex hormones and CRC risk. PubMed and Scopus were searched until June 2020 for prospective studies evaluating the association between pre-diagnostic plasma/serum concentrations of estradiol, testosterone and sex-hormone binding globulin (SHBG) and CRC risk. Summary relative risks (RRs) and 95% confidence intervals (CIs) were estimated using the inverse-variance weighted random-effects model based on the DerSimonian-Laird estimator. Eight studies were included in the meta-analysis after evaluating 3,859 non-duplicate records. Four of the eight studies had a nested case–control design, one study was a case-cohort and the rest three studies were cohort studies, and they included on average 295 cases (range:48–732) and 2,105 controls. No associations were found for endogenous sex steroid hormones in men or post-menopausal women with CRC risk, with evidence for substantial heterogeneity observed among women. Findings from this meta-analysis do not support presence of associations between pre-diagnostic concentrations of testosterone, estradiol and SHBG with incident CRC risk in men and post-menopausal women.
Sofianopoulou E, Kaptoge S, Afzal S, et al., 2021, Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses, The Lancet Diabetes & Endocrinology, Vol: 9, Pages: 837-846, ISSN: 2213-8587
BackgroundRandomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks.MethodsObservational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline. Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died. Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality.FindingsObservational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations. In population-wide genetic analyses, there were no associations of genetically-predicted 25(OH)D with coronary heart disease, stroke, or all-cause mortality. However, for the participants with vitamin D deficiency (25[OH]D concentration <25 nmol/L), genetic analyses provided strong evidence for an inverse association with all-cause mortality (odds ratio [OR] per 10 nmol/L increase in genetically-predicted 25[OH]D concentration 0·69 [95% CI 0·59–0&middo
Mori N, Keski-Rahkonen P, Gicquiau A, et al., 2021, Endogenous circulating sex hormone concentrations and colon cancer risk in postmenopausal women: a prospective study and meta-analysis, JNCI Cancer Spectrum, Vol: 5, Pages: 1-10, ISSN: 2515-5091
BackgroundObservational studies have consistently reported that postmenopausal hormone therapy use is associated with lower colon cancer risk. However, epidemiological studies examining the associations between circulating concentrations of endogenous estrogens and colorectal cancer have reported inconsistent results.MethodsWe investigated the associations between circulating concentrations of estrone, estradiol, free estradiol, testosterone, free testosterone, androstenedione, dehydroepiandrosterone (DHEA), progesterone, and sex hormone binding globulin (SHBG) with colon cancer risk in a nested case–control study of 1,028 postmenopausal European women (512 colon cancer cases, 516 matched controls) who were non-current users of exogenous hormones at blood collection. Multivariable conditional logistic regression models were used to compute odds ratios (ORs) and 95% confidence intervals (CIs) to evaluate the association between circulating sex hormones and colon cancer risk. We also conducted a dose-response meta-analysis of prospective studies of circulating estrone and estradiol with colorectal, colon, and rectal cancer risk in postmenopausal women. All statistical tests were 2-sided.ResultsIn the multivariable model, a non-statistically significant positive relationship was found between circulating estrone and colon cancer risk (OR per log2-1 unit increment = 1.17, 95%CI = 1.00–1.38; ORquartile4-quartile1 = 1.33, 95%CI = 0.89–1.97, Ptrend = 0.20). Circulating concentrations of estradiol, free estradiol, testosterone, free testosterone, androstenedione, DHEA, progesterone, and SHBG were not associated with colon cancer risk. In the dose-response meta-analysis, no clear evidence of associations were found between circulating estradiol, and estrone concentrations with colorectal, colon, and rectal cancer risk.ConclusionOur observational and meta-analysis results do not support an association between circulating concentrations of endogenous sex horm
Charvat H, Freisling H, Noh H, et al., 2021, Excess body fatness during early to mid-adulthood and survival from colorectal and breast cancer: a pooled analysis of five international cohort studies, Cancer Epidemiology, Biomarkers and Prevention, Vol: 31, Pages: 325-333, ISSN: 1055-9965
BACKGROUND: Here, we explore the association between excess weight during early to mid-adulthood and survival in patients diagnosed with breast and colorectal cancer, using a pooled analysis of five cohort studies and study participants from 11 countries. METHODS: Participant-level body mass index (BMI) trajectories were estimated by fitting a growth curve model using over 2 million repeated BMI measurements from close to 600,000 cohort participants. Cumulative measures of excess weight were derived. Data from over 23,000 patients with breast and colorectal cancer were subsequently analyzed using time-to-event models for death with the date of diagnosis as start of follow-up. Study-specific results were combined through a random effect meta-analysis. RESULTS: We found a significant dose-response relationship (P trend = 0.013) between the average BMI during early and mid-adulthood and death from breast cancer, with a pooled HR of 1.31 (1.07-1.60) and the time to death shortened by 16% for average BMI above 25 kg/m2 compared with average BMI less than or equal to 22.5 kg/m2, respectively. Similar results were found for categories of cumulative time spent with excess weight. There was no association between excess body fatness during early to mid-adulthood and death in patients with colorectal cancer. CONCLUSIONS: Excess body fatness during early to mid-adulthood is associated not only with an increased risk of developing cancer, but also with a lower survival in patients with breast cancer. IMPACT: Our results emphasize the importance of public health policies aimed at reducing overweight during adulthood and inform future studies on the relationship between excess weight and cancer outcomes.
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