scholarly journals Circulating concentrations of micro-nutrients and risk of breast cancer: A Mendelian randomization study

2019 ◽  
Author(s):  
N. Papadimitriou ◽  
N. Dimou ◽  
D. Gill ◽  
I. Tzoulaki ◽  
N. Murphy ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Mendelian Randomization ◽  
World Health ◽  
Sensitivity Analyses ◽  
International Agency ◽  
Inverse Association ◽  
Health Organization ◽  
Genetically Determined

AbstractBackgroundThe epidemiological literature reports inconsistent associations between consumption or circulating concentrations of micro-nutrients and breast cancer risk. We investigated associations between genetically determined concentrations of 11 micro-nutrients (beta-carotene, calcium, copper, folate, iron, magnesium, phosphorus, selenium, vitamin B6, vitamin B12 and zinc) and breast cancer risk using Mendelian randomization (MR).Materials and methodsA two-sample MR study was conducted using 122,977 women with breast cancer, of whom 69,501 were estrogen receptor positive (ER+ve) and 21,468 were ER−ve, 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.ResultsOne standard deviation (SD: 0.08 mmol/L) higher genetically determined concentration of magnesium was associated with a 17% (odds ratio [OR]: 1.17, 95% confidence interval [CI]: 1.10 to 1.25, P=9.1 × 10−7) and 20% (OR: 1.20, 95% CI: 1.11 to 1.30, P=3.17 × 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 determined phosphorus concentration and ER−ve breast cancer (OR: 0.84, 95% CI: 0.72 to 0.98, P=0.03). A suggestive inverse association was observed for a SD (0.48 mg/dL) higher genetically determined calcium concentration with overall breast cancer (OR: 0.91, 95% CI: 0.83 to 1.00, P=0.06). There was little evidence that any of the other nutrients were associated with breast cancer. The results for magnesium were robust under all sensitivity analyses.ConclusionsHigher circulating concentrations of magnesium, phosphorus and calcium may affect breast cancer risk. Further work is required to replicate these findings and investigate underlying mechanisms.key messageWe conducted a Mendelian randomization study to investigate whether concentrations of 11 micro-nutrients are associated with risk of breast cancer. An increased risk of overall and oestrogen-receptor positive disease was observed for genetically higher concentrations of magnesium and inverse associations were observed for phosphorus and calcium concentrationsWhere authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization.

scholarly journals Coffee consumption and risk of breast cancer: a Mendelian Randomization study

2020 ◽  
Author(s):  
Merete Ellingjord-Dale ◽  
Nikos Papadimitriou ◽  
Michalis Katsoulis ◽  
Chew Yee ◽  
Niki Dimou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Random Effects ◽  
Mendelian Randomization ◽  
Coffee Consumption ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Inverse Association ◽  
Er Positive

AbstractBackgroundObservational studies have reported either null or weak protective associations for coffee consumption and risk of breast cancer.MethodsWe conducted a two-sample Mendelian randomization 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.ResultsOne 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).ConclusionsThe 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 inverse association.

scholarly journals Insulin-like growth factor-1 (IGF-1), insulin-like growth factor-binding protein-3 (IGFBP-3) and breast cancer risk: observational and Mendelian randomization analyses

2019 ◽  
Author(s):  
Neil Murphy ◽  
Anika Knuppel ◽  
Nikos Papadimitriou ◽  
Richard M Martin ◽  
Konstantinos K Tsilidis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
World Health ◽  
International Agency ◽  
Insulin Like Growth Factor ◽  
Health Organization ◽  
The Uk ◽  
Igfbp 3

AbstractBackgroundEpidemiological evidence supports a positive association between circulating insulin-like growth factor-1 (IGF-1) concentrations and breast cancer risk, but both the magnitude and causality of this relationship are uncertain. We conducted observational analyses with adjustment for regression dilution bias, and Mendelian randomization (MR) analyses to allow causal inference.Patients and methodsWe investigated the associations between circulating IGF-1 concentrations and incident breast cancer risk in 206,263 women in the UK Biobank. Multivariable hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. HRs were corrected for regression dilution using repeat IGF-1 measures available in a subsample of 6,711 women. For the MR analyses, genetic variants associated with circulating IGF-1 and IGFBP-3 levels were identified and their association with breast cancer was examined with two-sample MR methods using genome-wide data from 122,977 cases and 105,974 controls.ResultsIn the UK Biobank, after a median follow-up of 7.1 years, 4,360 incident breast cancer cases occurred. In the multivariable-adjusted models corrected for regression dilution, higher IGF-1 concentrations were associated with a greater risk of breast cancer (HR per 5 nmol/L increment of IGF-1=1.11, 95%CI=1.07-1.16). Similar positive associations were found by follow-up time, menopausal status, body mass index, and other risk factors. In the MR analyses, a 5 nmol/L increment in genetically-predicted IGF-1 concentration was associated with greater breast cancer risk (odds ratio [OR]=1.05, 95%CI=1.01-1.10; Pvalue=0.02), with a similar effect estimate for estrogen positive (ER+) tumors, but no effect found for estrogen negative (ER-) tumors. Genetically-predicted IGFBP-3 concentrations were not associated with breast cancer risk (OR per 1-SD increment=1.00, 95%CI=0.97-1.04; Pvalue=0.98).ConclusionOur results support a probable causal relationship between circulating IGF-1 concentrations and breast cancer, suggesting that interventions targeting the IGF pathway may be beneficial in preventing breast tumorigenesis.DisclaimerWhere authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization.

scholarly journals Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis

2018 ◽  
Vol 48 (3) ◽  
pp. 795-806 ◽  
Author(s):  
Xiang Shu ◽  
Lang Wu ◽  
Nikhil K Khankari ◽  
Xiao-Ou Shu ◽  
Thomas J Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Type 2 Diabetes ◽  
Estrogen Receptor ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Mendelian Randomization ◽  
Menopausal Status ◽  
Inverse Association ◽  
Fasting Insulin

Abstract Background In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p  =  5.09  ×  10–4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p  =  4.02  ×  10–4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p  =  5.05  ×  10–19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p  =  9.22  ×  10–6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.

scholarly journals Coffee consumption and risk of breast cancer: A Mendelian randomization study

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0236904
Author(s):  
Merete Ellingjord-Dale ◽  
Nikos Papadimitriou ◽  
Michail Katsoulis ◽  
Chew Yee ◽  
Niki Dimou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Random Effects ◽  
Mendelian Randomization ◽  
Coffee Consumption ◽  
Sensitivity Analyses ◽  
European Ancestry ◽  
Er Positive ◽  
The Impact

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.

scholarly journals Lipids, Anthropometric Measures, Smoking and Physical Activity Mediate the Causal Pathway from Education to Breast Cancer in Women: A Mendelian Randomization Study

2021 ◽  
Author(s):  
Hongkai Li ◽  
Lei Hou ◽  
Yuanyuan Yu ◽  
Xiaoru Sun ◽  
Xinhui Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Physical Activity ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Mendelian Randomization ◽  
Sensitivity Analyses ◽  
Causal Mechanism ◽  
Level Of Education ◽  
Causal Pathways ◽  
Causal Pathway

Abstract Background Our objective is to investigate whether obtaining a higher level of education was causally associated with lower breast cancer risk and to identify the causal mechanism linking them. Methods Firstly, we performed a meta-analysis for educational attainment on breast cancer using 33 MR studies, including 15 case-control studies, 10 cross-sectional studies, and 8 cohort studies. Secondly, the main data analysis used publicly available summary-level data from two large GWAS consortia (Breast Cancer Association Consortium [BCAC] and the Social Science Genetic Association Consortium [SSGAC]). Mendelian randomization (MR) analysis used 65 genetic variants derived from the SSGAC as instrumental variables for years of schooling. The outcomes were the overall breast cancer risk (122,977 cases/105,974 controls in women) and its two subtypes: estrogen receptor (ER)-positive breast cancer (ER+: 69,501 cases) and ER-negative breast cancer (ER-: 21,468 cases). Furthermore, six additional consortia were analyzed to investigate the causal pathways from education to breast cancer. The fixed and random effects inverse variance weighted methods were used to estimate the causal effects, along with other additional MR methods as sensitivity analyses. Results The results showed that each additional standard deviation of 4.2 years of education was causally associated with a 27% lower risk of ER- (OR 0.73, 95% CI [0.64, 0.84]; P-value < 0.001). However, very weak causal relationship was found with overall breast cancer and no causal association with ER + risk, consistent with the sensitivity analyses. A genetic predisposition for higher education was causally associated with lower ER- risk and was found to be partially related to hip circumference, body mass index, triglyceride and HDL levels, smoking, and physical activity. Conclusion A low level of education is a causal risk factor in the development of ER- as it is associated with a poor lipid profile, anthropometric measurements, smoking, and types of physical activity.

scholarly journals Physical activity and risks of breast and colorectal cancer: A Mendelian randomization analysis

2019 ◽  
Author(s):  
Nikos Papadimitriou ◽  
Niki Dimou ◽  
Konstantinos K Tsilidis ◽  
Barbara Banbury ◽  
Richard M Martin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Physical Activity ◽  
Colorectal Cancer ◽  
World Health Organization ◽  
Mendelian Randomization ◽  
World Health ◽  
International Agency ◽  
P Value ◽  
Anatomical Site ◽  
Health Organization

AbstractPhysical 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 randomization 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]: 0.59, 95% confidence interval [CI]: 0.42 to 0.84, P-value=0.003) and colorectal cancer (OR: 0.66, 95% CI: 0.53 to 0.82, P-value=2*E-4). We found similar magnitude inverse associations by breast cancer subtype and by colorectal cancer anatomical site. 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.DisclaimerWhere authors are identified as personnel of the International Agency for Research on Cancer / World Health Organization, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer / World Health Organization.

scholarly journals A Mendelian randomization analysis of circulating lipid traits and breast cancer risk

2019 ◽  
Vol 49 (4) ◽  
pp. 1117-1131 ◽  
Author(s):  
Alicia Beeghly-Fadiel ◽  
Nikhil K Khankari ◽  
Ryan J Delahanty ◽  
Xiao-Ou Shu ◽  
Yingchang Lu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Standard Deviation ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Total Cholesterol ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Sensitivity Analyses ◽  
Standard Deviation Increase ◽  
Randomization Analysis

Abstract Background Conventional epidemiologic studies have evaluated associations between circulating lipid levels and breast cancer risk, but results have been inconsistent. As Mendelian randomization analyses may provide evidence for causal inference, we sought to evaluate potentially unbiased associations between breast cancer risk and four genetically predicted lipid traits. Methods Previous genome-wide association studies (GWAS) have identified 164 discrete variants associated with high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), triglycerides and total cholesterol. We used 162 of these unique variants to construct weighted genetic scores (wGSs) for a total of 101 424 breast cancer cases and 80 253 controls of European ancestry from the Breast Cancer Association Consortium (BCAC). Unconditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between per standard deviation increase in genetically predicted lipid traits and breast cancer risk. Additional Mendelian randomization analysis approaches and sensitivity analyses were conducted to assess pleiotropy and instrument validity. Results Corresponding to approximately 15 mg/dL, one standard deviation increase in genetically predicted HDL-C was associated with a 12% increased breast cancer risk (OR: 1.12, 95% CI: 1.08–1.16). Findings were consistent after adjustment for breast cancer risk factors and were robust in several sensitivity analyses. Associations with genetically predicted triglycerides and total cholesterol were inconsistent, and no association for genetically predicted LDL-C was observed. Conclusions This study provides strong evidence that circulating HDL-C may be associated with an increased risk of breast cancer, whereas LDL-C may not be related to breast cancer risk.

scholarly journals Height and Body Mass Index as Modifiers of Breast Cancer Risk in BRCA1/2 Mutation Carriers: A Mendelian Randomization Study

2018 ◽  
Vol 111 (4) ◽  
pp. 350-364 ◽  
Author(s):  
Frank Qian ◽  
Shengfeng Wang ◽  
Jonathan Mitchell ◽  
Lesley McGuffog ◽  
Daniel Barrowdale ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Body Mass Index ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Body Mass ◽  
Mendelian Randomization ◽  
Mutation Carriers

Use of Statins and Breast Cancer: A Meta-Analysis of Seven Randomized Clinical Trials and Nine Observational Studies

2005 ◽  
Vol 23 (34) ◽  
pp. 8606-8612 ◽  
Author(s):  
Stefanos Bonovas ◽  
Kalitsa Filioussi ◽  
Nikolaos Tsavaris ◽  
Nikolaos M. Sitaras
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Publication Bias ◽  
Observational Studies ◽  
Fixed Effects ◽  
Randomized Clinical Trials ◽  
Meta Analysis ◽  
Sensitivity Analyses ◽  
Fixed Effects Model

Purpose A growing body of evidence suggests that statins may have chemopreventive potential against breast cancer. Laboratory studies demonstrate that statins induce apoptosis and reduce cell invasiveness in various cell lines, including breast carcinoma cells. However, the clinical relevance of these data remains unclear. The nonconclusive nature of the epidemiologic data prompted us to conduct a detailed meta-analysis of the studies published on the subject in peer-reviewed literature. Patients and Methods A comprehensive search for articles published up until 2005 was performed; reviews of each study were conducted; and data were abstracted. Before meta-analysis, the studies were evaluated for publication bias and heterogeneity. Pooled relative risk (RR) estimates and 95% CIs were calculated using the random and the fixed-effects models. Subgroup and sensitivity analyses were also performed. Results Seven large randomized trials and nine observational studies (five case-control and four cohort studies) contributed to the analysis. We found no evidence of publication bias or heterogeneity among the studies. Statin use did not significantly affect breast cancer risk (fixed effects model: RR = 1.03; 95% CI, 0.93 to 1.14; random effects model: RR = 1.02; 95% CI, 0.89 to 1.18). When the analyses were stratified into subgroups, there was no evidence that study design substantially influenced the estimate of effects. Furthermore, the sensitivity analysis confirmed the stability of our results. Conclusion Our meta-analysis findings do not support a protective effect of statins against breast cancer. However, this conclusion is limited by the relatively short follow-up times of the studies analyzed. Further studies are required to investigate the potential decrease in breast cancer risk among long-term statin users.

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