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 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 Investigating Causal Relations Between Circulating Metabolites and Alzheimer’s Diseases: A Mendelian Randomization Study

2021 ◽  
Author(s):  
Shu-Yi Huang ◽  
Yu-Xiang Yang ◽  
Ya-Ru Zhang ◽  
Kevin Kuo ◽  
Hong-Qi Li ◽  
...  
Keyword(s):  
Total Cholesterol ◽  
Ldl Cholesterol ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Serum Total Cholesterol ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Primary Analysis ◽  
Standard Deviation Increase ◽  
Increased Risk

Abstract BackgroundMetabolomics is a promising approach that can be used to understand pathophysiological pathways of Alzheimer disease (AD). However, the relationships between metabolism and AD are poorly understood. The aim of this study is to investigate the causal association between circulating metabolites and risk of AD by combining metabolomics with genomics through two-sample Mendelian randomization (MR) approach.MethodsGenetic associations with 123 circulating metabolic traits were utilized as exposures. A large summary statistics data from International Genomics of Alzheimer’s Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was further performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD and 272,244 controls). We utilized the inverse-variance weighted method as primary analysis and four additional MR methods (MR-Egger, weighted median, weighted mode, and MR pleiotropy residual sum and outlier) for sensitivity analyses.ResultsWe found one-fold increased risk of developing AD per standard deviation increase in the levels of circulating ApoB (odd ratio (OR)=3.18; 95% confidence interval (CI): 1.52–6.66, P=0.0022) and glycoprotein acetyls (OR=1.21; 95% CI: 1.05–1.39, P=0.0093), serum total cholesterol (OR=2.73; 95% CI: 1.41-5.30, P=0.0030), and low-density lipoprotein (LDL) cholesterol (OR=2.34; 95% CI: 1.53-3.57, P=0.0001). Whereas glutamine (OR=0.81; 95% CI: 0.71-0.92, P=0.0011) were significantly associated with lower risk of AD. We also detected causal effects of several different composition of LDL fractions on increased AD risk, which has been verified in validation. However, we found no association between circulating high-density lipoprotein cholesterol and AD.ConclusionsOur findings provided robust evidence supporting causal effects of circulating glycoprotein acetyls, ApoB, LDL cholesterol, and serum total cholesterol on higher risk of AD, whereas glutamine showed the protective effect. Further research is required to decipher the biological pathways underpinning associations.

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 Association of hyperlipidemia with breast cancer in Bangladeshi women

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Fatama Akter Chowdhury ◽  
Md Faridul Islam ◽  
Mahnaz Tabassum Prova ◽  
Mahbuba Khatun ◽  
Iffat Sharmin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Total Cholesterol ◽  
Benign Breast Disease ◽  
Density Lipoprotein ◽  
Breast Disease ◽  
Control Group ◽  
Lipid Levels ◽  
Healthy Women

Abstract Background The association of circulating lipids with breast cancer is being debated. The objective of this study was to examine the relationship between abnormal plasma lipids and breast cancer risk in Bangladeshi women. Methods This was a case-control study designed using a population of 150 women (50 women in each group). The lipid levels of women with breast cancer were compared to the lipid levels of women with benign breast disease (control group 1) and healthy women (control group 2). Study samples were collected from the Department of Surgery, Bangabandhu Sheikh Mujib Medical University, for a period of 1 year. Ethical measures were in compliance with the current Declaration of Helsinki. Statistical analysis was performed with SPSS version 26. Results All of the comparison groups shared similar sociodemographic, anthropometric and obstetric characteristics. The incidence of dyslipidemia was significantly higher in breast cancer patients (96%) than in healthy women (84%) and patients with benign breast disease (82%) (P < 0.05 for both). The levels of total cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol among the breast cancer patient group were significantly higher than those among both benign breast disease patients and healthy women (P < 0.05), except for high-density lipoprotein (HDL) cholesterol. Adjusting for other factors, body mass index (BMI) (kg/m2) (> 23) [OR 53.65; 95% CI: 5.70–504.73; P < 0.001] and total cholesterol (mg/dl) (≥ 200) [OR 16.05; 95% CI: 3.13–82.29; P < 0.001] were independently associated with breast cancer. Conclusions Total cholesterol and BMI are independent predictors of breast cancer risk among Bangladeshi women.

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 Assessing a causal relationship between circulating lipids and breast cancer risk: Mendelian randomization study

2019 ◽  
Author(s):  
Kelsey E. Johnson ◽  
Katherine M. Siewert ◽  
Derek Klarin ◽  
Scott M. Damrauer ◽  
Kyong-Mi Chang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Causal Relationship ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Breast Cancers

AbstractObjectiveTo assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein cholesterol, HDL; low-density lipoprotein cholesterol, LDL; triglycerides, TG) with risk for breast cancer.DesignMendelian randomization (MR) study.Setting and ParticipantsData from genome-wide association studies in up to 215,551 subjects from the Million Veterans Project were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on breast cancer risk was evaluated using genetic data from the BCAC consortium based on 122,977 breast cancer cases and 105,974 controls.ExposuresGenetically modified plasma levels of LDL, HDL, or TG.Main Outcomes and MeasuresOdds ratio (OR) for breast cancer risk per standard-deviation increase in HDL, LDL, or TG.ResultsWe observed that a 1-SD genetically determined increase in HDL levels is associated with an increased risk for all breast cancers (HDL: OR=1.08, 95% CI=1.04-1.13, P=7.4×10−5).Multivariable MR analysis, which adjusted for the effects of LDL, TG, body mass index, and age at menarche, corroborated this observation for HDL (OR=1.06, 95% CI=1.03-1.10, P=4.9×10−4) and also a relationship between LDL and breast cancer risk (OR=1.03, 95% CI=1.01-1.07, P=0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for breast cancers (OR=1.11, 95% CI=1.06–1.16, P=1.5×10−6), including gene-specific associations at ABCA1, APOE-APOC1-APOC4-APOC2 and CETP. In addition, we find evidence that genetic variation at the ABO locus affects both lipid levels and breast cancer.ConclusionsGenetically elevated plasma HDL levels appear to increase breast cancer risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal to develop potential therapeutic strategies aimed at altering the HDL-mediated effect on breast cancer risk.

scholarly journals Investigating Causal Relations Between Circulating Metabolites and Alzheimer’s Diseases: a Mendelian Randomization Study

2021 ◽  
Author(s):  
Shu-Yi Huang ◽  
Yu-Xiang Yang ◽  
Ya-Ru Zhang ◽  
Kevin Kuo ◽  
Hong-Qi Li ◽  
...  
Keyword(s):  
Total Cholesterol ◽  
Ldl Cholesterol ◽  
Mendelian Randomization ◽  
Density Lipoprotein ◽  
Serum Total Cholesterol ◽  
Causal Effects ◽  
Sensitivity Analyses ◽  
Primary Analysis ◽  
Standard Deviation Increase ◽  
Increased Risk

Abstract BackgroundMetabolomics is a promising approach that can be used to understand pathophysiological pathways of Alzheimer disease (AD). However, the relationships between metabolism and AD are poorly understood. The aim of this study is to investigate the causal association between circulating metabolites and risk of AD by combining metabolomics with genomics through two-sample Mendelian randomization (MR) approach. MethodGenetic associations with 123 circulating metabolic traits were utilized as exposures. A large summary statistics data from International Genomics of Alzheimer’s Project was used in primary analysis, including 21,982 AD cases and 41,944 controls. Validation was further performed using family history of AD data from UK Biobank (27,696 cases of maternal AD, 14,338 cases of paternal AD and 272,244 controls). We utilized the inverse-variance weighted method as primary analysis and four additional MR methods (MR-Egger, weighted median, weighted mode, and MR pleiotropy residual sum and outlier) for sensitivity analyses. ResultsWe found one-fold increased risk of developing AD per standard deviation increase in the levels of circulating ApoB (odd ratio (OR)=3.18; 95% confidence interval (CI): 1.52–6.66, P=0.0022) and glycoprotein acetyls (OR=1.21; 95% CI: 1.05–1.39, P=0.0093), serum total cholesterol (OR=2.73; 95% CI: 1.41-5.30, P=0.0030), and low-density lipoprotein (LDL) cholesterol (OR=2.34; 95% CI: 1.53-3.57, P=0.0001). Whereas glutamine (OR=0.81; 95% CI: 0.71-0.92, P=0.0011) were significantly associated with lower risk of AD. We also detected causal effects of several different composition of LDL fractions on increased AD risk, which has been verified in validation. However, we found no association between circulating high-density lipoprotein cholesterol and AD. ConclusionsOur findings provided robust evidence supporting causal effects of circulating glycoprotein acetyls, ApoB, LDL cholesterol, and serum total cholesterol on higher risk of AD, whereas glutamine showed the protective effect. Further research is required to decipher the biological pathways underpinning associations.

Sign in / Sign up

Export Citation Format

Share Document