1046Physical activity and sitting time in relation to breast cancer risk: A Mendelian randomization analysis

Abstract Background Greater physical activity (PA) and less sitting time (ST) have been associated with lower breast cancer (BC) risk in observational studies, but causality is undetermined. Mendelian randomization (MR) investigates causality by using genotype to simulate randomized trials within observational data. A recent summary-data MR study assessed PA and BC by estrogen-receptor (ER) status. We aimed to examine PA and ST in relation to invasive BC risk overall and by molecular subtype. Methods We performed two-sample MR using individual-level Breast Cancer Association Consortium data from 125,684 women (69,869 cases), and summary-level UK Biobank genetic data for the exposure (n = 91,105). We used imputed single nucleotide polymorphisms (SNPs) previously associated (p < 5x10-8) with accelerometer-measured PA (n-SNPs=5) or ST (n = 6). We estimated odds ratios (OR) from inverse-variance weighted MR. Results Greater PA was associated with lower risk of BC (OR = 0.48;95%CI=0.30-0.78 per standard deviation [SD] in activity). Estimates were inverse for all subtypes, particularly ER + (OR=0.45; 95%CI=0.25-0.83), PR + (OR=0.43;95%CI=0.22-0.85), and HER2 + (OR = 0.48; 95%CI=0.26-0.89). Greater ST was associated with higher risk of hormone-receptor-negative tumours, particularly triple-negative (ER-/PR-/HER2-) (OR = 2.04; 95%CI=1.06-3.93 per SD in ST). Estimates overall and for most other subtypes were elevated but had wide CIs crossing null. Sensitivity analyses (weighted-median MR and MR-Egger) did not suggest strong pleiotropic effects for either exposure. Conclusions Greater PA and lower ST reduces risk of all breast cancers, and hormone-receptor negative tumours, respectively. More widespread adoption of active lifestyles will lower burden from the most common cancer in women. Key messages More active and less sedentary lifestyles reduce risk of breast cancer.

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Genetically Determined Levels of Serum Metabolites and Risk of Neuroticism: A Mendelian Randomization Study

The International Journal of Neuropsychopharmacology ◽

10.1093/ijnp/pyaa062 ◽

2020 ◽

Author(s):

Li Qian ◽

Yajuan Fan ◽

Fengjie Gao ◽

Binbin Zhao ◽

Bin Yan ◽

...

Keyword(s):

Uric Acid ◽

Lower Risk ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Strong Predictor ◽

Causal Effects ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Genetic Associations ◽

Inverse Variance

Abstract Background Neuroticism is a strong predictor for a variety of social and behavioral outcomes, but the etiology is still unknown. Our study aims to provide a comprehensive investigation of causal effects of serum metabolome phenotypes on risk of neuroticism using Mendelian randomization (MR) approaches. Methods Genetic associations with 486 metabolic traits were utilized as exposures, and data from a large genome-wide association study of neuroticism were selected as outcome. For MR analysis, we used the standard inverse-variance weighted (IVW) method for primary MR analysis and 3 additional MR methods (MR-Egger, weighted median, and MR pleiotropy residual sum and outlier) for sensitivity analyses. Results Our study identified 31 metabolites that might have causal effects on neuroticism. Of the 31 metabolites, uric acid and paraxanthine showed robustly significant association with neuroticism in all MR methods. Using single nucleotide polymorphisms as instrumental variables, a 1-SD increase in uric acid was associated with approximately 30% lower risk of neuroticism (OR: 0.77; 95% CI: 0.62–0.95; PIVW = 0.0145), whereas a 1-SD increase in paraxanthine was associated with a 7% higher risk of neuroticism (OR: 1.07; 95% CI: 1.01–1.12; PIVW = .0145). Discussion Our study suggested an increased level of uric acid was associated with lower risk of neuroticism, whereas paraxanthine showed the contrary effect. Our study provided novel insight by combining metabolomics with genomics to help understand the pathogenesis of neuroticism.

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Carnitine and COVID-19 Susceptibility and Severity: A Mendelian Randomization Study

Frontiers in Nutrition ◽

10.3389/fnut.2021.780205 ◽

2021 ◽

Vol 8 ◽

Author(s):

Chunyu Li ◽

Ruwei Ou ◽

Qianqian Wei ◽

Huifang Shang

Keyword(s):

Causal Relationship ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Carnitine Level ◽

Standard Deviation Increase ◽

Inverse Variance ◽

Weighted Median ◽

Genetically Determined

Background: Carnitine, a potential substitute or supplementation for dexamethasone, might protect against COVID-19 based on its molecular functions. However, the correlation between carnitine and COVID-19 has not been explored yet, and whether there exists causation is unknown.Methods: A two-sample Mendelian randomization (MR) analysis was conducted to explore the causal relationship between carnitine level and COVID-19. Significant single nucleotide polymorphisms from genome-wide association study on carnitine (N = 7,824) were utilized as exposure instruments, and summary statistics of the susceptibility (N = 1,467,264), severity (N = 714,592) and hospitalization (N = 1,887,658) of COVID-19 were utilized as the outcome. The causal relationship was evaluated by multiplicative random effects inverse variance weighted (IVW) method, and further verified by another three MR methods including MR Egger, weighted median, and weighted mode, as well as extensive sensitivity analyses.Results: Genetically determined one standard deviation increase in carnitine amount was associated with lower susceptibility (OR: 0.38, 95% CI: 0.19–0.74, P: 4.77E−03) of COVID-19. Carnitine amount was also associated with lower severity and hospitalization of COVID-19 using another three MR methods, though the association was not significant using the IVW method but showed the same direction of effect. The results were robust under all sensitivity analyses.Conclusions: A genetic predisposition to high carnitine levels might reduce the susceptibility and severity of COVID-19. These results provide better understandings on the role of carnitine in the COVID-19 pathogenesis, and facilitate novel therapeutic targets for COVID-19 in future clinical trials.

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Periodontal disease increases the host susceptibility to COVID-19 and its severity: a Mendelian randomization study

Journal of Translational Medicine ◽

10.1186/s12967-021-03198-2 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Yi Wang ◽

Hui Deng ◽

Yihuai Pan ◽

Lijian Jin ◽

Rongdang Hu ◽

...

Keyword(s):

Periodontal Disease ◽

Genome Wide Association Study ◽

Mendelian Randomization ◽

Host Susceptibility ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

Inverse Variance ◽

Weighted Median ◽

First Time

Abstract Background Emerging evidence shows that periodontal disease (PD) may increase the risk of Coronavirus disease 2019 (COVID-19) complications. Here, we undertook a two-sample Mendelian randomization (MR) study, and investigated for the first time the possible causal impact of PD on host susceptibility to COVID-19 and its severity. Methods Summary statistics of COVID-19 susceptibility and severity were retrieved from the COVID-19 Host Genetics Initiative and used as outcomes. Single nucleotide polymorphisms associated with PD in Genome-wide association study were included as exposure. Inverse-variance weighted (IVW) method was employed as the main approach to analyze the causal relationships between PD and COVID-19. Three additional methods were adopted, allowing the existence of horizontal pleiotropy, including MR-Egger regression, weighted median and weighted mode methods. Comprehensive sensitivity analyses were also conducted for estimating the robustness of the identified associations. Results The MR estimates showed that PD was significantly associated with significantly higher susceptibility to COVID-19 using IVW (OR = 1.024, P = 0.017, 95% CI 1.004–1.045) and weighted median method (OR = 1.029, P = 0.024, 95% CI 1.003–1.055). Furthermore, it revealed that PD was significantly linked to COVID-19 severity based on the comparison of hospitalization versus population controls (IVW, OR = 1.025, P = 0.039, 95% CI 1.001–1.049; weighted median, OR = 1.030, P = 0.027, 95% CI 1.003–1.058). No such association was observed in the cohort of highly severe cases confirmed versus those not hospitalized due to COVID-19. Conclusions We provide evidence on the possible causality of PD accounting for the susceptibility and severity of COVID-19, highlighting the importance of oral/periodontal healthcare for general wellbeing during the pandemic and beyond.

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Elucidation of a Causal Relationship Between Platelet Count and Hypertension: A Bi-Directional Mendelian Randomization Study

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.743075 ◽

2021 ◽

Vol 8 ◽

Author(s):

Po-Chun Chiu ◽

Amrita Chattopadhyay ◽

Meng-Chun Wu ◽

Tzu-Hung Hsiao ◽

Ching-Heng Lin ◽

...

Keyword(s):

Platelet Count ◽

Causal Relationship ◽

Mendelian Randomization ◽

Causal Effect ◽

Sensitivity Analyses ◽

Exact Nature ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Inverse Variance ◽

Weighted Median

Hypertension has been reported as a major risk factor for diseases such as cardiovascular disease, and associations between platelet activation and risk for hypertension are well-established. However, the exact nature of causality between them remains unclear. In this study, a bi-directional Mendelian randomization (MR) analysis was conducted on 15,996 healthy Taiwanese individuals aged between 30 and 70 years from the Taiwan Biobank, recorded between 2008 and 2015. The inverse variance weighted (IVW) method was applied to determine the causal relationship between platelet count and hypertension with single nucleotide polymorphisms as instrumental variables (IVs). Furthermore, to check for pleiotropy and validity of the IVs, sensitivity analyses were performed using the MR-Egger, weighted median and simple median methods. This study provided evidence in support of a positive causal effect of platelet count on the risk of hypertension (odds ratio: 1.149, 95% confidence interval: 1.131–1.578, P < 0.05), using the weighted median method. A significant causal effect of platelet count on hypertension was observed using the IVW method. No pleiotropy was observed. The causal effect of hypertension on platelet count was found to be non-significant. Therefore, the findings from this study provide evidence that higher platelet count may have a significant causal effect on the elevated risk of hypertension for the general population of Taiwan.

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Causal Associations between Serum Urea and Cancer: A Mendelian Randomization Study

Genes ◽

10.3390/genes12040498 ◽

2021 ◽

Vol 12 (4) ◽

pp. 498

Author(s):

Yandi Sun ◽

Jingjia Li ◽

Zihao Qu ◽

Ze Yang ◽

Xueyao Jia ◽

...

Keyword(s):

Genome Wide Association Study ◽

Mendelian Randomization ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Serum Urea ◽

Urea Level ◽

Genome Wide ◽

Inverse Variance ◽

Weighted Median ◽

First Time

Urea is largely derived from the urea cycle reactions through hepatic detoxification of free ammonia and cleared by urination, and the serum urea level is a crucial medical indicator for measuring the kidney function in patients with nephropathy; however, investigative revelations pointing to the serum urea level as a risk factor for cancer are very scarce, and relevant studies are restricted by potential biases. We aimed to explore the causal relationships of the serum urea level with cancer development by focusing on renal cell carcinoma (RCC) using the Mendelian randomization (MR) analyses. Summary estimates were collected from the inverse-variance weighted (IVW) method based on six single nucleotide polymorphisms (SNPs). The selected SNPs related to the serum urea were obtained from a large genome-wide association study (GWAS) of 13,312 European participants. The summary statistics of RCC were also available from public databases (IARC, n = 5219 cases, n = 8011 controls). Sensitivity analyses included the weighted median and MR-Egger methods. Serum urea was inversely associated with RCC in females (effect = 1.93; 95% CI: 1.24 to 3.01; p = 0.004) but exhibited null association with RCC in males, breast cancer (BRCA) in both genders and prostate cancer (PCa) in males. Similar conclusions were also drawn from the weighted median and MR-Egger. These findings reveal an intriguing link between serum urea and cancer risks for the very first time. Without ambiguity, the serum urea is causatively related to RCC specifically in females, although the mechanism(s) by which urea is involved in RCC development remains to be experimentally/clinically investigated. Our studies may well provide novel insights for RCC diagnosis, intervention and/or therapy.

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Effects of Glutamate and Aspartate on Prostate Cancer and Breast Cancer: A Mendelian Randomization Study

10.21203/rs.3.rs-744517/v1 ◽

2021 ◽

Author(s):

Lihong Zhang ◽

Yindan Lin ◽

Ze Yang ◽

Jingjia Li ◽

Yandi Sun ◽

...

Keyword(s):

Breast Cancer ◽

Prostate Cancer ◽

Confidence Interval ◽

Mendelian Randomization ◽

Association Studies ◽

Underlying Mechanism ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Breast Cancers ◽

Early Assessment

Abstract Background: Respectively, prostate cancer and breast cancer are the second most and most commonly diagnosed cancer in men and woman, and they account for major cancer-related deaths world-wide. Special attention aiming to find potentially effective early detection of, and intervention strategies against, prostate cancer (PCa) and breast cancer need to be paid.Objective: Utilizing Mendelian randomization (MR), we aimed to estimate how genetically predicted glutamate and aspartate levels affected prostate and breast cancers development. Methods: Single nucleotide polymorphisms (SNPs) were selected as instrumental variables (IVs) to predict the serum levels of glutamate and aspartate from the publicly available genome-wide association studies (GWASs), which were conducted to associate genetic variations with blood metabolite levels using comprehensive metabolite profiling in 1,960 adults and the glutamate and aspartate we chosen were two of 644 metabolites. The summary statistics for the largest and latest GWAS datasets for prostate cancer (61,106 controls and 79,148 cases) were from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium and datasets for breast cancer (113,789 controls and 133,384 cases) were from Breast Cancer Association Consortium (BCAC). The analyses were performed through two-sample MR method. Results: Serum level of aspartate was positively associated with prostate cancer (Effect = 1.043; 95% confidence interval, 1.003 to 1.084; P = 0.034) and breast cancer (Effect = 1.033; 95% confidence interval, 1.004 to 1.063; P = 0.028); however, glutamate was neither associated with prostate cancer and breast cancer. The potential causal associations were robust to the sensitivity analysis.Conclusions: Our study found that the level of serum aspartate could serve as a risk factor that contributed to the development of prostate and breast cancers. Efforts detailing the underlying mechanism(s) would be extremely valuable in early assessment/diagnosis and strategizing clinical intervention of both cancers.

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No causal effects of plasma homocysteine levels on the risk of coronary heart disease or acute myocardial infarction: A Mendelian randomization study

European Journal of Preventive Cardiology ◽

10.1177/2047487319894679 ◽

2019 ◽

pp. 204748731989467 ◽

Cited By ~ 3

Author(s):

Liu Miao ◽

Guo-Xiong Deng ◽

Rui-Xing Yin ◽

Rong-Jun Nie ◽

Shuo Yang ◽

...

Keyword(s):

Myocardial Infarction ◽

Acute Myocardial Infarction ◽

Coronary Heart Disease ◽

Heart Disease ◽

Mendelian Randomization ◽

Plasma Homocysteine ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Genome Wide ◽

Artery Disease

Background Although many observational studies have shown an association between plasma homocysteine levels and cardiovascular diseases, controversy remains. In this study, we estimated the role of increased plasma homocysteine levels on the etiology of coronary heart disease and acute myocardial infarction. Methods A two-sample Mendelian randomization study on disease was conducted, i.e. “coronary heart disease” ( n = 184,305) and “acute myocardial infarction” ( n = 181,875). Nine single nucleotide polymorphisms, which were genome-wide significantly associated with plasma homocysteine levels in 57,644 subjects from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) plus The Coronary Artery Disease (C4D) Genetics (CARDIoGRAMplusC4D) consortium genome-wide association study and were known to be associated at p < 5×10–8, were used as an instrumental variable. Results None of the nine single nucleotide polymorphisms were associated with coronary heart disease or acute myocardial infarction ( p > 0.05 for all). Mendelian randomization analysis revealed no causal effects of plasma homocysteine levels, either on coronary heart disease (inverse variance weighted; odds ratio = 1.015, 95% confidence interval = 0.923–1.106, p = 0.752) or on acute myocardial infarction (inverse variance weighted; odds ratio = 1.037, 95% confidence interval = 0.932–1.142, p = 0.499). The results were consistent in sensitivity analyses using the weighted median and Mendelian randomization-Egger methods, and no directional pleiotropy ( p = 0.213 for coronary heart disease and p = 0.343 for acute myocardial infarction) was observed. Sensitivity analyses confirmed that plasma homocysteine levels were not significantly associated with coronary heart disease or acute myocardial infarction. Conclusions The findings from this Mendelian randomization study indicate no causal relationship between plasma homocysteine levels and coronary heart disease or acute myocardial infarction. Conflicting findings from observational studies might have resulted from residual confounding or reverse causation.

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Multidisciplinary Approach to Neoadjuvant Endocrine Therapy in Breast Cancer: A Comprehensive Review

Revista Brasileira de Ginecologia e Obstetrícia / RBGO Gynecology and Obstetrics ◽

10.1055/s-0036-1597579 ◽

2016 ◽

Vol 38 (12) ◽

pp. 615-622 ◽

Cited By ~ 7

Author(s):

Tomás Reinert ◽

Susana Ramalho ◽

Rodrigo Gonçalves ◽

Carlos Barrios ◽

Marcia Graudenz ◽

...

Keyword(s):

Breast Cancer ◽

Endocrine Therapy ◽

Low Income ◽

Hormone Receptor ◽

Urban Areas ◽

Low Cost ◽

Locally Advanced Breast Cancer ◽

Locally Advanced ◽

Breast Cancers ◽

Neoadjuvant Endocrine Therapy

AbstractBreast cancer is the most common type of cancer and the leading cause of cancer-related death among women worldwide. Hormone receptor-positive (HR+) tumors represent the most common form of this disease, with more than 70% of breast cancers expressing these receptors. Response and benefit to neoadjuvant chemotherapy (NCT) varies according to HR expression, with lower responses in luminal tumors as compared with hormone receptor-negative (HR-) and human epidermal growth factor receptor 2-positive (HER2+) tumors. Neoadjuvant endocrine therapy (NET) is an option for selected patients with HR+ locally advanced breast cancer. Neoadjuvant endocrine therapy has a favorable toxicity profile, and is associated with benefits such as having low cost and being more easily available even for cancer care professionals outside major urban areas or tertiary centers. These factors are particularly relevant, as 70% of breast cancer deaths occur in women from low-income and middle-income countries. Additionally, NET is being increasingly explored, not simply to allow for less extensive surgery, but also as a scientific tool, with the use of biomarkers to predict outcomes in adjuvant trials and for the individual patient. This review details the current and most relevant evidence about NET for breast cancer as well as the future directions of this field.

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CDK4/6 inhibitors in breast cancer: beyond hormone receptor-positive HER2-negative disease

Therapeutic Advances in Medical Oncology ◽

10.1177/1758835918818346 ◽

2018 ◽

Vol 10 ◽

pp. 175883591881834 ◽

Cited By ~ 11

Author(s):

Adriana Matutino ◽

Carla Amaro ◽

Sunil Verma

Keyword(s):

Breast Cancer ◽

Hormone Receptor ◽

Growth Factor Receptor ◽

Metastatic Breast ◽

Progression Free Survival ◽

Breast Cancers ◽

Cyclin Dependent Kinase ◽

Her2 Positive ◽

Hormone Receptor Positive ◽

Epidermal Growth

The development of cyclin-dependent kinase (CDK) 4/6 inhibitors has been more prominent in hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancers, with a significant improvement in progression-free survival (PFS) in first and later lines of metastatic breast cancer (MBC) therapy. Preclinical evidence suggests that there is activity of CDK4/6 inhibitors in nonluminal cell lines. Here, we present a review of the current preclinical and clinical data on the use of CDK inhibitors in HER2-positive and triple-negative breast cancer (TNBC).

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Serum Iron Status and the Risk of Breast Cancer in Europeans: A 2-Sample Mendelian Randomisation Study

10.21203/rs.3.rs-57485/v1 ◽

2020 ◽

Author(s):

Chenyang Hou ◽

Qingzhi Hou ◽

Xing Xie ◽

Huifeng Wang ◽

Yueliang Chen ◽

...

Keyword(s):

Breast Cancer ◽

Instrumental Variables ◽

Serum Iron ◽

Iron Status ◽

Mendelian Randomisation ◽

Nucleotide Polymorphisms ◽

Simple Mode ◽

Inverse Variance ◽

Liberal Approach ◽

Mr Study

Abstract Background: Previous observational studies showed that there was a conflict about serum iron status and the risk of breast cancer, which could have an impact on the prevention of breast cancer.Object: We used a two sample Mendelian randomisation (MR) study to explore the causal relationship between iron status and the risk of breast cancer.Method: To select single nucleotide polymorphisms (SNPs) which could be used as instrumental variables for iron status, we used the Genetics of Iron Status consortium. Moreover, we used the OncoArray network to select SNPs of instrumental variables for the outcome (breast cancer). The conservative instruments (SNPs were all consistent with iron status) and liberal instruments (SNPs was associated with at least one of iron status) were used in MR analysis. In the conservative instruments set we used an inverse-variance weighted (IVW) approach, and in the liberal instruments set we used the IVW, MR-Egger regression, weighted median and simple mode approach. Results: In the conservative approach, none of the iron status were statistically significant for breast cancer or its subtypes. And in the liberal approach, transferrin was positively associated with ER-negative breast cancer by simple mode (OR for MR: 1.225; 95% CI: 1.064, 1.410; P=0.030). However, other iron statuses had no association with breast cancer or its subtypes (P>0.05).Conclusion: Our MR study, in the liberal approach, suggested that changes in the concentration of transferrin could increase the risk of ER-negative breast cancer, and other iron statuses had no effect on breast cancer or its subtypes. This could be verified in future studies.

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