Serum Iron Status and the Risk of Breast Cancer in Europeans: A 2-Sample Mendelian Randomisation 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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Serum iron status and the risk of breast cancer in the European population: a two-sample Mendelian randomisation study

Genes & Nutrition ◽

10.1186/s12263-021-00691-7 ◽

2021 ◽

Vol 16 (1) ◽

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 ◽

European Descent ◽

Simple Mode ◽

Liberal Approach ◽

Mr Study

Abstract Background Previous observational studies have provided conflicting results on the association between serum iron status and the risk of breast cancer. Considering the relevance of this relationship to breast cancer prevention, its elucidation is warranted. Object We used a two-sample Mendelian randomisation (MR) study to explore the causal relationship between serum iron status and the risk of breast cancer. Method To select single nucleotide polymorphisms (SNPs) that could be used as instrumental variables for iron status, we used the Genetics of Iron Status consortium, which includes 11 discovery and 8 replication cohorts, encompassing 48,972 individuals of European descent. Moreover, we used the OncoArray network to select SNPs that could be considered instrumental variables for the outcome of interest (breast cancer); this dataset included 122,977 individuals of European descent with breast cancer and 105,974 peers without breast cancer. Both conservative (SNPs associated with overall iron status markers) and liberal (SNPs associated with the levels of at least one iron status marker) approaches were used as part of the MR analysis. For the former, we used an inverse-variance weighted (IVW) method, whereas for the latter, we used the IVW, MR-Egger regression, weighted median and simple mode methods. Results When the conservative approach was used, iron status showed no significant association with the risk of breast cancer or any of its subtypes. However, when the liberal approach was used, transferrin levels were found to be positively associated with the risk of ER-negative breast cancer based on the simple mode method (OR for MR, 1.225; 95% CI, 1.064, 1.410; P = 0.030). Nevertheless, the levels of the other iron status markers showed no association with the risk of breast cancer or its subtypes (P > 0.05). Conclusion In our MR study, the liberal approach suggested that changes in the concentration of transferrin could increase the risk of ER-negative breast cancer, although the levels of other iron status markers had no effect on the risk of breast cancer or its subtypes. This should be verified in future studies.

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Circulating adiponectin levels and systemic lupus erythematosus: a two-sample Mendelian randomization study

Rheumatology ◽

10.1093/rheumatology/keaa506 ◽

2020 ◽

Author(s):

Yi-Lin Dan ◽

Peng Wang ◽

Zhongle Cheng ◽

Qian Wu ◽

Xue-Rong Wang ◽

...

Keyword(s):

Single Nucleotide Polymorphisms ◽

Instrumental Variables ◽

Mendelian Randomization ◽

Causal Effect ◽

Causal Effects ◽

European Ancestry ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Inverse Variance ◽

Weighted Median

Abstract Objectives Several studies have reported increased serum/plasma adiponectin levels in SLE patients. This study was performed to estimate the causal effects of circulating adiponectin levels on SLE. Methods We selected nine independent single-nucleotide polymorphisms that were associated with circulating adiponectin levels (P < 5 × 10−8) as instrumental variables from a published genome-wide association study (GWAS) meta-analysis. The corresponding effects between instrumental variables and outcome (SLE) were obtained from an SLE GWAS analysis, including 7219 cases with 15 991 controls of European ancestry. Two-sample Mendelian randomization (MR) analyses with inverse-variance weighted, MR-Egger regression, weighted median and weight mode methods were used to evaluate the causal effects. Results The results of inverse-variance weighted methods showed no significantly causal associations of genetically predicted circulating adiponectin levels and the risk for SLE, with an odds ratio (OR) of 1.38 (95% CI 0.91, 1.35; P = 0.130). MR-Egger [OR 1.62 (95% CI 0.85, 1.54), P = 0.195], weighted median [OR 1.37 (95% CI 0.82, 1.35), P = 0.235) and weighted mode methods [OR 1.39 (95% CI 0.86, 1.38), P = 0.219] also supported no significant associations of circulating adiponectin levels and the risk for SLE. Furthermore, MR analyses in using SLE-associated single-nucleotide polymorphisms as an instrumental variable showed no associations of genetically predicted risk of SLE with circulating adiponectin levels. Conclusion Our study did not find evidence for a causal relationship between circulating adiponectin levels and the risk of SLE or of a causal effect of SLE on circulating adiponectin levels.

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Maternal iron status during pregnancy and respiratory and atopic outcomes in the offspring: a Mendelian randomisation study

BMJ Open Respiratory Research ◽

10.1136/bmjresp-2018-000275 ◽

2018 ◽

Vol 5 (1) ◽

pp. e000275 ◽

Cited By ~ 5

Author(s):

Annabelle Bédard ◽

Sarah J Lewis ◽

Stephen Burgess ◽

A John Henderson ◽

Seif O Shaheen

Keyword(s):

Birth Cohort ◽

Iron Status ◽

Transferrin Saturation ◽

Late Pregnancy ◽

Forced Expiratory Volume ◽

Risk Scores ◽

Mendelian Randomisation ◽

Nucleotide Polymorphisms ◽

Common Genetic Variants ◽

Maternal Iron

IntroductionLimited evidence from birth cohort studies suggests that lower prenatal iron status may be a risk factor for childhood respiratory and atopic outcomes, but these observational findings may be confounded. Mendelian randomisation (MR) can potentially provide unconfounded estimates of causal effects by using common genetic variants as instrumental variables. We aimed to study the relationship between prenatal iron status and respiratory and atopic outcomes in the offspring using MR.MethodsIn the Avon Longitudinal Study of Parents and Children birth cohort, we constructed four maternal genotypic risk scores by summing the total number of risk alleles (associated with lower iron status) across single nucleotide polymorphisms known to be associated with at least one of four iron biomarkers (serum iron, ferritin, transferrin and transferrin saturation). We used MR to study their associations with respiratory and atopic outcomes in children aged 7–9 years (n=6002).ResultsWhen analyses were restricted to mothers without iron supplementation during late pregnancy, negative associations were found between the maternal transferrin saturation score and childhood forced expiratory volume in 1 s and forced vital capacity (difference in age, height and gender-adjusted SD units per SD increase in genotypic score: −0.05 (−0.09, −0.01) p=0.03, and −0.04 (−0.08, 0.00) p=0.04, respectively).ConclusionUsing MR we have found weak evidence suggesting that low maternal iron status during pregnancy may cause impaired childhood lung function.

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Serum 25-hydroxyvitamin D levels and risk of lung cancer and histologic types: a Mendelian randomisation analysis of the HUNT study

European Respiratory Journal ◽

10.1183/13993003.00329-2018 ◽

2018 ◽

Vol 51 (6) ◽

pp. 1800329 ◽

Cited By ~ 4

Author(s):

Yi-Qian Sun ◽

Ben M. Brumpton ◽

Carolina Bonilla ◽

Sarah J. Lewis ◽

Stephen Burgess ◽

...

Keyword(s):

Lung Cancer ◽

Cohort Study ◽

Population Based ◽

Mendelian Randomisation ◽

Nucleotide Polymorphisms ◽

Hydroxyvitamin D ◽

Inverse Variance ◽

25 Hydroxyvitamin D ◽

Histologic Types ◽

Genetically Determined

We aimed to investigate potential causal associations between serum 25-hydroxyvitamin D (25(OH)D) levels and incidence of lung cancer overall and histologic types.We performed a Mendelian randomisation analysis using a prospective cohort study in Norway, including 54 580 individuals and 676 incident lung cancer cases. A 25(OH)D allele score was generated based on the vitamin D-increasing alleles rs2282679, rs12785878 and rs10741657. Hazard ratios with 95% confidence intervals for incidence of lung cancer and histologic types were estimated in relation to the allele score. The inverse-variance weighted method using summarised data of individual single nucleotide polymorphisms was applied to calculate the Mendelian randomisation estimates.The allele score accounted for 3.4% of the variation in serum 25(OH)D levels. There was no association between the allele score and lung cancer incidence overall, with HR 0.99 (95% CI 0.93–1.06) per allele score. A 25 nmol·L−1increase in genetically determined 25(OH)D level was not associated with the incidence of lung cancer overall (Mendelian randomisation estimate HR 0.96, 95% CI 0.54–1.69) or any histologic type.Mendelian randomisation analysis did not suggest a causal association between 25(OH)D levels and risk of lung cancer overall or histologic types in this population-based cohort study.

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Genetically predicted physical activity levels are associated with lower colorectal cancer risk: a Mendelian randomisation study

British Journal of Cancer ◽

10.1038/s41416-020-01236-2 ◽

2021 ◽

Author(s):

Xiaomeng Zhang ◽

Evropi Theodoratou ◽

Xue Li ◽

Susan M. Farrington ◽

Philip J. Law ◽

...

Keyword(s):

Physical Activity ◽

Colorectal Cancer ◽

Cancer Risk ◽

Body Fat ◽

Instrumental Variables ◽

Sedentary Time ◽

Colorectal Cancer Risk ◽

European Ancestry ◽

Mendelian Randomisation ◽

Mr Study

Abstract Background We conducted a Mendelian randomisation (MR) study to investigate whether physical activity (PA) causes a reduction of colorectal cancer risk and to understand the contributions of effects mediated through changes in body fat. Methods Common genetic variants associated with self-reported moderate-to-vigorous PA (MVPA), acceleration vector magnitude PA (AMPA) and sedentary time were used as instrumental variables. To control for confounding effects of obesity, we included instrumental variables for body mass index (BMI), body fat percentage, waist circumference and arm, trunk and leg fat ratios. We analysed the effect of these instrumental variables in a colorectal cancer genome-wide association study comprising 31,197 cases and 61,770 controls of European ancestry by applying two-sample and multivariable MR study designs. Results We found decreased colorectal cancer risk for genetically represented measures of MVPA and AMPA that were additional to effects mediated through genetic measures of obesity. Odds ratio and 95% confidence interval (CI) per standard deviation increase in MVPA and AMPA was 0.56 (0.31, 1.01) and 0.60 (0.41, 0.88), respectively. No association has been found between sedentary time and colorectal cancer risk. The proportion of effect mediated through BMI was 2% (95% CI: 0, 14) and 32% (95% CI: 12, 46) for MVPA and AMPA, respectively. Conclusion These findings provide strong evidence to reinforce public health measures on preventing colorectal cancer that promote PA at a population level regardless of body fatness.

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Mendelian randomisation study of smoking exposure in relation to breast cancer risk

British Journal of Cancer ◽

10.1038/s41416-021-01432-8 ◽

2021 ◽

Author(s):

Hanla A. Park ◽

Sonja Neumeyer ◽

Kyriaki Michailidou ◽

Manjeet K. Bolla ◽

Qin Wang ◽

...

Keyword(s):

Breast Cancer ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Causal Effect ◽

Association Studies ◽

Sensitivity Analyses ◽

Mendelian Randomisation ◽

Genome Wide Association Studies ◽

Nucleotide Polymorphisms ◽

Smoking Exposure

Abstract Background Despite a modest association between tobacco smoking and breast cancer risk reported by recent epidemiological studies, it is still equivocal whether smoking is causally related to breast cancer risk. Methods We applied Mendelian randomisation (MR) to evaluate a potential causal effect of cigarette smoking on breast cancer risk. Both individual-level data as well as summary statistics for 164 single-nucleotide polymorphisms (SNPs) reported in genome-wide association studies of lifetime smoking index (LSI) or cigarette per day (CPD) were used to obtain MR effect estimates. Data from 108,420 invasive breast cancer cases and 87,681 controls were used for the LSI analysis and for the CPD analysis conducted among ever-smokers from 26,147 cancer cases and 26,072 controls. Sensitivity analyses were conducted to address pleiotropy. Results Genetically predicted LSI was associated with increased breast cancer risk (OR 1.18 per SD, 95% CI: 1.07–1.30, P = 0.11 × 10–2), but there was no evidence of association for genetically predicted CPD (OR 1.02, 95% CI: 0.78–1.19, P = 0.85). The sensitivity analyses yielded similar results and showed no strong evidence of pleiotropic effect. Conclusion Our MR study provides supportive evidence for a potential causal association with breast cancer risk for lifetime smoking exposure but not cigarettes per day among smokers.

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Urticaria and increased risk of rheumatoid arthritis: a two-sample Mendelian randomisation study in European population

Modern Rheumatology ◽

10.1093/mr/roab052 ◽

2021 ◽

Author(s):

Xue Yu ◽

Ming-Gang Deng ◽

Zi-Ying Tang ◽

Zhi-Jiang Zhang

Keyword(s):

Rheumatoid Arthritis ◽

Instrumental Variables ◽

Meta Analysis ◽

Sufficient Evidence ◽

Mendelian Randomisation ◽

Nucleotide Polymorphisms ◽

Global Test ◽

Increased Risk ◽

Variant Analysis ◽

Summary Data

ABSTRACT Background In recent years, a growing body of observational studies suggest that urticaria is associated with a higher risk of rheumatoid arthritis (RA). However, the causal association between urticaria and RA remains unknown. Objective To investigate the causal relationship of urticaria and RA in European populations by Mendelian randomisation (MR) approach. Methods We conducted two-sample MR analyses. Eleven single-nucleotide polymorphisms associated with urticaria were used as instrumental variables. The summary data on urticaria were derived from FinnGen Data Freeze 2. The summary data on RA were obtained from a published meta-analysis using European samples. Four MR methods were applied to the MR estimates. Three heterogeneity tests, including Cochran’s Q test, single variant analysis, and leave-one-out variant analysis, were used. The pleiotropy and horizontal pleiotropy among instrumental variables were assessed with MR-Egger regression intercept, MR pleiotropy residual sum and outlier global test, and PhenoScanner. Results The MR analysis suggested that urticaria was causally associated with RA (odds ratio = 1.114, 95% confidence interval = 1.024–1.211, p = .011). No genetic pleiotropy or horizontal pleiotropy was revealed by MR-Egger regression intercept and MR pleiotropy residual sum and outlier global test. The sensitivity analysis results were relatively robust. Conclusions The MR analysis suggested there was sufficient evidence to indicate urticaria is the cause of RA.

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

International Journal of Epidemiology ◽

10.1093/ije/dyab168.164 ◽

2021 ◽

Vol 50 (Supplement_1) ◽

Author(s):

Suzanne Dixon-Suen ◽

Sarah J. Lewis ◽

Richard M. Martin ◽

Terry Boyle ◽

Graham G. Giles ◽

...

Keyword(s):

Breast Cancer ◽

Hormone Receptor ◽

Mendelian Randomization ◽

Molecular Subtype ◽

Sitting Time ◽

Sensitivity Analyses ◽

Nucleotide Polymorphisms ◽

Breast Cancers ◽

Individual Level ◽

Inverse Variance

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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Association between depression and sleep apnoea: a Mendelian randomisation study

ERJ Open Research ◽

10.1183/23120541.00394-2021 ◽

2021 ◽

pp. 00394-2021

Author(s):

Gui Chen ◽

Junyang Xie ◽

Weixing Liu ◽

Tianhao Liang ◽

Xiao Liao ◽

...

Keyword(s):

Causal Effect ◽

Sleep Apnoea ◽

Mendelian Randomisation ◽

Nucleotide Polymorphisms ◽

Single Nucleotide ◽

Outlier Test ◽

Inverse Variance ◽

Close Relationship ◽

Weighted Median ◽

Summary Data

BackgroundStudies have reported a close relationship between depression and sleep apnoea, yet it is unknown whether these are causally related. Thus, we aimed to determine whether depression is associated with the aetiology of sleep apnoea.MethodsWe used publicly available genetic summary data from two large consortia, the Psychiatric Genomics Consortium, with data from 36 single-nucleotide polymorphisms (SNPs) closely associated with major depressive disorder (MDD) and UK Biobank, including 456 736 patients with sleep apnoea and 766 964 controls. For Mendelian randomisation (MR) analysis, we used the inverse-variance weighted method, weighted median method, MR-Egger regression, MR pleiotropy residual sum, and outlier test to retrieve summary data. Analyses were performed using the “TwoSampleMR” package in R.ResultsOf the 36 SNPs associated with MDD, we found statistically significant evidence of a potential causal effect of MDD on the risk of sleep apnoea (odds ratio 1.004, 95% confidence interval: 1.001–1.006, p=0.001). Similar results were obtained using the MR-Egger and weighted median methods. Additionally, we found no heterogeneity or pleiotropy.ConclusionsOur findings suggest that depression slightly increases the risk of sleep apnoea. Further investigation of the potential biological mechanisms is necessary.

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The association between low-density lipoprotein cholesterol predicted by HMGCR genetic variants and breast cancer risk may be mediated by body mass index

10.1101/464446 ◽

2018 ◽

Author(s):

Siddhartha P. Kar ◽

Hermann Brenner ◽

Graham G. Giles ◽

Dezheng Huo ◽

Roger L. Milne ◽

...

Keyword(s):

Breast Cancer ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Lipoprotein Cholesterol ◽

Low Density ◽

Nucleotide Polymorphisms ◽

Low Density Lipoprotein Cholesterol ◽

Genome Wide ◽

A Genome ◽

Mr Study

Orho-Melander et al. recently reported that lower low-density lipoprotein cholesterol (LDLC) as predicted by the T-allele of the variant rs12916 in HMGCR is associated with a decreased risk of developing breast cancer [odds ratio (OR) = 0.89; 95% confidence interval (CI): 0.82–0.96].1 This analysis was embedded in a wider Mendelian randomization (MR) study performed using genotype data from a prospective cohort of 26,589 individuals that included 16,022 women and 1176 incident breast cancer cases. HMGCR encodes 3-hydroxy-3-methylglutaryl-coenzyme A reductase, the enzyme inhibited by statins. The T-allele of rs12916 is associated with reduced HMGCR expression and therefore, in principle, its effects should be analogous to the effects of lifelong statin administration starting at birth.2 The MR study of Orho-Melander et al. also found that a genome-wide LDLC score based on 32 independent LDLC-associated single nucleotide polymorphisms (SNPs) was not associated with breast cancer. In light of this finding, they suggest that the protective effect of the rs12916 T-allele on breast cancer may either be specific to LDLC lowering via genetic inhibition of HMGCR or be the result of a distinct mechanism that is regulated by rs12916 and HMGCR.

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