Inflammatory Proteins Mediate the Causal Association between Sleep Traits and Breast Cancer: A Mendelian Randomization Study

BackgroundChanges in platelet indices are associated with breast cancer. But the causal relationship between them remains unclear.MethodsGenetic variation data of platelet indices, including platelet count (PLT), mean platelet volume (MPV), platelet distribution width (PDW), and plateletcrit (PCT), were collected as instrumental variables (IVs). We assessed their impact on the risk of overall breast cancer and its estrogen receptor (ER)+ and ER- subtypes through Mendelian randomization (MR) analysis, including IVs selection, multiple corrections, causality assessment, and sensitivity analysis. Additionally, the findings were validated using an independent dataset and extended the validation to East Asian populations.ResultsOur results found that PCT was significantly associated with an increased risk of overall breast cancer (OR, 1.0693 [95% CI, 1.0281–1.1121]; P = 0.0008) and its ER+ subtype (OR, 1.0691 [95% CI, 1.0233–1.1169]; P = 0.0028), while they were suggestive evidence of a causal relationship after excluding the outliers determined by MR-PRESSO test. After removing the outliers, the suggestive evidence of a causal relationship between PLT and the increased risk of overall breast cancer (OR, 1.0351 [95% CI, 1.0003–1.0711]; P = 0.0483) disappeared, whereas MPV was suggestively associated with an increased risk of overall breast cancer (P = 0.0291). PDW was suggestively associated with a lower risk of overall breast cancer (OR, 0.9597 [95% CI, 0.9236–0.9971]; P = 0.035) and ER+ (OR, 0.9528 [95% CI, 0.9118–0.9957]; P = 0.0315), ER- (OR, 0.9199 [95% CI, 0.8644–0.979]; P = 0.0085) subtypes, whose outlier-corrected results were consistent with raw causal estimates. These findings were replicated in an independent dataset but did not generalize to the East Asian population.ConclusionThis study reveals suggestive evidence of a causal relationship between platelet indices, specifically PCT, MPV, and PDW, and the risk of breast cancer and its subtypes.

Globally, breast cancer continues to be the leading cause of cancer-related incidence and mortality among females. Research has shown that sleep patterns significantly influence tumor onset and progression. In this research, the association was examined through the application of a two-sample Mendelian randomization (MR) approach. For the analysis of seven sleep patterns, genetic tools were sourced from both the UK Biobank and 23andMe, including morning/evening person (chronotype) n = 177,604, morning person (chronotype) n = 248,094, daytime dozing/sleepiness n = 193,472, getting up in the morning n = 193,717, and sleeplessness n = 193,987; sleep duration n = 192,810; and nap during the day n = 166,853. The Breast Cancer Association Consortium (BCAC) supplied genome-wide association studies (GWAS) data, including 133,384 breast cancer cases and 113,789 controls, alongside subtype-specific data with 106,278 cases and 91,477 controls. We discovered that chronotype encompasses both morning and evening types contributes to the risk of overall breast cancer. While daytime dozing and morning person (chronotype) are linked to a lower risk of breast cancer in general, In subtype-specific analyses, morning person (chronotype) was negatively associated with luminal B, HER2-negative-like, and daytime dozing was negatively correlated with luminal A-like, luminal B-like, and HER2-enriched-like. The study corroborates that chronotype is a danger element for breast cancer, aligning with previous observational findings. The association between being a morning person (chronotype) or having daytime dozing and a decreased risk of breast cancer underscores the significance of sleep patterns in formulating strategies for cancer prevention.

In previous observational studies, food-derived antioxidant vitamins have been suggested to be associated with breast cancer. However, the findings were inconsistent and the causal relationship could not be clearly elucidated. To confirm the potential causal relationship between food-derived antioxidants (retinol, carotene, vitamin C and vitamin E) and the risk of breast cancer, we conducted a two-sample Mendelian randomization (MR) study. The instrumental variables (IVs) as proxies of genetic liability to food-derived antioxidant vitamins were obtained from the UK Biobank Database. We extracted breast cancer data (122,977 cases and 105,974 controls) from the Breast Cancer Consortium (BCAC). In addition, we studied estrogen expression status categorically, including estrogen receptor positive (ER+) breast cancer (69,501 cases and 105,974 controls) and versus estrogen receptor (ER-) negative breast cancer (21,468 cases and 105,974 controls). We performed two-sample Mendelian randomization study, and inverse variance-weighted (IVW) test was regarded as main analysis. Sensitivity analyses were further conducted to assess heterogeneity and horizontal pleiotropy. The results of IVW showed that among the four food-derived antioxidants, only vitamin E had protective effect on the risk of overall breast cancer (OR = 0.837, 95% CI 0.757-0.926, P = 0.001) and ER+ breast cancer (OR = 0.823, 95% CI 0.693-0.977, P = 0.026). However, we found no association between food-derived vitamin E and ER- breast cancer. Our study suggested food-derived vitamin E can decrease the risk of breast cancer overall and ER+ breast cancer, and the robustness of our results was confirmed by sensitivity analyses.

Sleep duration suggests some association with osteoporosis and cardiometabolic diseases, but it is unknown if these associations are causal or confounded. In this two-sample Mendelian randomization (MR) study, we included the largest genome-wide association studies (GWASs) associated with sleep duration and the outcome measures of osteoporosis and cardiometabolic diseases. Finally, 25 single nucleotide polymorphisms (SNPs) associated with short sleep duration and 7 SNPs associated with long sleep duration obtained the genome-wide significance (P < 5 × 10−8) and were used as instrumental variables. Genetic predisposition to short sleep duration was strongly associated with increased risk of coronary artery disease (beta-estimate: 0.199, 95% confidence interval CI: 0.081 to 0.317, standard error SE:0.060, P value = 0.001) and heart failure (beta-estimate: 0.145, 95% CI: 0.025 to 0.264, SE:0.061, P value = 0.017), which were both confirmed by the sensitivity analyses. Both short and long sleep duration may reduce the estimated bone mineral density (eBMD, beta-estimate: -0.086, 95% CI: -0.141 to -0.031, SE:0.028, P value = 0.002 for short sleep duration; beta-estimate: -0.080, 95% CI: -0.120 to -0.041, SE:0.020, P value < 0.0001 for long sleep duration). There was limited evidence of associations between sleep duration and fracture, type 2 diabetes, atrial fibrillation, fasting glucose, fasting insulin, or HbA1c. This study provides robust evidence that short sleep duration is causally associated with high risk of coronary artery disease and heart failure and suggests that short sleep duration should be avoided to prevent these two cardiovascular diseases. Short and long sleep duration show some MR association with reduced eBMD, which indicates that both short and long sleep duration may be prevented to reduce the incidence of osteoporosis.

BackgroundThe relationship between migraine and breast cancer risk has generated conflicting findings. We attempted to assess the association between migraine and breast cancer risk using Mendelian randomization (MR) analysis.MethodsWe selected genetic instruments associated with migraine from a recently published genome-wide association studies (GWAS). Inverse variant weighted (IVW) analysis was adopted as the main method, and we also performed the weighted-median method and the MR‒Egger, MR pleiotropy residual sum and outlier (MR-PRESSO), and MR Robust Adjusted Profile Score (MR-RAPS) methods as supplements.ResultsOur MR suggested that any migraine (AM) was a risk factor for overall breast cancer (IVW: odds ratio (OR) = 1.072, 95% confidence intervals (CI) = 1.035–1.110, P = 8.78 × 10− 5, false discovery rate (FDR) = 7.36 × 10− 4) and estrogen receptor-positive (ER+) breast cancer (IVW: OR = 1.066, 95% CI = 1.023–1.111, P = 0.0024; FDR = 0.0108) but not estrogen receptor-negative (ER-) breast cancer. In its subtype analysis, women with a history of migraine without aura (MO) had an increased risk of ER- breast cancer (IVW: OR = 1.089, 95% CI = 1.019–1.163, P = 0.0118, FDR = 0.0354), and MO was suggestively associated with the risk of overall breast cancer (FDR > 0.05 and IVW P < 0.05). No significant heterogeneity or horizontal pleiotropy was found in the sensitivity analysis.ConclusionThis study suggested that women with AM have an increased risk of overall breast cancer and ER + breast cancer. MO was suggestively associated with the risk of overall breast cancer and ER- breast cancer.

Systemic Evaluation of Sleep Duration for Osteoporosis and Cardiometabolic Diseases: A Mendelian Randomization Study

Sleep Duration and Myocardial Infarction

Both short (<7 h per night) and long (≥9 h per night) sleep durations are related to atrial fibrillation (AF) and heart failure (HF), but their causality has not been confirmed. We applied Mendelian randomization (MR) approaches to estimate the causal association between genetically determined sleep duration and the risk of AF and HF. We performed two-sample MR analysis to obtain the effect of sleep duration on AF and HF. Instrumental variables were constructed using genetic variants known to be associated with continuous sleep duration, short sleep duration, and long sleep duration. MR estimates of the effect of sleep duration on AF and HF were derived based on two large meta-analyses of genome-wide association studies. The pooled MR estimate demonstrated a significant protective effect of continuous sleep duration on HF [odds ratio (OR) = 0.765, 95% confidence interval (CI) = 0.675–0.867; P = 2.64 × 10–5] and a suggestive inverse association of continuous sleep duration with AF (OR = 0.893, 95% CI = 0.804–0.991; P = 0.034). In addition, the results showed a suggestive detrimental effect of short sleep duration on the risk of AF (OR = 1.108, 95% CI = 1.017–1.207; P = 0.019) and HF (OR = 1.136, 95% CI = 1.025–1.258; P = 0.015). Conversely, there is no significant evidence for the causal protective effect of long sleep duration on AF (OR = 0.956, P = 0.410) and HF (OR = 0.921, P = 0.202). This MR study indicated that genetically determined continuous sleep duration has a significant protective effect on HF and a suggestive inverse association with AF. Short sleep duration is positively associated with the risk of AF and HF. Nevertheless, there is no significant evidence for the causal protective effect of long sleep duration on AF and HF. Larger intervention studies are required to confirm the effectiveness of improving sleep on reducing the incidence of AF and HF.

BackgroundPrevious 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.ObjectWe used a two-sample Mendelian randomisation (MR) study to explore the causal relationship between serum iron status and the risk of breast cancer.MethodTo 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.ResultsWhen 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).ConclusionIn 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.

It has long been hypothesized that personality plays a causative role in incidence and outcome of breast cancer (BC), but epidemiological evidence of association between personality and BC is inconsistent. We used two-sample Mendelian randomization analysis to estimate the impact of personality on the risk and survival of BC. In total, 109 single nucleotide polymorphisms (SNPs) were utilized as instruments of neuroticism from a large-scale Genome-Wide Association Studies (GWAS), and five SNPs were utilized as instruments of extraversion from Genetic of Personality Consortium and 23andMe. Genetic association with the risk and survival of overall and individual subtype BC were obtained from the Breast Cancer Association Consortium. Neuroticism is significantly associated with the risk of overall BC [odds ratio (OR) 1.06; 95% confidence interval (CI) 1.01-1.11; p = 0.015] and the risk of luminal A BC (OR 1.09; 95% CI 1.03-1.16; p = 0.004). Extraversion is not associated with the risk of BC. None of neuroticism or extraversion is associated with the survival of BC. Neuroticism was associated with a modest increased risk of BC and particularly luminal A BC.

Studies have found sleeping behaviors, such as sleep duration, to be associated with kidney function and cardiovascular disease risk. However, whether short or long sleep duration is a causative factor for kidney function impairment has been rarely studied. We studied data from participants aged 40-69 years in the UK Biobank prospective cohort, including 25,605 self-reporting short-duration sleep (<6 hours per 24 hours), 404,550 reporting intermediate-duration sleep (6-8 hours), and 35,659 reporting long-duration sleep (≥9 hours) in the clinical analysis. Using logistic regression analysis, we investigated the observational association between the sleep duration group and prevalent CKD stages 3-5, analyzed by logistic regression analysis. We performed Mendelian randomization (MR) analysis involving 321,260 White British individuals using genetic instruments (genetic variants linked with short- or long-duration sleep behavior as instrumental variables). We performed genetic risk score analysis as a one-sample MR and extended the finding with a two-sample MR analysis with CKD outcome information from the independent CKDGen Consortium genome-wide association study meta-analysis. Short or long sleep duration clinically associated with higher prevalence of CKD compared with intermediate duration. The genetic risk score for short (but not long) sleep was significantly related to CKD (per unit reflecting a two-fold increase in the odds of the phenotype; adjusted odds ratio, 1.80; 95% confidence interval, 1.25 to 2.60). Two-sample MR analysis demonstrated causal effects of short sleep duration on CKD by the inverse variance weighted method, supported by causal estimates from MR-Egger regression. These findings support an adverse effect of a short sleep duration on kidney function. Clinicians may encourage patients to avoid short-duration sleeping behavior to reduce CKD risk.

Environmental noise and breast cancer risk?

BackgroundDisrupted sleep and shift work are linked to multiple adverse health outcomes, but their association with reproductive endocrine disorders (REDs) and underlying mechanisms remain unclear. Understanding this relationship is crucial for public health, given the growing prevalence of sleep disturbances and shift work in modern societies.PurposeTo investigate the impact of sleep traits and shift work on RED risk in women, explore inflammatory mediation, and assess potential causality using Mendelian randomisation (MR).MethodsWe analysed 244,561 women in the UK Biobank. Sleep duration, quality, and shift work were self-reported. Cox models estimated hazard ratios (HRs) adjusting for demographic, lifestyle, and comorbidities. Interaction models tested joint effects of sleep and shift work. Mediation analyses examined inflammatory biomarkers. Two-sample MR analyses were conducted using large-scale genome-wide association study (GWAS) summary statistics to evaluate causal effects of sleep length or sleep quality traits on REDs.ResultsA U-shaped association was observed between sleep duration and RED risk, lowest at 7 h/day. Short (≤5 h/day; HR = 1.15, 95% CI: 1.02–1.31) and long (≥9 h/day; HR = 1.16, 95% CI: 1.04–1.29) sleep duration, poor sleep quality, and night shift work (HR = 1.40, 95% CI: 1.11–1.75) independently increased RED risk. The combination of night shift work and ≤5 h/day sleep duration showed the highest risk (HR = 1.72, p = 0.0219). Neutrophils, CRP, and leukocytes mediated 5–13% of these associations. MR analyses supported significant causal effects of short sleep duration, insomnia, and daytime napping on REDs.ConclusionAbnormal sleep duration, insomnia, and night shift work are independent risk factors for REDs in women, with inflammation partially mediating these associations. The highest risk was observed in women with short sleep combined with night shift work. MR analyses provide genetic evidence for the causal role of short sleep, insomnia, and daytime napping in REDs. These findings highlight the importance of screening for sleep disturbances and shift work in RED risk assessment, suggesting that interventions targeting sleep duration and shift work schedules may help reduce RED incidence and improve reproductive health. This study is the first to integrate both prospective and genetic evidence to identify causal pathways.

Fibroblast growth factors (FGFs) and their receptors (FGFRs) play key roles in several cellular processes such as differentiation, proliferation, migration and survival. Deregulation of the FGFR signaling pathway has been associated with human cancer including breast cancer, and GWAS-identified polymorphisms in the FGFR2 gene have been associated with risk of both overall and estrogen receptor (ER)-positive breast cancer. We conducted gene-based analysis in 26 genes in the FGFR signaling pathway to identify genes carrying genetic variation affecting risk of breast cancer and the specific ER subtypes. Tagging single nucleotide polymorphisms (SNPs) at ±10 kb of each gene were selected and genotyped in a customized Illumina Exome Array. Imputation was carried out using 1000 Genomes haplotypes. The analysis included 9,264 SNPs in 3,663 breast cancer cases (including 1,983 estrogen receptor-positive (ER+), and 1,098 estrogen receptor-negative (ER-)) and 4,687 controls from the African American Breast Cancer Epidemiology and Risk (AMBER) consortium, a collaborative study of four of the largest studies of breast cancer in African American women (Carolina Breast Cancer Study, Black Women's Health Study, Women's Circle of Health Study, and Multi-Ethnic Cohort). We used the adaptive rank-truncated product (ARTP) method implemented in R-package PIGE to determine the association of each gene in the FGFR signaling pathway with overall breast cancer, and ER subtypes. Analyses were adjusted for principal components of genetic variation to control for population stratification, age, geographic region of residence, study, and source of DNA. An alpha level of 0.002 ( = 0.05/26 genes) was used to determine statistical significance at the gene-wide level. After adjustment for multiple testing the FGF1 gene was associated with risk of ER-negative breast cancer (p = 0.001). The FGF1 gene codes for the fibroblast growth factor 1. Genetic variation in this gene has been reported to be associated with risk of ovarian cancer and with breast cancer survival. As expected, the FGFR2 gene was associated with risk of overall breast cancer (p = 0.001) and ER-positive breast cancer (p = 0.002). In summary, we found that the FGF1 gene affects risk of ER-negative breast cancer in African American women, and we confirmed the association of the FGFR2 gene with risk of overall and ER-positive breast cancer. These results highlight the importance of the FGFR signaling pathway in the pathogenesis of breast cancer, and suggest that different genes in the same pathway may be associated with different ER breast cancer subtypes. Citation Format: Edward A. Ruiz-Narvaez, Stephen Haddad, Christopher A. Haiman, Song Yao, Lara E. Sucheston-Campbell, Jeanette T. Bensen, Kathryn L. Lunetta, Andrew F. Olshan, Christine B. Ambrosone, Julie R. Palmer. Gene-based analysis of the fibroblast growth factor receptor signaling pathway identifies an association of the FGF1 gene with risk of estrogen receptor-negative breast cancer: The AMBER consortium. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2790. doi:10.1158/1538-7445.AM2015-2790

Introduction: Sleep duration and quality have been linked to atherosclerosis, however the effects on peripheral artery disease (PAD) specifically have not been well characterized. We conducted cohort, case-control, and Mendelian randomization analyses across three large multinational samples (Sweden, United Kingdom, United States) to evaluate associations between sleep traits and risk of PAD. Hypothesis: Abnormal sleep duration and poor sleep quality are associated with increased risk of PAD. Methods: Sleep traits (including duration, subjective quality, daytime napping, snoring, apnea, and insomnia) were assessed for associations with incident PAD using Cox proportional hazards regression within a cohort of 53,416 Swedish adults. Replication was sought in a case-control study of 28,123 PAD cases and 128,459 controls from the VA Million Veteran Program (MVP) and a cohort study of 452,028 individuals from the UK Biobank (UKB). Two-sample Mendelian randomization (MR) was used to estimate causal effects of sleep-related traits on PAD (31,307 PAD cases 211,753 controls). Results: Observational analyses demonstrated a U-shaped association between sleep duration and PAD risk. In Swedish adults, incident PAD risk was higher in those with short sleep (&lt;5 hours; hazard ratio (HR) 1.74; 95% confidence interval (CI) 1.31-2.31) or long sleep (≥8 hours; HR 1.24; 95% CI 1.08-1.43), compared to individuals with a sleep duration of 7 to &lt;8 hours/night. This finding was supported by case-control analysis in MVP and cohort analysis in UKB. Observational analysis also revealed positive associations between poor sleep quality (HR 1.81; 95% CI 1.13-2.90) and daytime napping (HR 1.32; 95% CI 1.18-1.49) with PAD. MR analysis supported an inverse association between sleep duration (odds ratio per hour increase, 0.79, 95% CI, 0.55, 0.89) and PAD, and an association between short sleep and increased PAD (odds ratio, 1.20, 95% CI, 1.04-1.38). MR also found an association between insomnia with PAD (OR 1.10; 95% CI 1.05-1.15) and a reverse association of PAD on shorter sleep (OR 1.05; 95% CI 1.01-1.10). Conclusions: Short sleep duration and measures of poor sleep quality may be causal risk factors for PAD. Maintenance of healthy sleep habits may help prevent PAD.