Protein Disulphide Isomerase and NADPH Oxidase 1 Cooperate to Control Platelet Function and Are Associated with Cardiometabolic Disease Risk Factors

Background: Protein disulphide isomerase (PDI) and NADPH oxidase 1 (Nox-1) regulate platelet function and reactive oxygen species (ROS) generation, suggesting potentially interdependent roles. Increased platelet reactivity and ROS production have been correlated with cardiometabolic disease risk factors. Objectives: To establish whether PDI and Nox-1 cooperate to control platelet function. Methods: Immunofluorescence microscopy was utilised to determine expression and localisation of PDI and Nox-1. Platelet aggregation, fibrinogen binding, P-selectin exposure, spreading and calcium mobilization were measured as markers of platelet function. A cross-sectional population study (n = 136) was conducted to assess the relationship between platelet PDI and Nox-1 levels and cardiometabolic risk factors. Results: PDI and Nox-1 co-localized upon activation induced by the collagen receptor GPVI. Co-inhibition of PDI and Nox-1 led to additive inhibition of GPVI-mediated platelet aggregation, activation and calcium flux. This was confirmed in murine Nox-1−/− platelets treated with PDI inhibitor bepristat, without affecting bleeding. PDI and Nox-1 together contributed to GPVI signalling that involved the phosphorylation of p38 MAPK, p47phox, PKC and Akt. Platelet PDI and Nox-1 levels were upregulated in obesity, with platelet Nox-1 also elevated in hypertensive individuals. Conclusions: We show that PDI and Nox-1 cooperate to control platelet function and are associated with cardiometabolic risk factors.

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Cognitive function and cardiometabolic disease risk factors in rural South Africa: baseline evidence from the HAALSI study

BMC Public Health ◽

10.1186/s12889-019-7938-z ◽

2019 ◽

Vol 19 (1) ◽

Cited By ~ 1

Author(s):

Brian Houle ◽

Thomas Gaziano ◽

Meagan Farrell ◽

F. Xavier Gómez-Olivé ◽

Lindsay C. Kobayashi ◽

...

Keyword(s):

Risk Factors ◽

South Africa ◽

Cognitive Function ◽

Cardiometabolic Risk ◽

Disease Risk ◽

Cardiometabolic Risk Factors ◽

Cardiometabolic Disease ◽

Rural South ◽

Rural South Africa ◽

Cardiometabolic Disease Risk

Abstract Background Evidence on cognitive function in older South Africans is limited, with few population-based studies. We aimed to estimate baseline associations between cognitive function and cardiometabolic disease risk factors in rural South Africa. Methods We use baseline data from “Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa” (HAALSI), a population-based study of adults aged 40 and above in rural South Africa in 2015. Cognitive function was measured using measures of time orientation, immediate and delayed recall, and numeracy adapted from the Health and Retirement Study cognitive battery (overall total cognitive score range 0–26). We used multiple linear regression to estimate associations between cardiometabolic risk factors (including BMI, hypertension, dyslipidemia, diabetes, history of stroke, alcohol frequency, and smoking status) and the overall cognitive function score, adjusted for potential confounders. Results In multivariable-adjusted analyses (n = 3018; male = 1520; female = 1498; median age 59 (interquartile range 50–67)), cardiometabolic risk factors associated with lower cognitive function scores included: diabetes (b = − 1.11 [95% confidence interval: − 2.01, − 0.20] for controlled diabetes vs. no diabetes); underweight BMI (b = − 0.87 [CI: − 1.48, − 0.26] vs. normal BMI); and current and past smoking history compared to never smokers. Factors associated with higher cognitive function scores included: obese BMI (b = 0.74 [CI: 0.39, 1.10] vs. normal BMI); and controlled hypertension (b = 0.53 [CI: 0.11, 0.96] vs. normotensive). Conclusions We provide an important baseline from rural South Africa on the associations between cardiometabolic disease risk factors and cognitive function in an older, rural South African population using standardized clinical measurements and cut-offs and widely used cognitive assessments. Future studies are needed to clarify temporal associations as well as patterns between the onset and duration of cardiometabolic conditions and cognitive function. As the South African population ages, effective management of cardiometabolic risk factors may be key to lasting cognitive health.

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Replication study reveals miR-483-5p as an important target in prevention of cardiometabolic disease

BMC Cardiovascular Disorders ◽

10.1186/s12872-021-01964-0 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Widet Gallo ◽

Filip Ottosson ◽

Cecilia Kennbäck ◽

Amra Jujic ◽

Jonathan Lou S. Esguerra ◽

...

Keyword(s):

Risk Factors ◽

Logistic Regression ◽

Cardiometabolic Risk ◽

Carotid Atherosclerosis ◽

Tissue Injury ◽

Control Sample ◽

Cardiometabolic Risk Factors ◽

Cardiometabolic Disease ◽

Micro Rnas

Abstract Background Alterations in levels of circulating micro-RNAs might reflect within organ signaling or subclinical tissue injury that is linked to risk of diabetes and cardiovascular risk. We previously found that serum levels of miR-483-5p is correlated with cardiometabolic risk factors and incidence of cardiometabolic disease in a case–control sample from the populations-based Malmö Diet and Cancer Study Cardiovascular Cohort (MDC-CC). We here aimed at replicating these findings and to test for association with carotid atherosclerosis. Methods We measured miR-483-5p in fasting serum of 1223 healthy subjects from the baseline examination of the population-based, prospective cohort study Malmö Offspring Study (MOS) and correlated miR-483-5p to cardiometabolic risk factors and to incidence of diabetes mellitus and coronary artery disease (CAD) during 3.7 (± 1.3) years of follow-up using logistic regression. In both MOS and MDC-CC we related mir-483-5p to carotid atherosclerosis measured with ultrasound. Results In cross-sectional analysis miR-483-5p was correlated with BMI, waist circumference, HDL, and sex. After adjustment for age and sex, the association remained significant for all risk factors except for HDL. Logistic regression analysis showed significant associations between miR-483-5p and new-onset diabetes (OR = 1.94, 95% CI 1.06–3.56, p = 0.032) and cardiovascular disease (OR = 1.99, 95% CI 1.06–3.75, p = 0.033) during 3.7 (± 1.3) years of follow-up. Furthermore, miR-483-5p was significantly related with maximum intima-media thickness of the carotid bulb in MDC-CC (p = 0.001), but not in MOS, whereas it was associated with increasing number of plaques in MOS (p = 0.007). Conclusion miR-483-5p is related to an unfavorable cardiometabolic risk factor profile and predicts diabetes and CAD, possibly through an effect on atherosclerosis. Our results encourage further studies of possible underlying mechanisms and means of modifying miR-483-5p as a possible interventional target in prevention of cardiometabolic disease.

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Do maternal intrauterine environmental influences that lower offspring birthweight causally increase offspring cardiometabolic risk factors in later life? A Mendelian randomization study of 45,849 genotyped parent offspring pairs in the HUNT study

10.1101/2020.05.04.20091173 ◽

2020 ◽

Cited By ~ 1

Author(s):

Gunn-Helen Moen ◽

Ben Brumpton ◽

Cristen Willer ◽

Bjørn Olav Åsvold ◽

Kåre Birkeland ◽

...

Keyword(s):

Risk Factors ◽

Genetic Risk ◽

Cardiometabolic Risk ◽

Later Life ◽

Early Years ◽

Cardiometabolic Risk Factors ◽

Causal Effects ◽

Cardiometabolic Disease ◽

Intrauterine Environment ◽

Hunt Study

AbstractIntroductionThere is a robust and well-documented observational relationship between lower birthweight and higher risk of cardiometabolic disease in later life. The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that adverse environmental factors in utero or in the early years of life result in increased future risk of cardiometabolic disease. Our aim was to investigate whether there was evidence for causal effects of the intrauterine environment, as proxied by maternal single nucleotide polymorphisms (SNPs) that influence offspring birthweight independent of offspring genotype, on offspring cardiometabolic risk factors such as blood pressure, non-fasting glucose, body mass index (BMI), and lipid levels.MethodsWe investigated whether a genetic risk score of maternal SNPs associated with offspring birthweight was also associated with offspring cardiometabolic risk factors, after controlling for offspring genotypes at the same loci, in up to 26,057 mother-offspring pairs from the Nord-Trøndelag Health (HUNT) Study. We also conducted similar analyses in 19,792 father-offspring pairs from the same study to investigate whether there was evidence that any such causal effects operated through the postnatal, rather than the intrauterine environment. To take account of the considerable cryptic relatedness in HUNT, we implemented a computationally efficient genetic linear mixed model using the OpenMx software package to perform our analyses.ResultsWe found little evidence for a maternal genetic effect of birthweight associated variants on offspring cardiometabolic risk factors after adjusting for offspring genotypes at the same loci. Likewise, we found little evidence for paternal genetic effects on offspring cardiometabolic risk factors performing similar analyses in father-offspring pairs. In contrast, offspring genetic risk scores of birthweight associated variants were strongly related to many cardiometabolic risk factors, even after conditioning on maternal genotypes at the same loci.ConclusionOur results suggest that the maternal intrauterine environment, as proxied by maternal SNPs that influence offspring birthweight, is unlikely to be a major determinant of adverse cardiometabolic outcomes in population based samples of individuals. In contrast, genetic pleiotropy appears to explain some of the observational relationship between offspring birthweight and future cardiometabolic risk.

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Mendelian randomization study of maternal influences on birthweight and future cardiometabolic risk in the HUNT cohort

Nature Communications ◽

10.1038/s41467-020-19257-z ◽

2020 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Gunn-Helen Moen ◽

Ben Brumpton ◽

Cristen Willer ◽

Bjørn Olav Åsvold ◽

Kåre I. Birkeland ◽

...

Keyword(s):

Risk Factors ◽

Cardiometabolic Risk ◽

Genetic Risk Score ◽

Genetic Effect ◽

Later Life ◽

Population Based ◽

Cardiometabolic Risk Factors ◽

Cardiometabolic Disease ◽

Health And Disease ◽

Lower Birthweight

Abstract There is a robust observational relationship between lower birthweight and higher risk of cardiometabolic disease in later life. The Developmental Origins of Health and Disease (DOHaD) hypothesis posits that adverse environmental factors in utero increase future risk of cardiometabolic disease. Here, we explore if a genetic risk score (GRS) of maternal SNPs associated with offspring birthweight is also associated with offspring cardiometabolic risk factors, after controlling for offspring GRS, in up to 26,057 mother–offspring pairs (and 19,792 father–offspring pairs) from the Nord-Trøndelag Health (HUNT) Study. We find little evidence for a maternal (or paternal) genetic effect of birthweight associated variants on offspring cardiometabolic risk factors after adjusting for offspring GRS. In contrast, offspring GRS is strongly related to many cardiometabolic risk factors, even after conditioning on maternal GRS. Our results suggest that the maternal intrauterine environment, as proxied by maternal SNPs that influence offspring birthweight, is unlikely to be a major determinant of adverse cardiometabolic outcomes in population based samples of individuals.

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Inflammatory markers are altered in severe mental disorders independent of comorbid cardiometabolic disease risk factors

Psychological Medicine ◽

10.1017/s0033291718004142 ◽

2019 ◽

Vol 49 (10) ◽

pp. 1749-1757 ◽

Cited By ~ 6

Author(s):

Ragni H. Mørch ◽

Ingrid Dieset ◽

Ann Færden ◽

Elina J. Reponen ◽

Sigrun Hope ◽

...

Keyword(s):

Risk Factors ◽

Mental Disorders ◽

T Cell Activation ◽

Psychotropic Medication ◽

Inflammatory Markers ◽

Cardiometabolic Risk ◽

Disease Risk ◽

Interleukin 2 ◽

Cardiometabolic Risk Factors ◽

Severe Mental Disorders

AbstractBackgroundInflammation and immune activation have been implicated in the pathogenesis of severe mental disorders and cardiovascular disease (CVD). Despite high level of comorbidity, many studies of the immune system in severe mental disorders have not systematically taken cardiometabolic risk factors into account.MethodsWe investigated if inflammatory markers were increased in schizophrenia (SCZ) and affective (AFF) disorders independently of comorbid CVD risk factors. Cardiometabolic risk factors (blood lipids, body mass index and glucose) and CVD-related inflammatory markers CXCL16, soluble interleukin-2 receptor (sIL-2R), soluble CD14 (sCD14), macrophage inhibitory factor and activated leukocyte cell adhesion molecule (ALCAM) were measured inn= 992 patients (SCZ, AFF), andn= 647 healthy controls. We analyzed the inflammatory markers before and after controlling for comorbid cardiometabolic risk factors, and tested for association with psychotropic medication and symptom levels.ResultsCXCL16 (p= 0.03) and sIL-2R (p= 7.8 × 10−5) were higher, while sCD14 (p= 0.05) were lower in patients compared to controls after controlling for confounders, with significant differences in SCZ for CXCL16 (p= 0.04) and sIL-2R (p= 1.1 × 10−5). After adjustment for cardiometabolic risk factors higher levels of sIL-2R (p= 0.001) and lower sCD14 (p= 0.002) remained, also in SCZ (sIL-2R,p= 3.0 × 10−4and sCD14,p= 0.01). The adjustment revealed lower ALCAM levels (p= 0.03) in patients. We found no significant associations with psychotropic medication or symptom levels.ConclusionThe results indicate that inflammation, in particular enhanced T cell activation and impaired monocyte activation, are associated with severe mental disorders independent of comorbid cardiometabolic risk factors. This suggests a role of novel pathophysiological mechanisms in severe mental disorders, particularly SCZ.

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Abstract P082: Elevated Circulating Endothelial-Derived Microvesicles Are Associated With Obesity-Related Endothelial Dysfunction

Hypertension ◽

10.1161/hyp.76.suppl_1.p082 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

L. Madden Brewster ◽

Tyler D Bammert ◽

Jamie G Hijmans ◽

Caitlin A Dow ◽

Anabel Goulding ◽

...

Keyword(s):

Risk Factors ◽

Endothelial Dysfunction ◽

Body Fat ◽

Cardiometabolic Risk ◽

Disease Risk ◽

Normal Weight ◽

Cardiometabolic Risk Factors ◽

High Risk Populations ◽

Health And Disease ◽

Middle Aged Adults

Background: Obesity reduces the number of years lived free of cardiovascular disease (CVD) and increases the number of years lived with CVD, contributing to increased morbidity and mortality risk across all ages. Experimental and clinical studies indicate that a proatherogenic endothelial phenotype is a major consequence of increased adiposity and a primary mechanism underlying obesity-related CVD. Extracellular microvesicles, particularly endothelial cell-derived microvesicles (EMVs), are seminal functional modulators of vascular health and disease. The purpose of this study was to determine: 1) if circulating EMV levels are elevated with obesity, independent of other cardiometabolic risk factors; and if so, 2) whether circulating EMVs are associated with obesity-related endothelial vasodilator dysfunction. Methods: Thirty sedentary, middle-aged adults (45-63 years) were studied: 15 normal weight (10M/5F; age: 56±1 yr; BMI: 23.2±0.4 kg/m2; body fat: 25.1±2.4 %) and 15 obese (10M/5F; age: 54±1 yr; BMI: 31.5±0.3 kg/m2; body fat: 37.2±1.7 %). All subjects were free of other cardiometabolic risk factors and overt disease. EMV identification (CD31 + /42b - ) and concentration in peripheral blood were determined by flow cytometry. Forearm blood flow (FBF: via plethysmography) was assessed in response to intra-arterial infusions of acetylcholine (4.0, 8.0 and 16.0 μg/100 mL tissue/min) and sodium nitroprusside (1.0, 2.0 and 4.0 μg/100 mL tissue/min). Results: Circulating EMV levels were ~100% higher (P<0.05) in obese (182±14 EMV/μL) compared with normal weight (91±12 EMV/μL) adults. FBF response to acetylcholine was significantly lower (~35%) in the obese (from 4.0±0.2 to 10.3±0.6 mL/100 mL tissue/min vs 4.3±0.3 to 15.4±0.8 mL/100 mL tissue/min) group. Circulating EMVs were significantly and inversely associated with total FBF response to acetylcholine (r=-0.55). Conclusions: Obesity, independent of other cardiometabolic risk factors, is associated with elevated circulating levels of EMVs. Higher circulating EMVs in obese adults may contribute to adiposity-related endothelial dysfunction and vascular disease risk. Indeed, circulating EMVs have been linked to disease risk, severity and outcome in other high-risk populations.

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Increased C-Reactive Protein in Brazilian Children: Association with Cardiometabolic Risk and Metabolic Syndrome Components (PASE Study)

Cardiology Research and Practice ◽

10.1155/2019/3904568 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 6

Author(s):

Lara Gomes Suhett ◽

Helen Hermana Miranda Hermsdorff ◽

Naruna Pereira Rocha ◽

Mariane Alves Silva ◽

Mariana De Santis Filgueiras ◽

...

Keyword(s):

Risk Factors ◽

Metabolic Syndrome ◽

Cardiometabolic Risk ◽

Disease Risk ◽

Elevated Serum ◽

Cardiometabolic Risk Factors ◽

C Reactive Protein ◽

Reactive Protein ◽

Hs Crp ◽

Brazilian Children

C-reactive protein (CRP) is a marker of subclinical inflammation that has been found to be associated with cardiovascular disease risk. However, few studies have investigated the relationship between CRP and cardiometabolic markers in a representative sample of prepubescent children. The objective was to evaluate the high-sensitive CRP (hs-CRP) and its association with traditional and nontraditional cardiometabolic risk factors, as well as metabolic syndrome (MetS) components in Brazilian children. This is a cross-sectional representative study, with participants of the Schoolchildren Health Assessment Survey (PASE). Children from 8 to 9 years old (n=350) enrolled in public and private schools in the municipality of Viçosa, Minas Gerais, Brazil, were evaluated. Sociodemographic evaluation was performed through a semistructured questionnaire. Anthropometric, body composition, clinical, and biochemical measures were analyzed for cardiometabolic risk assessment. The total mean of serum hs-CRP concentration was 0.62 (±1.44) mg/L. hs-CRP was significantly correlated with several anthropometric, biochemical, and clinical parameters in this population (P<0.05). hs-CRP was positively associated with the accumulation of cardiometabolic risk factors and MetS components (P<0.05). Children with excessive weight; abdominal obesity; increased gynoid and android body fat; low HDL-c; hyperglycemia; and elevated uric acid, homocysteine, and apoB had higher chances of presenting increased hs-CRP (P<0.05). In this study, Brazilian children with cardiometabolic risk already presented elevated serum hs-CRP concentration. hs-CRP was associated with the increase of traditional and nontraditional cardiometabolic risk factors, as well as the accumulation of MetS components.

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Cross-sectional association between diet quality and cardiometabolic risk by education level in Mexican adults

Public Health Nutrition ◽

10.1017/s1368980019001678 ◽

2019 ◽

Vol 23 (2) ◽

pp. 264-274 ◽

Cited By ~ 1

Author(s):

Nancy López-Olmedo ◽

Barry M Popkin ◽

Penny Gordon-Larsen ◽

Lindsey Smith Taillie

Keyword(s):

Risk Factors ◽

Diet Quality ◽

Cardiometabolic Risk ◽

Disease Risk ◽

Education Level ◽

Dietary Quality ◽

Cardiometabolic Disease ◽

Cross Sectional ◽

Unit Increase ◽

Cardiometabolic Disease Risk

AbstractObjective:Understanding the association between diet quality and cardiometabolic risk by education level is important for preventing increased cardiometabolic risk in the Mexican population, especially considering pre-existing disparities in diet quality. The present study examined the cross-sectional association of overall diet quality with cardiometabolic risk, overall and by education level, among Mexican men and women.Design:Cardiometabolic risk was defined by using biomarkers and diet quality by the Mexican Diet Quality Index. We computed sex-specific multivariable logistic regression models.Setting:Mexico.Participants:Mexican men (n 634) and women (n 875) participating in the Mexican National Health and Nutrition Survey 2012.Results:We did not find associations of diet quality with cardiometabolic risk factors in the total sample or in men by education level. However, we observed that for each 10-unit increase in the dietary quality score, the odds of diabetes risk in women with no reading/writing skills was 0·47 (95 % CI 0·26, 0·85) relative to the odds in women with ≥10 years of school (referent). Similarly, for each 10-unit increase of the dietary quality score, the odds of having three v. no lipid biomarker level beyond the risk threshold in lower-educated women was 0·27 (95 % CI 0·12, 0·63) relative to the odds in higher-educated women.Conclusions:Diet quality has a stronger protective association with some cardiometabolic disease risk factors for lower- than higher-educated Mexican women, but no association with cardiometabolic disease risk factors among men. Future research will be needed to understand what diet factors could be influencing the cardiometabolic disease risk disparities in this population.

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Duration of obesity exposure between ages 10 and 40 years and its relationship with cardiometabolic disease risk factors: A cohort study

PLoS Medicine ◽

10.1371/journal.pmed.1003387 ◽

2020 ◽

Vol 17 (12) ◽

pp. e1003387

Author(s):

Tom Norris ◽

Tim J. Cole ◽

David Bann ◽

Mark Hamer ◽

Rebecca Hardy ◽

...

Keyword(s):

Risk Factors ◽

Cohort Study ◽

Cardiometabolic Risk ◽

Disease Risk ◽

Density Lipoprotein ◽

Negative Control ◽

Cardiometabolic Disease ◽

Birth Cohorts ◽

Lifetime Exposure ◽

Cardiometabolic Disease Risk

Background Individuals with obesity do not represent a homogeneous group in terms of cardiometabolic risk. Using 3 nationally representative British birth cohorts, we investigated whether the duration of obesity was related to heterogeneity in cardiometabolic risk. Methods and findings We used harmonised body mass index (BMI) and cardiometabolic disease risk factor data from 20,746 participants (49.1% male and 97.2% white British) enrolled in 3 British birth cohort studies: the 1946 National Survey of Health and Development (NSHD), the 1958 National Child Development Study (NCDS), and the 1970 British Cohort Study (BCS70). Within each cohort, individual life course BMI trajectories were created between 10 and 40 years of age, and from these, age of obesity onset, duration spent obese (range 0 to 30 years), and cumulative obesity severity were derived. Obesity duration was examined in relation to a number of cardiometabolic disease risk factors collected in mid-adulthood: systolic (SBP) and diastolic blood pressure (DBP), high-density-lipoprotein cholesterol (HDL-C), and glycated haemoglobin (HbA1c). A greater obesity duration was associated with worse values for all cardiometabolic disease risk factors. The strongest association with obesity duration was for HbA1c: HbA1c levels in those with obesity for <5 years were relatively higher by 5% (95% CI: 4, 6), compared with never obese, increasing to 20% (95% CI: 17, 23) higher in those with obesity for 20 to 30 years. When adjustment was made for obesity severity, the association with obesity duration was largely attenuated for SBP, DBP, and HDL-C. For HbA1c, however, the association with obesity duration persisted, independent of obesity severity. Due to pooling of 3 cohorts and thus the availability of only a limited number harmonised variables across cohorts, our models included adjustment for only a small number of potential confounding variables, meaning there is a possibility of residual confounding. Conclusions Given that the obesity epidemic is characterised by a much earlier onset of obesity and consequently a greater lifetime exposure, our findings suggest that health policy recommendations aimed at preventing early obesity onset, and therefore reducing lifetime exposure, may help reduce the risk of diabetes, independently of obesity severity. However, to test the robustness of our observed associations, triangulation of evidence from different epidemiological approaches (e.g., mendelian randomization and negative control studies) should be obtained.

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Selection into shift work is influenced by educational attainment and body mass index: A Mendelian randomization study

10.1101/2020.03.10.20032698 ◽

2020 ◽

Author(s):

Iyas Daghlas ◽

Rebecca C. Richmond ◽

Jacqueline M. Lane ◽

Hassan S. Dashti ◽

Hanna M. Ollila ◽

...

Keyword(s):

Risk Factors ◽

Body Mass Index ◽

Educational Attainment ◽

Body Mass ◽

Shift Work ◽

Cardiometabolic Risk ◽

Mendelian Randomization ◽

Cardiometabolic Risk Factors ◽

Cardiometabolic Disease ◽

Sleep Timing

AbstractBackgroundShift work is associated with increased cardiometabolic disease risk, but whether this association is influenced by cardiometabolic risk factors driving selection into shift work is currently unclear. We addressed this question using Mendelian randomization (MR) in the UK Biobank.MethodsWe created genetic risk scores (GRS) associating with nine cardiometabolic risk factors (including education, body mass index [BMI], smoking, and alcohol consumption), and tested associations of each GRS with self-reported current frequency of shift work and night shift work amongst employed UKB participants of European ancestry (n=190,573). We used summary-level MR sensitivity analyses and multivariable MR to probe robustness of the identified effects, and tested whether effects were mediated through sleep timing preference.ResultsGenetically instrumented lower educational attainment and higher body mass index increased odds of reporting frequent shift work (odds ratio [OR] per 3.6 years [1-SD] decrease in educational attainment=2.40, 95% confidence interval [CI]=2.22-2.59, p=4.84 × 10−20; OR per 4.7kg/m2 [1-SD] increase in BMI=1.30, 95%CI=1.14-1.47, p=5.85 × 10−05). Results were unchanged in sensitivity analyses allowing for different assumptions regarding horizontal pleiotropy, and the effects of education and BMI were independent in multivariable MR. No causal effects were evident for the remaining factors, nor for any exposures on selection out of shift work. Sleep timing preference did not mediate any causal effects.ConclusionsEducational attainment and BMI may influence selection into shift work, which may have implications for epidemiologic associations of shift work with cardiometabolic disease.Key messagesAlthough it has been hypothesized that cardiometabolic risk factors and diseases may influence selection into shift work, little evidence for such an effect is currently available.Using Mendelian randomization, we assessed whether cardiometabolic risk factors and diseases influenced selection into or out of shift work in the UK Biobank.Our results were consistent with a causal effect of both higher BMI and lower educational attainment on selection into current shift work, with stronger effects seen for shift work that is more frequent and includes more night shifts.Using multivariable Mendelian randomization, we found that effects of higher BMI and lower education were independent. Sleep timing preference had a null effect on shift work selection and therefore did not mediate these effects.Selection through education and BMI may bias the relationship of shift work with cardiometabolic disease. Social mechanisms underlying these effects warrant further investigation.

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