What explains the effect of education on cardiovascular disease? Applying Mendelian randomization to identify the consequences of education inequality

Key PointsQuestionWhat is the role of body mass index, systolic blood pressure and smoking in mediating the effect of education on cardiovascular disease risk?FindingWe find consistent evidence that body mass index, systolic blood pressure and smoking mediate the effect of education, explaining up to 18%, 27% and 33% respectively. Including all three risk factors in a model together explains around 40% of the effect of education.MeaningIntervening on body mass index, systolic blood pressure and smoking would lead to reductions in cases of CVD attributable to lower levels of education. Over half of the effect of education on risk of cardiovascular disease is not mediated through these risk factors.ImportanceLower levels of education are causally related to higher cardiovascular risk, but the extent to which this is driven by modifiable risk factors also associated with education is unknown.ObjectiveTo investigate the role of body mass index, systolic blood pressure and smoking in explaining the effect of education on risk of cardiovascular disease outcomes.DesignMultivariable regression analysis of observational data and Mendelian randomization (MR) analysis of genetic data.SettingUK Biobank and international genome-wide association study consortia.ParticipantsPredominantly individuals of European ancestry.Main outcomes and measuresThe effects of education (per 1-standard deviation increase, equivalent to 3.6 years) on coronary heart disease, cardiovascular disease (all subtypes), myocardial infarction and stroke risk (all measured in odds ratio, OR), and the degree to which this is mediated through body mass index, systolic blood pressure and smoking.ResultsEach additional standard deviation of education associated with 13% lower risk of coronary heart disease (OR 0.87, 95% confidence interval [CI] 0.84 to 0.89) in observational analysis and 37% lower risk (OR 0.63, 95% CI 0.60 to 0.67) in Mendelian randomization analysis. As a proportion of the total risk reduction, body mass index mediated 15% (95% CI 13% to 17%) and 18% (95% CI 14% to 23%) in the observational and Mendelian randomization estimates, respectively. Corresponding estimates for systolic blood pressure were 11% (95% CI 9% to 13%) and 21% (95% CI 15% to 27%), and for smoking, 19% (15% to 22%) and 33% (95% CI 17% to 49%). All three risk factors combined mediated 42% (95% CI 36% to 48%) and 36% (95 % CI 16% to 63%) of the effect of education on coronary heart disease in observational and Mendelian randomization respectively. Similar results were obtained when investigating risk of stroke, myocardial infarction and all-cause cardiovascular disease.Conclusions and relevanceBMI, SBP and smoking mediate a substantial proportion of the protective effect of education on risk of cardiovascular outcomes and intervening on these would lead to reductions in cases of CVD attributable to lower levels of education. However, more than half of the protective effect of education remains unexplained and requires further investigation.

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P4346Religious education and midlife observance are associated with lower coronary heart disease (CHD) mortality 23 years later

European Heart Journal ◽

10.1093/eurheartj/ehz745.0754 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

S Eilat-Adar ◽

U Goldbourt

Keyword(s):

Blood Pressure ◽

Body Mass Index ◽

Socioeconomic Status ◽

Coronary Heart Disease ◽

Heart Disease ◽

Systolic Blood Pressure ◽

Body Mass ◽

Reference Group ◽

Middle Aged

Abstract Objective To determine whether self-reported religiosity is associated with decreased coronary mortality risk in middle-aged men when rates are adjusted for known confounders. Design The Israeli Ischemic Heart Disease (IIHD) Project (n=10,232) was chosen by stratified sampling of civil servants and municipal male employees, men aged 40–65 in 1963. Subjects were seen upon enrollment (1963) and at two follow-up visits (1965 and 1968). Extent of religiosity according to belief and practice collected in 1965 on a scale from 1 to 5. Religiosity was defined as follow: (1) The most-strict observance of religious rules “Haredim”. (2) “Religious” (3) “Traditional” (4) “Secular” (5) The part of the latter who declared themselves to be “nonbelievers” were categorized as “agnostic”. Main outcome measure Coronary heart disease (CHD) death, determined from death certificates in 23 years of follow-up Results Among 9245 participants, 1098 died from CHD during 23 years follow up. Ever smoking, Body mass index (BMI) and socioeconomic status were significantly lower while age and diabetes were higher according to increasing religiosity. Religiosity was inversely related to CHD mortality. Demographic, anthropometric characteristics according to religion, and odds ratio (OR), 95% confidence interval (95% CI), for CHD mortality, (using agnostic as a reference group) are presented in table 1. Characteristics according to religion Religiosity Haredim (n=2103) Religious (n=1528) Traditional (n=1782) Secular (n=2085) Agnostic (n=1747) P for trend Age years (SD) 50.2 (6.9) 48.8 (6.6) 48.4 (6.7) 48.8 (6.6) 45.9 (6.8) <0.001 Ever smoking% 58.7 67.6 70.7 71.9 72.6 0.001 Systolic blood pressure (mmHg) 136 (21) 135 (20) 135 (21) 134 (20) 135 (20) 0.115 Diabetes (%) 9.8 11.1 8.3 8.8 6.5 <0.001 Socioeconomic status 2.2 (1.3) 2.3 (1.1) 2.7 (1.1) 2.7 (1.2) 3.1 (1.4) <0.001 BMI kg/m2 (SD) 22.5 (3.6) 25.9 (3.5) 25.9 (3.2) 25.6 (3.2) 25.4 (2.9) 0.028 Cholesterol (mg%) 201 (38) 207 (41) 208 (39) 214 (40) 218 (40) 0.001 Number of death (% category) 187 (8.9) 161 (10.5) 185 (10.4) 228 (10.9) 225 (12.9) <0.001 OR (95% CI)* 0.67 (0.53–0.85) 0.85 (0.67–1.08) 0.84 (0.67–1.05) 0.87 (0.71–1.08) 1 *Adjusted for age, cigarette smoking, systolic blood pressure, diabetes, socioeconomic status, body mass index and cholesterol. Conclusion Religiosity was associated with lower CHD death in employed middle aged Israeli men followed up prospectively for 23 years.

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Risk factors mediating the effect of body mass index and waist-to-hip ratio on cardiovascular outcomes: Mendelian randomization analysis

International Journal of Obesity ◽

10.1038/s41366-021-00807-4 ◽

2021 ◽

Author(s):

Dipender Gill ◽

Verena Zuber ◽

Jesse Dawson ◽

Jonathan Pearson-Stuttard ◽

Alice R. Carter ◽

...

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Cardiovascular Disease ◽

Body Mass Index ◽

Body Mass ◽

Mendelian Randomization ◽

European Ancestry ◽

Standard Deviation Increase ◽

Waist To Hip Ratio ◽

Artery Disease

Abstract Background Higher body mass index (BMI) and waist-to-hip ratio (WHR) increase the risk of cardiovascular disease, but the extent to which this is mediated by blood pressure, diabetes, lipid traits, and smoking is not fully understood. Methods Using consortia and UK Biobank genetic association summary data from 140,595 to 898,130 participants predominantly of European ancestry, Mendelian randomization mediation analysis was performed to investigate the degree to which systolic blood pressure (SBP), diabetes, lipid traits, and smoking mediated an effect of BMI and WHR on the risk of coronary artery disease (CAD), peripheral artery disease (PAD) and stroke. Results The odds ratio of CAD per 1-standard deviation increase in genetically predicted BMI was 1.49 (95% CI 1.39 to 1.60). This attenuated to 1.34 (95% CI 1.24 to 1.45) after adjusting for genetically predicted SBP (proportion mediated 27%, 95% CI 3% to 50%), to 1.27 (95% CI 1.17 to 1.37) after adjusting for genetically predicted diabetes (41% mediated, 95% CI 18% to 63%), to 1.47 (95% CI 1.36 to 1.59) after adjusting for genetically predicted lipids (3% mediated, 95% −23% to 29%), and to 1.46 (95% CI 1.34 to 1.58) after adjusting for genetically predicted smoking (6% mediated, 95% CI −20% to 32%). Adjusting for all the mediators together, the estimate attenuated to 1.14 (95% CI 1.04 to 1.26; 66% mediated, 95% CI 42% to 91%). A similar pattern was observed when considering genetically predicted WHR as the exposure, and PAD or stroke as the outcome. Conclusions Measures to reduce obesity will lower the risk of cardiovascular disease primarily by impacting downstream metabolic risk factors, particularly diabetes and hypertension. Reduction of obesity prevalence alongside control and management of its mediators is likely to be most effective for minimizing the burden of obesity.

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Risk Factors for Cardiovascular Diseases: a Study at National Institute of Cardiovascular Diseases (NICVD)

Bangladesh Medical Journal ◽

10.3329/bmj.v39i2.7031 ◽

1970 ◽

Vol 39 (2) ◽

pp. 16-21

Author(s):

S Jabeen ◽

M Haque

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Body Mass Index ◽

Coronary Heart Disease ◽

Medical Journal ◽

Heart Disease ◽

Cardiovascular Diseases ◽

Systolic Blood Pressure ◽

Key Words ◽

Key Words Risk Factors

Key words: Risk factors; Coronary Heart Disease (CHD); Systolic Blood Pressure (SBP); Diastolic Blood PRessure (DBP); Body Mass Index (BMI); Waist Hip Ratio (WHR)DOI: 10.3329/bmj.v39i2.7031Bangladesh Medical Journal 2010, 39(2) pp.16-21

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The N363S Polymorphism of the Glucocorticoid Receptor: Potential Contribution to Central Obesity in Men and Lack of Association with Other Risk Factors for Coronary Heart Disease and Diabetes Mellitus1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.5.7465 ◽

2001 ◽

Vol 86 (5) ◽

pp. 2270-2274 ◽

Cited By ~ 1

Author(s):

Mark G. Dobson ◽

Christopher P. F. Redfern ◽

Nigel Unwin ◽

Jolanta U. Weaver

Keyword(s):

Diabetes Mellitus ◽

Risk Factors ◽

Blood Pressure ◽

Body Mass Index ◽

Coronary Heart Disease ◽

Heart Disease ◽

Glucocorticoid Receptor ◽

Body Mass ◽

Central Obesity ◽

Density Lipoprotein

Considerable evidence suggests that diabetes mellitus and hypertension are influenced by genetic factors. Studies in humans have associated glucocorticoid receptor (GR) polymorphisms with high blood pressure, insulin sensitivity, body mass index, increased visceral fat, and variations in tissue-specific steroid sensitivity. The N363S polymorphism of the GR results in an asparagine to serine amino acid substitution in a modulatory region of the receptor. Phosphorylation of serine residues in this region has been shown to enhance transactivation of GR responsive genes. The aim of this study was to investigate the association between the 363S allele and risk factors for coronary heart disease and diabetes mellitus in a population of European origin living in the northeast of the United Kingdom. Blood samples from 135 males and 240 females were characterized for 363 allele status. The overall frequency of the 363S allele was 3.0%, 23 heterozygotes (7 males and 16 females) but no 363S homozygotes were identified. The data show a significant association of the 363S allele with increased waist to hip ratio in males but not females. This allele was not associated with blood pressure, body mass index, serum cholesterol, triglycerides, low-density lipoprotein and high-density lipoprotein cholesterol levels, and glucose tolerance status. The results of this study suggest that this GR polymorphism may contribute to central obesity in men. Further studies are required to elucidate the properties of GR363S at a molecular level.

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Body mass index and metabolic risk factors for coronary heart disease in women

European Heart Journal ◽

10.1053/euhj.2000.2469 ◽

2001 ◽

Vol 22 (1) ◽

pp. 46-55 ◽

Cited By ~ 47

Author(s):

W Ashton

Keyword(s):

Risk Factors ◽

Body Mass Index ◽

Coronary Heart Disease ◽

Heart Disease ◽

Body Mass ◽

Metabolic Risk Factors ◽

Metabolic Risk

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Risk factors mediating the effect of body-mass index and waist-to-hip ratio on cardiovascular outcomes: Mendelian randomization analysis

10.1101/2020.07.15.20154096 ◽

2020 ◽

Author(s):

Dipender Gill ◽

Verena Zuber ◽

Jesse Dawson ◽

Jonathan Pearson-Stuttard ◽

Alice R Carter ◽

...

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Cardiovascular Disease ◽

Body Mass Index ◽

Body Mass ◽

European Ancestry ◽

Standard Deviation Increase ◽

Waist To Hip Ratio ◽

Increased Risk ◽

Artery Disease

Background: Higher body-mass index (BMI) and waist-to-hip ratio (WHR) increase the risk of cardiovascular disease, but the extent to which this is mediated by blood pressure, diabetes, lipid traits and smoking is not fully understood. Methods: Using consortia and UK Biobank genetic association summary data from 140,595 to 898,130 participants predominantly of European ancestry, MR mediation analysis was performed to investigate the degree to which genetically predicted systolic blood pressure (SBP), diabetes, lipid traits and smoking mediated an effect of genetically predicted BMI and WHR on risk of coronary artery disease (CAD), peripheral artery disease (PAD) and stroke. Results: The 49% (95% confidence interval [CI] 39%-60%) increased risk of CAD conferred per 1-standard deviation increase in genetically predicted BMI attenuated to 34% (95% CI 24%-45%) after adjusting for genetically predicted SBP, to 27% (95% CI 17%-37%) after adjusting for genetically predicted diabetes, to 47% (95% CI 36%-59%) after adjusting for genetically predicted lipids, and to 46% (95% CI 34%-58%) after adjusting for genetically predicted smoking. Adjusting for all the mediators together, the increased risk attenuated to 14% (95% CI 4%-26%). A similar pattern of attenuation was observed when considering genetically predicted WHR as the exposure, and PAD or stroke as the outcomes. Conclusions: Measures to reduce obesity will lower risk of cardiovascular disease primarily by impacting on downstream metabolic risk factors, particularly diabetes and hypertension. Reduction of obesity prevalence alongside control and management of its mediators is likely to be most effective for minimizing the burden of obesity.

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Relation Between Preclinical Atherosclerosis and Venous Thromboembolism in Patients With Thrombophilias – Longitudinal Study

Physiological Research ◽

10.33549/physiolres.932879 ◽

2014 ◽

pp. S403-S409 ◽

Cited By ~ 1

Author(s):

O. AUZKÝ ◽

R. DEMBOVSKÁ ◽

J. MRÁZKOVÁ ◽

Š. NOVÁKOVÁ ◽

L. PAGÁČOVÁ ◽

...

Keyword(s):

Risk Factors ◽

Blood Pressure ◽

Body Mass Index ◽

Longitudinal Study ◽

Venous Thromboembolism ◽

Waist Circumference ◽

Systolic Blood Pressure ◽

Body Mass ◽

History Of ◽

Preclinical Atherosclerosis

Preclinical atherosclerosis may represent a risk factor for venous thromboembolism (VTE). In longitudinal study we followed longitudinally 96 patients (32 men) with thrombophilias with (n=51) and without (n=45) history of VTE. In both groups we studied the changes of preclinical atherosclerosis at peripherally located arteries detected by ultrasound. In addition, we assessed changes in selected risk factors of atherosclerosis. During the mean follow-up of 56.0±7.62 months we did not find significant change in preclinical atherosclerosis defined as Belcaro score in either group (–3 % in the VTE group vs 0 % in non VTE group). Significant increase in body mass index (1.03±1.98 kg*m-2, resp. 1.21±1.67 kg*m-2, p<0.01) and non-significant increase in systolic blood pressure were detected in both groups. Waist circumference increased significantly only in patients without VTE (4.11±7.84 cm, p<0.05). No differences in changes of risk factors under study between both groups were detected. In summary, patients with thrombophilia and history of VTE showed no evidence of greater progression of atherosclerosis or increase in traditional risk factors of atherosclerosis than patients with thrombophilia without history of VTE. Unfavorable changes of body mass index, waist circumference and systolic blood pressure were detected in both groups during study period.

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