scholarly journals Milk intake and incident stroke and coronary heart disease in populations of European descent: A Mendelian Randomization study

2021 ◽  
pp. 1-25
Author(s):  
L.E.T. Vissers ◽  
I. Sluijs ◽  
S. Burgess ◽  
N.G. Forouhi ◽  
H. Freisling ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Mendelian Randomization ◽  
Cox Regression ◽  
Milk Intake ◽  
Outcome Analysis ◽  
Milk Consumption ◽  
Uk Biobank ◽  
Chd Risk ◽  
Residual Confounding

Abstract Higher milk intake has been associated with a lower stroke risk, but not with risk of coronary heart disease (CHD). Residual confounding or reverse causation cannot be excluded. Therefore, we estimated the causal association of milk consumption with stroke and CHD risk through instrumental variable (IV) and gene-outcome analyses. IV analysis included 29,328 participants (4,611 stroke; 9,828 CHD) of the EPIC-CVD (8 European countries) and EPIC-NL case-cohort studies. rs4988235, a lactase persistence (LP) single nucleotide polymorphism which enables digestion of lactose in adulthood was used as genetic instrument. Intake of milk was first regressed on rs4988235 in a linear regression model. Next, associations of genetically predicted milk consumption with stroke and CHD were estimated using Prentice-weighted Cox regression. Gene-outcome analysis included 777,024 participants (50,804 cases) from MEGASTROKE (including EPIC-CVD), UK Biobank and EPIC-NL for stroke, and 483,966 participants (61,612 cases) from CARDIoGRAM, UK Biobank and EPIC-CVD and EPIC-NL for CHD. In IV analyses, each additional LP allele was associated with a higher intake of milk in EPIC-CVD (β=13.7 g/day; 95%CI: 8.4-19.1) and EPIC-NL (36.8 g/day; 20.0-53.5). Genetically predicted milk intake was not associated with stroke (HR per 25 g/day 1.05; 95%CI: 0.94-1.16) or CHD (1.02; 0.96-1.08). In gene-outcome analyses, there was no association of rs4988235 with risk of stroke (odds ratios 1.02; 0.99-1.05) or CHD (0.99; 0.95-1.03). Current Mendelian Randomization analysis does not provide evidence for a causal inverse relationship between milk consumption and stroke or CHD risk.

Abstract P150: Association of Cholesterol Measures With Coronary Heart Disease Risk in Blacks and Whites in the Reasons for Geographic and Racial Differences in Stroke Study (regards)

Circulation ◽  
2020 ◽  
Vol 141 (Suppl_1) ◽  
Author(s):  
Neil Zakai ◽  
Jessica Minnier ◽  
Monika M Safford ◽  
Lisandro Colantonio ◽  
Marguerite M Irvin ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Total Cholesterol ◽  
Racial Differences ◽  
Cox Regression ◽  
Disease Risk ◽  
Point Estimate ◽  
Chd Risk ◽  
Increased Risk ◽  
Blacks And Whites

Introduction: Abnormal plasma lipid levels associate with coronary heart disease (CHD) risk. Race interaction for these associations are not established. Hypothesis: We hypothesized that the association of HDL, LDL, and triglyceride with CHD is stronger in whites versus blacks. Methods: The REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort recruited 30,283 black and white individuals aged 45+ from the contiguous U.S. from 2003-7. Participants were followed until December 31, 2016 for CHD events (i.e., myocardial infarction or CHD death), participants with history of CHD at baseline were excluded. Cox regression models were used to assess the association between baseline lipids and incident CHD events adjusting for traditional cardiovascular risk factors. Results: With 23,894 participants (57.8% white and 58.4% female, mean age 64.11± 9.32), over a median 9.9 years of follow-up, 1,487 CHD events occurred (615 among blacks). Overall, higher total Cholesterol, LDL cholesterol, and triglycerides were associated with increased risk of CHD in both blacks and whites with no evidence of a race interaction (Table 1). For HDL, the point estimate was more protective in whites (HR 0.90) than in blacks (HR 0.98), but the interaction was non-significant (p=0.15). However, when HDL was stratified into clinical categories (<40, 40-59, and ≥60), the reduction in point estimates was maintained among whites (HR 1.00, 0.88, and 0.74) but not among blacks (HR 1.00, 1.31, and 1.19) for HDL <40, 40-59, and ≥60 respectively, p-interaction 0.01. Conclusion: Total cholesterol, LDL, and triglycerides predict CHD risk equally in blacks and whites in the REGARDS study, however there is heterogeneity in the protective effect by race, especially when traditional clinical categories are used. In whites, higher HDL is associated with reduced risk, whereas in blacks the association is not maintained. These findings suggest that HDL levels are a more viable metric for white than blacks to predict CHD risk.

scholarly journals Evidence for a causal association between milk intake and cardiometabolic disease outcomes using a two-sample Mendelian Randomization analysis in up to 1,904,220 individuals

2021 ◽  
Author(s):  
Karani Santhanakrishnan Vimaleswaran ◽  
Ang Zhou ◽  
Alana Cavadino ◽  
Elina Hyppönen
Keyword(s):  
Large Scale ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Density Lipoprotein ◽  
Milk Intake ◽  
Milk Consumption ◽  
Causal Association ◽  
Uk Biobank ◽  
Meta Analyses ◽  
Mr Study

Abstract Background High milk intake has been associated with cardio-metabolic risk. We conducted a Mendelian Randomization (MR) study to obtain evidence for the causal relationship between milk consumption and cardio-metabolic traits using the lactase persistence (LCT-13910 C > T, rs4988235) variant as an instrumental variable. Methods We tested the association of LCT genotype with milk consumption (for validation) and with cardio-metabolic traits (for a possible causal association) in a meta-analysis of the data from three large-scale population-based studies (1958 British Birth Cohort, Health and Retirement study, and UK Biobank) with up to 417,236 participants and using summary statistics from consortia meta-analyses on intermediate traits (N = 123,665–697,307) and extended to cover disease endpoints (N = 86,995–149,821). Results In the UK Biobank, carriers of ‘T’ allele of LCT variant were more likely to consume milk (P = 7.02 × 10−14). In meta-analysis including UK Biobank, the 1958BC, the HRS, and consortia-based studies, under an additive model, ‘T’ allele was associated with higher body mass index (BMI) (Pmeta-analysis = 4.68 × 10−12) and lower total cholesterol (TC) (P = 2.40 × 10−36), low-density lipoprotein cholesterol (LDL-C) (P = 2.08 × 10−26) and high-density lipoprotein cholesterol (HDL-C) (P = 9.40 × 10−13). In consortia meta-analyses, ‘T’ allele was associated with a lower risk of coronary artery disease (OR:0.86, 95% CI:0.75–0.99) but not with type 2 diabetes (OR:1.06, 95% CI:0.97–1.16). Furthermore, the two-sample MR analysis showed a causal association between genetically instrumented milk intake and higher BMI (P = 3.60 × 10−5) and body fat (total body fat, leg fat, arm fat and trunk fat; P < 1.37 × 10−6) and lower LDL-C (P = 3.60 × 10−6), TC (P = 1.90 × 10−6) and HDL-C (P = 3.00 × 10−5). Conclusions Our large-scale MR study provides genetic evidence for the association of milk consumption with higher BMI but lower serum cholesterol levels. These data suggest no need to limit milk intakes with respect to cardiovascular disease risk, with the suggested benefits requiring confirmation in further studies.

scholarly journals Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis

2020 ◽  
Author(s):  
Tricia M. Peters ◽  
Michael V. Holmes ◽  
J. Brent Richards ◽  
Tom Palmer ◽  
Vincenzo Forgetta ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
Chd Risk ◽  
Unit Increase

<b>Objective</b>: Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding. <p><b>Methods</b>: Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (N=251,420 women and 212,049 men). Weighted-median, MR Egger, MR-PRESSO and radial MR from summary-level analyses were used for pleiotropy assessment. </p> <p><b>Results</b>: MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.08-1.18 per 1-log unit increase in odds of type 2 diabetes) and men (OR 1.21, 95% CI 1.17-1.26 per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy, however, results were similar after correction for outlier SNPs.</p> <p><b>Conclusions</b>: This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes.</p>

scholarly journals Association of high sensitive C-reactive protein with coronary heart disease: a Mendelian randomization study

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Qian Zhuang ◽  
Chong Shen ◽  
Yanchun Chen ◽  
Xianghai Zhao ◽  
Pengfei Wei ◽  
...  
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Regression Model ◽  
Mendelian Randomization ◽  
Cox Regression ◽  
Causal Effect ◽  
C Reactive Protein ◽  
Reactive Protein ◽  
Hs Crp

Abstract Objectives Whether high sensitivity C-reactive protein (hs-CRP) has a causal effect on coronary heart disease (CHD) is unclear. This study investigated the causal effect of hs-CRP on CHD risk using Mendelian Randomization (MR) analysis. Methods A total of 3802 subjects were recruited in the follow-up study. Linear regression model was used to evaluate the relationship between CRP polymorphisms and hs-CRP. Survival receiver operator characteristic curve method was used to explore the cut-off of hs-CRP on CHD incidence. Cox regression model was applied to detect the association of hs-CRP with CHD by calculating the hazard ratio (HR) and 95% confidence interval (CI). Rs1205 and rs876537 in CRP were selected as instrumental variables in MR analysis. Results During a median follow-up time of 5.01 years, 98 CHD incidence was identified (47.03/104 person-years). Hs-CRP was significantly increased among rs1205 and rs876537 genotypes with r values of 0.064 and 0.066, respectively. Hs-CRP 1.08 mg/L was identified as the cut-off value with a maximum value of sensitivity and specificity on prediction of CHD. Participants with ≥1.08 mg/L of hs-CRP has a higher risk of CHD incidence than that of participants with < 1.08 mg/L, the adjusted HR (95% CI) was 1.69 (1.11–2.60) with a P value of 0.016. No significant casual association was observed between hs-CRP and CHD with a P value of 0.777. Conclusions The association between hs-CRP and CHD is unlikely to be causal, hs-CRP might be a predictor for incidence of CHD in general population.

scholarly journals A robust and efficient method for Mendelian randomization with hundreds of genetic variants: unravelling mechanisms linking HDL-cholesterol and coronary heart disease

2019 ◽  
Author(s):  
Stephen Burgess ◽  
Christopher N Foley ◽  
Elias Allara ◽  
James R Staley ◽  
Joanna MM Howson
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Efficient Method ◽  
Genetic Variants ◽  
Mendelian Randomization ◽  
Mean Squared Error ◽  
Causal Effect ◽  
Hdl Cholesterol ◽  
Distribution Width ◽  
Chd Risk

Mendelian randomization (MR) investigations with large numbers of genetic variants are becoming increasingly common. However, the reliability of findings from a MR investigation is dependent on the validity of the genetic variants as instrumental variables. We developed a method to identify groups of genetic variants with similar causal effect estimates, which may represent distinct mechanisms by which the risk factor influences the outcome. Our contamination mixture method is a robust and efficient method for valid MR in the presence of invalid IVs. Compared to other robust methods, our method had the lowest mean squared error across a range of realistic scenarios. The method is fast and efficient, and can perform analysis with hundreds of variants in a fraction of a second. In a MR analysis for high-density lipoprotein (HDL) cholesterol and coronary heart disease (CHD) risk, the method identified 11 variants associated with increased HDL-cholesterol, decreased triglyceride levels, and decreased CHD risk that had the same directions of associations with platelet distribution width and other blood cell traits, suggesting a shared mechanism linking lipids and CHD risk relating to platelet aggregation.

scholarly journals Shared mechanisms between coronary heart disease and depression: findings from a large UK general population-based cohort

2019 ◽  
Author(s):  
Golam M Khandaker ◽  
Verena Zuber ◽  
Jessica MB Rees ◽  
Livia Carvalho ◽  
Amy M Mason ◽  
...  
Keyword(s):  
Risk Factors ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Genetic Risk ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Population Based ◽  
Depression Risk ◽  
Chd Risk ◽  
Unit Increase

ABSTRACTWhile comorbidity between coronary heart disease (CHD) and depression is evident, it is unclear whether the two diseases have shared underlying mechanisms. We performed a range of analyses in 367,703 unrelated middle-aged participants of European ancestry from UK Biobank, a population based cohort study, to assess whether comorbidity is primarily due to genetic or environmental factors, and to test whether cardiovascular risk factors and CHD are likely to be causally related to depression using Mendelian randomization. We showed family history of heart disease was associated with a 20% increase in depression risk (95% confidence interval [CI] 16% to 24%, p<0.0001), but a genetic risk score that is strongly associated with CHD risk was not associated with depression. An increase of one standard deviation in the CH D genetic risk score was associated with 71% higher CHD risk, but 1% higher depression risk (95% CI 0% to 3%; p=0.11). Mendelian randomization analyses suggested that triglycerides, interleukin-6 (IL-6), and C-reactive protein (CRP) are likely causal risk factors for depression. The odds ratio for depression per standard deviation increase in genetically-predicted triglycerides was 1.18 (95% CI 1.09 to 1.27; p=2×10-5); per unit increase in genetically-predicted log-transformed I L-6 was 0.74 (95% CI 0.62 to 0.89; p=0.0012); and per unit increase in genetically-predicted log-transformed CRP was 1.18 (95% CI 1.07 to 1.29; p=0.0009). Our analyses suggest that comorbidity between depression and CHD arises largely from shared environmental factors. I L-6, CRP and triglycerides, are likely to be causally linked with depression, so could be targets for treatment and prevention of depression.

scholarly journals Sex Differences in the Risk of Coronary Heart Disease Associated With Type 2 Diabetes: A Mendelian Randomization Analysis

2020 ◽  
Author(s):  
Tricia M. Peters ◽  
Michael V. Holmes ◽  
J. Brent Richards ◽  
Tom Palmer ◽  
Vincenzo Forgetta ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Genome Wide Association Study ◽  
Mendelian Randomization ◽  
Causal Effect ◽  
Sensitivity Analyses ◽  
Chd Risk ◽  
Unit Increase

<b>Objective</b>: Observational studies have demonstrated that type 2 diabetes is a stronger risk factor for coronary heart disease (CHD) in women compared with men. However, it is not clear whether this reflects a sex differential in the causal effect of diabetes on CHD risk or results from sex-specific residual confounding. <p><b>Methods</b>: Using 270 single nucleotide polymorphisms (SNPs) for type 2 diabetes identified in a type 2 diabetes genome-wide association study, we performed a sex-stratified Mendelian randomization (MR) study of type 2 diabetes and CHD using individual participant data in UK Biobank (N=251,420 women and 212,049 men). Weighted-median, MR Egger, MR-PRESSO and radial MR from summary-level analyses were used for pleiotropy assessment. </p> <p><b>Results</b>: MR analyses showed that genetic risk of type 2 diabetes increased the odds of CHD for women (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.08-1.18 per 1-log unit increase in odds of type 2 diabetes) and men (OR 1.21, 95% CI 1.17-1.26 per 1-log unit increase in odds of type 2 diabetes). Sensitivity analyses showed some evidence of directional pleiotropy, however, results were similar after correction for outlier SNPs.</p> <p><b>Conclusions</b>: This MR analysis supports a causal effect of genetic liability to type 2 diabetes on risk of CHD that is not stronger for women than men. Assuming a lack of bias, these findings suggest that the prevention and management of type 2 diabetes for CHD risk reduction is of equal priority in both sexes.</p>

Associations of observational and genetically determined caffeine intake with coronary artery disease and diabetes

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A Said ◽  
Y.J Van De Vegte ◽  
N Verweij ◽  
P Van Der Harst
Keyword(s):  
Coronary Artery Disease ◽  
Coronary Artery ◽  
Mendelian Randomization ◽  
Cox Regression ◽  
Caffeine Intake ◽  
Uk Biobank ◽  
Genome Wide ◽  
Artery Disease ◽  
Genetically Determined

Abstract Background Caffeine is the most widely consumed psychostimulant and is associated with lower risk of coronary artery disease (CAD) and type 2 diabetes (T2D). However, whether these associations are causal remains unknown. Objectives This study aimed to identify genetic variants associated with caffeine intake, and to investigate possible causal links between genetically determined caffeine intake and CAD or T2D. Additionally, we aimed to replicate previous observational findings between caffeine intake and CAD or T2D. Methods Genome wide associated studies (GWAS) were performed on caffeine intake from coffee, tea or both in 407,072 UK Biobank participants. Identified variants were used in a two-sample Mendelian randomization (MR) approach to investigate evidence for causal links between caffeine intake and CAD in CARDIoGRAMplusC4D (60,801 cases; 123,504 controls) or T2D in DIAGRAM (26,676 cases; 132,532 controls). Observational associations were tested within UK Biobank using Cox regression analyses. Results Moderate observational caffeine intakes from coffee or tea were associated with lower risks of CAD or T2D compared to no or high intake, with the lowest risks at intakes of 120–180 mg/day from coffee for CAD (HR=0.77 [95% CI: 0.73–0.82; P&lt;1e-16]), and 300–360 mg/day for T2D (HR=0.76 [95% CI: 0.67–0.86]; P=1.57e-5). GWAS identified 51 novel genetic loci associated with caffeine intake, enriched for central nervous system genes. In contrast to observational analyses, MR analyses in CARDIoGRAMplusC4D and DIAGRAM yielded no evidence for causal links between caffeine intake and the development of CAD or T2D. Conclusions MR analyses indicate caffeine intake might not protect against CAD or T2D, despite protective associations in observational analyses. Manhattan_plot_CaffeineIntake Funding Acknowledgement Type of funding source: None

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

2019 ◽  
pp. 204748731989467 ◽  
Author(s):  
Liu Miao ◽  
Guo-Xiong Deng ◽  
Rui-Xing Yin ◽  
Rong-Jun Nie ◽  
Shuo Yang ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Acute Myocardial Infarction ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Mendelian Randomization ◽  
Plasma Homocysteine ◽  
Sensitivity Analyses ◽  
Nucleotide Polymorphisms ◽  
Genome Wide ◽  
Artery Disease

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

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