scholarly journals Investigating pleiotropic effects of statins on ischemic heart disease in the UK Biobank using Mendelian randomisation

eLife ◽  
2020 ◽  
Vol 9 ◽  
Author(s):  
CM Schooling ◽  
JV Zhao ◽  
SL Au Yeung ◽  
GM Leung
Keyword(s):  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Pleiotropic Effects ◽  
Ischemic Heart ◽  
Mendelian Randomisation ◽  
Uk Biobank ◽  
Pcsk9 Inhibitors ◽  
Mediated Effects ◽  
Reverse Pattern ◽  
The Uk

We examined whether specifically statins, of the major lipid modifiers (statins, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe) have pleiotropic effects on ischemic heart disease (IHD) via testosterone in men or women. As a validation, we similarly assessed whether a drug that unexpectedly likely increases IHD also operates via testosterone. Using previously published genetic instruments we conducted a sex-specific univariable and multivariable Mendelian randomization study in the UK Biobank, including 179918 men with 25410 IHD cases and 212080 women with 12511 IHD cases. Of these three lipid modifiers, only genetically mimicking the effects of statins in men affected testosterone, which partly mediated effects on IHD. Correspondingly, genetically mimicking effects of anakinra on testosterone and IHD presented a reverse pattern to that for statins. These insights may facilitate the development of new interventions for cardiovascular diseases as well as highlighting the importance of sex-specific explanations, investigations, prevention and treatment.

scholarly journals Age and sex specific effects of APOE genotypes on ischemic heart disease and its risk factors in the UK Biobank

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Mengyu Li ◽  
Jie V. Zhao ◽  
Man Ki Kwok ◽  
C. Mary Schooling
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Pulse Pressure ◽  
Glycated Haemoglobin ◽  
Ischemic Heart ◽  
Uk Biobank ◽  
The Uk ◽  
Age And Sex

AbstractAPOE genotypes are associated with ischemic heart disease (IHD), several other cardiovascular diseases and dementia. Previous studies have not comprehensively considered all genotypes, especially ε2ε2, nor associations by age and sex, although IHD incidence differs by sex. In the UK Biobank, including 391,992 white British participants, we compared effects of APOE genotypes on IHD and its risk factors. Compared to the ε3ε3 genotype, ε2ε2 was not clearly associated with IHD but was associated with lower plasma apolipoprotein B (apoB). The ε2ε3 genotype conferred lower IHD risk, systolic blood pressure (SBP), pulse pressure and plasma apoB than ε3ε3. ε3ε4 and ε4ε4 conferred higher IHD risk, higher pulse pressure and plasma apoB, but lower glycated haemoglobin (HbA1c) than ε3ε3. The associations by age and sex were fairly similar, except ε2ε2 compared to ε3ε3 was marginally positively associated with IHD in the younger age group and nominally inversely associated with SBP in men. ε3ε4 compared to ε3ε3 was nominally positively associated with SBP in women. APOE genotypes affect IHD risk increasingly from ε2ε3, ε3ε3, ε3ε4 to ε4ε4, with similar patterns for pulse pressure and plasma apoB, but not for diabetes. Associations with blood pressure differed by sex. Greater understanding of products of APOE and their effects might generate targets of intervention.

Gluten Intake and All-Cause and Cause-Specific Mortality: Prospective Findings from the UK Biobank

2020 ◽  
Author(s):  
Inken Behrendt ◽  
Mathias Fasshauer ◽  
Gerrit Eichner
Keyword(s):  
Heart Disease ◽  
Celiac Disease ◽  
Ischemic Heart Disease ◽  
Primary Objective ◽  
Ischemic Heart ◽  
Uk Biobank ◽  
Disease Mortality ◽  
Specific Mortality ◽  
Ischemic Heart Disease Mortality ◽  
The Uk

ABSTRACT Background Gluten has been linked to adverse effects on metabolic and vascular health. Objectives The present study determines the association between dietary gluten intake and all-cause (primary objective), as well as cause-specific, mortality in people without celiac disease. Methods Gluten intake was estimated in 159,265 participants of the UK Biobank which is a large multicenter, prospective cohort study initiated in 2006. Cox proportional hazard regression models were used and HRs were determined for all-cause and cause-specific mortality. All models were adjusted for confounders and multiple testing. Results Median (IQR) age was 57 (49–62) y with 52.1% of participants being female. Gluten intake was 8.5 (5.1–12.4) g/d with significantly higher consumption in males [10.0 (6.3–14.1) g/d] than in females [7.2 (4.6–10.7) g/d] (P < 0.0001). During a median follow-up of 11.1 (10.6–11.9) y and 1.8 million person-years, 6259 deaths occurred. Gluten intake was not significantly associated with all-cause mortality after adjusting for confounders (HR: 1.00; 95% CI: 1.00, 1.01; P = 0.59). Dietary gluten was not significantly associated with cancer (HR: 1.00; 95% CI: 1.00, 1.01; raw P = 0.24) or noncancer (HR: 1.00; 95% CI: 0.99, 1.01; raw P = 0.56) mortality. However, gluten intake was positively associated with ischemic heart disease mortality (HR: 1.02; 95% CI: 1.01, 1.04; raw P = 0.003, Holm-adjusted P = 0.04). Conclusions Gluten intake is not significantly associated with all-cause and cancer mortality in adults without celiac disease. The findings support the hypothesis that limiting gluten intake is unlikely to provide significant overall survival benefits on a population level. The positive association between gluten intake and ischemic heart disease mortality requires further study.

scholarly journals The Effect of Elevated Body Mass Index on Ischemic Heart Disease Risk: Causal Estimates from a Mendelian Randomisation Approach

PLoS Medicine ◽  
2012 ◽  
Vol 9 (5) ◽  
pp. e1001212 ◽  
Author(s):  
Børge G. Nordestgaard ◽  
Tom M. Palmer ◽  
Marianne Benn ◽  
Jeppe Zacho ◽  
Anne Tybjærg-Hansen ◽  
...  
Keyword(s):  
Body Mass Index ◽  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Body Mass ◽  
Disease Risk ◽  
Ischemic Heart ◽  
Mendelian Randomisation ◽  
Elevated Body Mass Index ◽  
Ischemic Heart Disease Risk ◽  
Heart Disease Risk

Secondary prevention of ischemic heart disease and PCSK9 inhibitors

Therapy ◽  
2021 ◽  
Vol 2_2021 ◽  
pp. 105-111
Author(s):  
Kuznetzov A.A. Kuznetzov ◽  
Mal G.S. Mal ◽  
◽  
Keyword(s):  
Heart Disease ◽  
Secondary Prevention ◽  
Ischemic Heart Disease ◽  
Ischemic Heart ◽  
Pcsk9 Inhibitors

scholarly journals Effect of glutamate and aspartate on ischemic heart disease, blood pressure, and diabetes: a Mendelian randomization study

2019 ◽  
Vol 109 (4) ◽  
pp. 1197-1206 ◽  
Author(s):  
Jie V Zhao ◽  
M K Kwok ◽  
C Mary Schooling
Keyword(s):  
Blood Pressure ◽  
Sensitivity Analysis ◽  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Evolutionary Biology ◽  
Mendelian Randomization ◽  
Meta Analysis ◽  
Genetic Selection ◽  
Ischemic Heart ◽  
Uk Biobank

ABSTRACT Background Evolutionary biology suggests reproduction trades off against longevity. Genetic selection in favor of fertility and ischemic heart disease (IHD) exists in humans. Observationally, soy protects against IHD. Soy amino acids, glutamate and aspartate, may lower androgens. No large randomized controlled trials testing their health effects exist. Objective Using Mendelian randomization, we assessed how genetically predicted glutamate and aspartate affected IHD, blood pressure, and diabetes. Methods A separate sample instrumental variable analysis with genetic instruments was used to obtain unconfounded estimates using genetic variants strongly (P < 5 × 10−8) and solely associated with glutamate or aspartate applied to an IHD case (n ≤76,014)–control (n ≤ 264,785) study (based on a meta-analysis of CARDIoGRAMplusC4D 1000 Genomes, UK Biobank CAD SOFT GWAS and Myocardial Infarction Genetics and CARDIoGRAM Exome), blood pressure from the UK Biobank (n ≤ 361,194), and the DIAbetes Genetics Replication And Meta-analysis diabetes case (n = 26,676)–control (n = 132,532) study. A weighted median and MR-Egger were used for a sensitivity analysis. Results Glutamate was not associated with IHD, blood pressure, or diabetes after correction for multiple comparisons. Aspartate was inversely associated with IHD (odds ratio (OR) 0.92 per log-transformed standard deviation (SD); 95% confidence interval (CI) 0.88, 0.96) and diastolic blood pressure (−0.03; 95% CI −0.04, −0.02) using inverse variance weighting, but not diabetes (OR 1.00; 95% CI 0.91, 1.09). Associations were robust to the sensitivity analysis. Conclusions Our findings suggest aspartate may play a role in IHD and blood pressure, potentially underlying cardiovascular benefits of soy. Clarifying the mechanisms would be valuable for IHD prevention and for defining a healthy diet.

scholarly journals Genetically predicted sex hormone binding globulin and ischemic heart disease in men and women: a univariable and multivariable Mendelian randomization study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jie V. Zhao ◽  
C. Mary Schooling
Keyword(s):  
Heart Disease ◽  
Ischemic Heart Disease ◽  
Mendelian Randomization ◽  
Sex Hormone ◽  
Ischemic Heart ◽  
Sex Hormone Binding Globulin ◽  
Inverse Association ◽  
Hormone Binding ◽  
The Uk

AbstractMen are more vulnerable to ischemic heart disease (IHD) than women, possibly due to testosterone. Correspondingly, sex hormone binding globulin (SHBG) which lowers circulating testosterone might protect men against IHD. SHBG may also affect IHD independent of testosterone, which has not previously been examined. To assess the sex-specific role of SHBG in IHD, in univariable Mendelian randomization (MR), we used sex-specific, genome-wide significant genetic variants to predict SHBG, and examined their association with IHD in the UK Biobank. We also replicated using genetic instruments from Japanese men and applied to Biobank Japan. To assess the role of SHGB independent of testosterone in men, we used multivariable MR controlling for testosterone. Genetically predicted SHBG was associated with lower IHD risk in men [odds ratio (OR) 0.78 per standard deviation, 95% confidence interval (CI) 0.70 to 0.87], and the association was less clear in women. The estimates were similar in Japanese. The inverse association remained after controlling for testosterone in men (OR 0.79, 95% CI 0.71 to 0.88). SHBG might lower the risk of IHD in men, with a role independent of testosterone. Exploring intervention strategies that increase SHBG is important for targeting IHD treatments.

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