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

Schooling, CM; Zhao, JV; Yeung, SL Au; Leung, GM

doi:10.7554/elife.58567

Cited by 29 publications

(33 citation statements)

References 92 publications

(139 reference statements)

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“…It's result was consistent with our results. In addition, Schooling et al [46] investigated the pleiotropic effect of statins on CHD and found that the effect of statins on CHD was mediated by BT, and they found that BT was positively correlated with CHD, which was consistent with our point estimate of BT.…”

Section: Discussionsupporting

confidence: 87%

Causal effect of sex hormone-binding globulin and testosterone on coronary heart disease: A multivariable and network Mendelian randomization analysis

Hou

et al. 2021

International Journal of Cardiology

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Background: Although observational studies have shown an association between sex hormone-binding globulin (SHBG), testosterone (T) and cardiovascular diseases (CVD), controversy remains. In this study, we aim to explore the causal effects of SHBG and T on Coronary heart disease (CHD). Methods: We used univariable, network and multivariable mendelian randomization (MR) analysis to investigate the causal effect of SHBG and T on CHD. We performed inverse variance weighted (IVW) MR as the primary analysis, with the robustness of this approach further tested by other methods in sensitivity analysis. The SHBG and T were collected from the UK Biobank data, about 180,000 men aged 40 to 69 years. CHD was collected from CARDIoGRAMplusC4D 1000 Genomes-based GWAS, which was a meta-analysis including 48 studies and involving 60,801 CHD cases and 123,504 controls. Results: Using univariable MR-IVW, the results suggested that a one standard deviation (SD) increase in SHBG, the risk of CHD decreased by approximately 14% (OR (95% CI): 0.86(0.76,0.97)), and that a SD increase in total testosterone (TT), the risk also decreased, approximately 8% (OR (95% CI): 0.92(0.85,0.99)). Multivariable MR showed that both SHBG and TT had no direct causal effect with CHD (a SD increase in SHBG: OR (95% CI):0.75 (0.57,1.00), P = 0.053; a SD increase in TT: OR (95% CI): 1.05(0.90,1.22), P = 0.53). In the network MR analysis, the results suggested that TT might act as mediator in the causal pathway from SHBG to CHD and account for 93% of the total effect of SHBG on CHD, and that SHBG might be a mediator in the causal pathway from TT to CHD and account for 67% of the total effect of TT on CHD. Conclusions: Genetically predicted SHBG and TT were negatively correlated with CHD in both univariable and network MR, which may provide a causal explanation behind the observed conclusion. In addition, TT and SHBG had a bidirectional causal effect. Further work is required to disentangle the downstream effects of SHBG/TT on CHD and the molecular pathways involved, as the simultaneous regulation of SHBG and TT may make it a viable strategy for the prevention or treatment of CHD.

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Section: Discussionsupporting

confidence: 87%

Causal effect of sex hormone-binding globulin and testosterone on coronary heart disease: A multivariable and network Mendelian randomization analysis

Hou

et al. 2021

International Journal of Cardiology

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“…Previous MR studies have suggested that calcium increases the risk of ischemic heart disease (IHD) [ 38 – 40 ] and SHBG reduces it [ 40 ], so these mechanisms together might have a relatively neutral effect on IHD in women. Sex-specific effects of calcium and SHBG on IHD have not been fully assessed, so how these effects would affect specifically women is unknown, although broadly statins appear to have the same effects on IHD in men and women after accounting for testosterone [ 8 ]. SHBG inactivates sex hormones, so lowering SHBG might increase the availability of sex hormones and increase the risk of any related conditions.…”

Section: Discussionmentioning

confidence: 99%

“…We cannot exclude the possibility that some novel effects of statins have been missed, which could be addressed by repeating this study when larger sex-specific genetic studies are available. Third, we used rs12916 and associated genetic variants as a surrogate for the pharmacological effects of statins [ 12 ], which mimics a life-long small dose of endogenous statins [ 8 , 10 , 13 ], so the MR estimates represent life-long inhibition of HMGCR [ 8 , 10 ] and do not necessarily reflect the effects of statin treatment which generally starts in middle age [ 10 , 61 ]. These estimates are usually different in magnitude from the short-term effects of pharmacologic interventions in an RCT [ 62 ] although similar effect sizes have been seen for genetically mimicked statins and use of statins [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

“…rs12916 downregulates hepatic HMGCR expression and hence lowers serum LDL-c [ 12 ]. We used the lead SNPs rs11591147 [ 23 ] and rs10260606 [ 8 , 24 ] to genetically mimic PCSK9 inhibitors and ezetimibe respectively (Additional file 1 : Table S1). In sensitivity analysis for significant phenotypes for rs12916, we used all genetic variants mimicking statins taking into account their correlations, and similarly for PCSK9 inhibitors and ezetimibe (correlation coefficient matrixes shown at Additional file 1 : Table S2-4).…”

Section: Methodsmentioning

confidence: 99%

“…Beyond their effectiveness as a cardiovascular intervention via lipid modification, pleiotropic effects of statins have long been suggested [ 3 – 5 ]. Cardiovascular-related pleiotropic effects of statins may include beneficial effects via a range of potentially inter-related factors, including inflammatory responses [ 6 , 7 ], endothelial function [ 5 ], possibly prothrombin time, and sex hormones [ 8 ]. More recently, Mendelian randomization (MR) studies have indicated that statins may reduce the risk of cancer by a lipid-independent pathway [ 9 ] as well as specifically reducing epithelial ovarian cancer [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

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A phenome-wide association study of genetically mimicked statins

Schooling

2021

BMC Med

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Background Beyond their success in cardiovascular disease prevention, statins are increasingly recognized to have sex-specific pleiotropic effects. To gain additional insight, we characterized associations of genetically mimicked statins across the phenotype sex-specifically. We also assessed whether any apparently non-lipid effects identified extended to genetically mimicking other widely used lipid modifiers (proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors and ezetimibe) or were a consequence of low-density lipoprotein cholesterol (LDL-c). Methods We performed a sex-specific phenome-wide association study assessing the association of genetic variants in HMGCR, mimicking statins, with 1701 phenotypes. We used Mendelian randomization (MR) to assess if any non-lipid effects found were evident for genetically mimicked PCSK9 inhibitors and ezetimibe or for LDL-c. Results As expected, genetically mimicking statins was inversely associated with LDL-c, apolipoprotein B (ApoB), and total cholesterol (TC) and positively associated with glycated hemoglobin (HbA1c) and was related to body composition. Genetically mimicking statins was also inversely associated with serum calcium, sex hormone-binding globulin (SHBG), and platelet count and positively associated with basal metabolic rate (BMR) and mean platelet volume. Stronger associations with genetically mimicked statins were evident for women than men for lipid traits (LDL-c, ApoB, and TC), calcium, and SHBG, but not for platelet attributes, body composition, or BMR. Genetically mimicking PCSK9 inhibitors or ezetimibe was also associated with lower lipids, but was not related to calcium, SHBG, BMR, or body composition. Genetically higher LDL-c increased lipids and decreased BMR, but did not affect calcium, HbA1c, platelet attributes, or SHBG with minor effects on body composition. Conclusions Similar inverse associations were found for genetically mimicking statins on lipid traits in men and women as for other lipid modifiers. Besides the positive associations with HbA1c, BMI (which may explain the higher BMR), and aspects of body composition in men and women, genetically mimicking statins was additionally associated with platelet attributes in both sexes and was inversely associated with serum calcium and SHBG in women. This genetic evidence suggests potential pathways that contribute to the effects of statins particularly in women. Further investigation is needed to confirm these findings and their implications for clinical practice.

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Dose-Response Associations of Lipid Traits With Coronary Artery Disease and Mortality

Yang,

Mason,

Wood

et al. 2024

JAMA Netw Open

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ImportanceApolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) are associated with coronary artery disease (CAD). However, trial evidence for the association of intensive LDL-C lowering and TG lowering with mortality is less definitive.ObjectivesTo investigate the associations of apoB, LDL-C, and TG with CAD and mortality, both overall and by sex and age, and to characterize the shapes of these associations.Design, Setting, and ParticipantsThis genetic association study used linear and nonlinear mendelian randomization (MR) to analyze a population-based cohort of individuals of European ancestry from the UK Biobank, which recruited participants from 2006 to 2010 with follow-up information updated until September 2021. Data analysis occurred from December 2022 to November 2023.ExposuresGenetically predicted apoB, LDL-C, and TG.Main Outcomes and MeasuresThe primary outcomes were CAD, all-cause mortality, and cause-specific mortality. Genetic associations with CAD were calculated using logistic regression, associations with all-cause mortality using Cox proportional hazards regression, and associations with cause-specific mortality using cause-specific Cox proportional hazards regression with censoring for other causes of mortality.ResultsThis study included 347 797 participants (mean [SD] age, 57.2 [8.0] years; 188 330 female [54.1%]). There were 23 818 people who developed CAD and 23 848 people who died. Genetically predicted apoB was positively associated with risk of CAD (odds ratio [OR], 1.65 per SD increase; 95% CI 1.57-1.73), all-cause mortality (hazard ratio [HR], 1.11; 95% CI, 1.06-1.16), and cardiovascular mortality (HR, 1.36; 95% CI, 1.24-1.50), with some evidence for larger associations in male participants than female participants. Findings were similar for LDL-C. Genetically predicted TG was positively associated with CAD (OR, 1.60; 95% CI 1.52-1.69), all-cause mortality (HR, 1.08; 95% CI, 1.03-1.13), and cardiovascular mortality (HR, 1.21; 95% CI, 1.09-1.34); however, sensitivity analyses suggested evidence of pleiotropy. The association of genetically predicted TG with CAD persisted but it was no longer associated with mortality outcomes after controlling for apoB. Nonlinear MR suggested that all these associations were monotonically increasing across the whole observed distribution of each lipid trait, with no diminution at low lipid levels. Such patterns were observed irrespective of sex or age.Conclusions and relevanceIn this genetic association study, apoB (or, equivalently, LDL-C) was associated with increased CAD risk, all-cause mortality, and cardiovascular mortality, all in a dose-dependent way. TG may increase CAD risk independent of apoB, although the possible presence of pleiotropy is a limitation. These insights highlight the importance of apoB (or, equivalently, LDL-C) lowering for reducing cardiovascular morbidity and mortality across its whole distribution.

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

Cited by 29 publications

References 92 publications

Causal effect of sex hormone-binding globulin and testosterone on coronary heart disease: A multivariable and network Mendelian randomization analysis

Causal effect of sex hormone-binding globulin and testosterone on coronary heart disease: A multivariable and network Mendelian randomization analysis

A phenome-wide association study of genetically mimicked statins

Dose-Response Associations of Lipid Traits With Coronary Artery Disease and Mortality

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