Key points Do apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) increase the risk of coronary artery disease (CAD), all-cause mortality, or cause-specific mortality ? ? And, if so, what are the forms of these associations? Findings In this genetic association study using Mendelian randomization that included 347,797 participants of European ancestry from the UK Biobank, genetically predicted apoB and LDL-C were positively associated with coronary heart disease, all-cause mortality, and mortality. cardiovascular, all in a dose-dependent manner. Genetically predicted triglycerides (TG) were positively associated with coronary artery disease (CAD), although the presence of pleiotropy was suggested. Meaning These findings suggest that reduction in apoB (or, equivalently, LDL-C) may be associated with a reduction in cardiovascular morbidity and mortality across its observed distribution. |
Lipid control is essential to prevent cardiovascular morbidity and mortality. Apolipoprotein B (apoB) is emerging as the predominant trait explaining the etiological associations of lipid traits with coronary artery disease (CAD). The association of low-density lipoprotein cholesterol (LDL-C) with CAD is widely accepted and the association of triglycerides (TG) with CAD is also gaining acceptance. However, the dose-response associations of these lipid traits with CAD and mortality remain unclear.
Randomized clinical trials (RCTs) have shown that LDL-C lowering reduces cardiovascular disease (CVD) events and mortality, and intensive LDL-C lowering further reduces CVD events compared to standard lowering of LDL-C. However, no reduction in all-cause mortality or coronary artery disease (CAD) mortality has been demonstrated in trials comparing more and less intensive statin treatments, or in trials adding PCSK9 inhibitors. (proprotein convertase subtilisin and kexin type 9) or ezetimibe to basic treatment with statins.
RCT meta-regression suggests that magnitude of LDL-C reduction is associated with greater reduction in all-cause mortality and coronary artery disease (CAD) mortality in trials of people with low LDL-C. highest initial. RCTs have shown that therapies that primarily lower triglycerides (TG) (i.e., fibrates and omega-3 supplements) reduce coronary artery disease (CAD) events, but have little detectable effect on all-cause mortality. the causes or mortality due to CAD. Previous studies have demonstrated adverse associations of lipid modifiers with myopathy, elevated liver enzymes, and type 2 diabetes.
Taken together, these studies raise the question about the balance of risks and benefits of lipid lowering, particularly for groups with low baseline LDL-C or TG values, as well as for women (who have a lower risk of CAD than men). , and for older people (who generally have more non-cardiovascular comorbidities than younger people).
Observational studies have demonstrated J-shaped associations between LDL-C and TG with all-cause mortality. However, the shape of these associations could also be an indicator of confounding or selection bias. Better understanding the shape of associations of lipid traits with CAD and mortality has clinical implications for determining lipid-lowering targets for the prevention of coronary artery disease (CAD).
Mendelian randomization (MR), an instrumental variable analysis with genetic instruments, takes advantage of genetic randomization at conception to obtain less confounding estimates than conventional observational studies. MR is based on the instrumental variable assumptions of relevance, independence, and exclusion restriction (i.e., genetic instruments must be associated with the exposure, share no common cause with the outcome, and be independent of the outcome given the exposure). .
Previous MRI studies have suggested that apoB, LDL-C, and TG are positively associated with the risk of coronary heart disease and all-cause mortality. However, these studies did not take into account possible nonlinearity and differences by sex or age. To address the gap, we first performed linear MR analyzes to evaluate the associations of genetically predicted apoB, LDL-C, and TG with CAD, all-cause mortality, and cause-specific mortality.
Importance
Apolipoprotein B (apoB), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG) are associated with coronary artery disease (CAD). However, evidence from trials on the association of intensive LDL-C lowering and TG lowering with mortality is less definitive.
Goals
To investigate the associations of apoB, LDL-C and TG with CAD and mortality, both globally and by sex and age, and characterize the forms of these associations.
Design, environment and participants
This 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 through September 2021. The analysis Data collection was carried out from December 2022 to November 2023.
Exhibitions
Genetically predicted ApoB, LDL-C and TG.
Main results and measures
The primary outcomes were coronary artery disease (CAD), all-cause mortality, and cause-specific mortality. Genetic associations with coronary artery disease (CAD) were estimated using logistic regression, associations with all-cause mortality using Cox proportional hazards regression, and associations with cause-specific mortality using proportional hazards regression. Cox model for specific causes with censoring for other causes of mortality.
Results
This study included 347,797 participants (mean [SD] age, 57.2 [8.0] years; 188,330 women [54.1%]). There were 23,818 people who developed DKA and 23,848 people who died.
Genetically predicted apoB was positively associated with risk of coronary heart disease (odds ratio [OR], 1.65 per SD increase; 95% CI, 1.57-1.73) and all-cause mortality (relative risk [HR], 1.11; 95% CI, 1.06-1.16) and cardiovascular mortality (HR, 1.36; 95% CI, 1.24-1.50), with some evidence of associations greater in male participants than in female participants.
The findings were similar for LDL-C .
Genetically predicted triglycerides (TG) were 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 analyzes suggested evidence of pleiotropy . The genetically predicted association of TG with CAD persisted, but was no longer associated with mortality outcomes after controlling for apoB.
Nonlinear Mendelian randomization (MR) suggested that all of these associations increased monotonically across the observed distribution of each lipid trait, with no decrease at low lipid levels. These patterns were observed regardless of sex or age.
Figure: The x-axis represents the apoB level in g/l or the TG level in mmol/l. The y-axis represents the odds ratio (OR) for CAD or the Hazard Ratio (HR) for all-cause mortality relative to the reference, plotted on a logarithmic scale. The median of each lipid trait is established as a reference (1.0 g/l for apoB and 1.5 mmol/l for TG). Black lines represent dose-response association and blue shading represents 95% CIs. The trend test assesses whether there is a linear trend in the stratum-specific estimates, and the fractional polynomial test examines whether a nonlinear model fits the exposure-outcome association better than a linear model.
Conclusions and relevance
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