Causal association between lipoproteins and risk of coronary artery disease—a systematic review and meta-analysis of Mendelian randomization studies

Objective

To systematically evaluate the causal effect of lipoproteins to the risk of coronary artery disease (CAD) by systematic review and meta-analysis of the associated Mendelian randomization (MR) studies.

Methods

This systematic review was registered in PROSPERO (ID CRD42023465430). Searches from the databases (e.g., PubMed, Embase, Cochrane, Web of Science) and non-database sources to collect MR studies. The search time frame was from the database inception to August 2023. After data extraction, quality evaluation was performed, and the meta-analysis with bias evaluation was carried out with RevMan software.

Results

A total of 5,828,409 participants from 21 records were included. Quality and bias assessment was performed by evaluating the internal three assumptions of MR studies. Meta-analysis for the causal association between non-HDL lipoproteins and CAD showed a significantly positive association between LDL and CAD (OR 1.37, 95% CI 1.26–1.49; P < 0.001, I² = 95%), apoB and CAD (OR 1.38, 95% CI 1.11–1.71; P = 0.003, I² = 98%), and Lp(a) and CAD (OR 1.21, 95% CI 1.12–1.31; P < 0.001, I² = 99%). Interestingly, although there was no statistical significance in the association between VLDL/apoA1 and CAD (both P > 0.05), the pooled non-HDL lipoproteins showed a significantly positive association with CAD (OR 1.28, 95% CI 1.22–1.34; P < 0.001, I² = 99%). For the HDL lipoproteins, the pooled OR showed a significantly negative association with CAD (OR 0.84, 95% CI 0.72–0.98; P = 0.002, I² = 72%). However, the protective effect of HDL on CAD diminished when analyzed together with apoA1 and/or apoB (both P > 0.05). The funnel plot did not show serious publication bias, and sensitivity analysis performed relatively well robustness of the causal association of LDL, apoB, Lp(a), and total cholesterol with CAD.

Conclusion

The present meta-analysis suggests an overall effect of causal association between lipoproteins and CAD. Most of the non-HDL lipoproteins (LDL, apoB, Lp(a)) promote CAD, while the protective effect of HDL in CAD still needs to be verified in the future.

Graphical abstract

• The roles of lipoproteins in the development of CAD have been raised due to various reasons, and no systemic review has analyzed data from MR studies yet.

• This study included a total of 5,828,409 participates from 21 records with quality and bias assessed.

• The present meta-analysis suggests a overall effect of causal association between lipoproteins and CAD. Most of the non-HDL lipoproteins (LDL, apoB, Lp(a)) promotes CAD, while the protective effect of HDL in CAD still need to be verified in future.