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The relationship between lipoprotein(a) and risk of cardiovascular disease: a Mendelian randomization analysis
Shiyue Wang1, Li Zha1, Jian Chen1
1The Fourth Affiliated Hospital of Harbin Medical University Cardiovascular Medical Department, Harbin, 150000, Heilongjiang, China.
Insights
This study found that elevated Lipoprotein(a) [Lp(a)] levels causally increase the risk of coronary heart disease, aortic aneurysm, and large artery stroke. These findings support better Lp(a) management to reduce cardiovascular disease.
Area of Science:
- Cardiovascular Genetics
- Epidemiology
- Precision Medicine
Background:
- Lipoprotein(a) [Lp(a)] is a recognized residual risk factor for cardiovascular disease (CVD) even with optimal low-density lipoprotein cholesterol (LDL-C) levels.
- The causal link between Lp(a) and various CVDs remains under investigation, with limited existing evidence.
Purpose of the Study:
- To investigate the potential causal relationship between Lipoprotein(a) [Lp(a)] and multiple cardiovascular diseases (CVDs) using a large-scale genome-wide association study (GWAS) dataset.
- To leverage Mendelian randomization (MR) to assess the etiological role of Lp(a) in conditions including coronary heart disease (CHD), aortic aneurysm (AA), and ischemic stroke (IS).
Main Methods:
- Employed a two-sample Mendelian randomization (MR) analysis utilizing a large GWAS dataset for Lp(a) (n=377,590) from European populations.
- Analyzed associations between Lp(a) and various CVDs, including AA, atrial fibrillation (AF), CHD, hypertension (HBP), heart failure (HF), and different types of stroke (IS, ISL, ISS, LIS), using inverse variance weighted (IVW) methods as the primary approach.
- Utilized sensitivity analyses including MR-Egger, weighted median, and MR-PRESSO to ensure the robustness of the findings.
Main Results:
- The MR analysis indicated a significant causal relationship between elevated Lp(a) levels and an increased risk of aortic aneurysm (OR=1.005, P=0.009), coronary heart disease (OR=1.003, P=0.010), and large artery stroke (OR=1.003, P=9.50E-11).
- No significant causal association was found between Lp(a) and atrial fibrillation, hypertension, heart failure, overall ischemic stroke, small vessel stroke, or lacunar stroke.
- Sensitivity analyses, including MR-PRESSO, corroborated the primary findings regarding the causal links between Lp(a) and specific CVDs.
Conclusions:
- This Mendelian randomization study provides strong evidence for a causal role of Lipoprotein(a) [Lp(a)] in the development of coronary heart disease, aortic aneurysm, and large artery stroke.
- The findings underscore the importance of considering Lp(a) as a therapeutic target for CVD prevention.
- Improved management strategies targeting Lp(a) may lead to a significant reduction in the overall burden of cardiovascular disease.
Background:
Lipoprotein(a) [Lp(a)] is one of the residual risk factors for cardiovascular disease (CVD) in the setting of optimal low-density lipoprotein cholesterol (LDL-C). The association between Lp(a) and CVD is still in the exploratory phase, with few studies indicating a causal connection between Lp(a) and various CVD.
Methods:
Lp(a) (n = 377,590) was a genome-wide association study (GWAS) based on European populations from Neale Lab. Large GWAS datasets for CVD, including aortic aneurysm(AA) (n = 209,366), atrial fibrillation(AF) (n = 1,030,836), coronary heart disease(CHD) (n = 361,194), secondary hypertension(HBP) (n = 164,147), heart failure(HF) (n = 208,178), ischemic stroke (IS) (n = 218,792), large artery atherosclerosis stroke(ISL) (n = 150, 765), small vessel stroke(ISS) (n = 198,048), lacunar stroke(LIS) (n = 225,419), and pulmonary embolism(PE) (n = 218,413) were also based on European populations. We performed separate univariate two-sample Mendelian randomization (MR) analysis for Lp(a) and CVD as described above. We evaluated this connection mainly using the random-effects inverse variance weighted technique(IVW1) with a 95% confidence interval (CI) for the odds ratio (OR). This was supplemented by MR-Egger, weighted median, maximum likelihood, penalized weighted median, and fixed-effects inverse variance weighted methods. MR-PRESSO offers another means of statistical detection.
Results:
Our two-sample MR, which was predominately based on IVW1, revealed a causal relationship between Lp(a) and AA (OR = 1.005, 95%CI: 1.001-1.010, P = 0.009), CHD (OR = 1.003, 95%CI 1.001-1.004, P = 0.010), and ISL (OR = 1.003, 9 5%CI 1.002-1.004, P = 9.50E-11), in addition, there is no causal association with AF, HBP, HF, IS, ISS, LIS, or PE. Similar conclusions were reached by the MR-PRESSO method.
Conclusion:
This MR study suggested a causal relationship between Lp(a) and CHD, AA, and ISL, but not associated with AF, HF, IS, LIS, ISS, HBP, or PE. Our work further verifies the association between Lp(a) and various CVD, resulting in improved Lp(a) management and a reduction in the prevalence of CVD.
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