Association of Lipoprotein (a) variants with risk of cardiovascular disease: a Mendelian randomization study

Abstract

Background: There is a well-documented empirical relationship between lipoprotein (a) [Lp(a)] and cardiovascular disease (CVD); however, causal evidence, especially from the Chinese population, is lacking. Therefore, this study aims to estimate the causal association between variants in genes affecting Lp(a) concentrations and CVD in people of Han Chinese ethnicity.

Methods: Two-sample Mendelian randomization analysis was used to assess the causal effect of Lp(a) concentrations on the risk of CVD. Summary statistics for Lp(a) variants were obtained from 1256 individuals in the Cohort Study on Chronic Disease of Communities Natural Population in Beijing, Tianjin and Hebei. Data on associations between single-nucleotide polymorphisms (SNPs) and CVD were obtained from recently published genome-wide association studies.

Results: Thirteen SNPs associated with Lp(a) levels in the Han Chinese population were used as instrumental variables. Genetically elevated Lp(a) was inversely associated with the risk of atrial fibrillation [odds ratio (OR), 0.94; 95% confidence interval (95%CI), 0.901-0.987; P = 0.012)], the risk of arrhythmia (OR, 0.96; 95%CI, 0.941-0.990; P = 0.005), the left ventricular mass index (OR, 0.97; 95%CI, 0.949-1.000; P = 0.048), and the left ventricular internal dimension in diastole (OR, 0.97; 95%CI, 0.950-0.997; P = 0.028) according to the inverse-variance weighted method. No significant association was observed for congestive heart failure (OR, 0.99; 95% CI, 0.950-1.038; P = 0.766), ischemic stroke (OR, 1.01; 95%CI, 0.981-1.046; P = 0.422), and left ventricular internal dimension in systole (OR, 0.98; 95%CI, 0.960-1.009; P = 0.214).

Conclusions: This study provided evidence that genetically elevated Lp(a) was inversely associated with atrial fibrillation, arrhythmia, the left ventricular mass index and the left ventricular internal dimension in diastole, but not with congestive heart failure, ischemic stroke, and the left ventricular internal dimension in systole in the Han Chinese population. Further research is needed to identify the mechanism underlying these results and determine whether genetically elevated Lp(a) increases the risk of coronary heart disease or other CVD subtypes.

Keywords: Arrhythmia; Atrial fibrillation; Cardiovascular risk; Congestive heart failure; East Asian; Ischemic stroke; Lipoprotein (a).

Fig. 1

Conceptual framework for the Mendelian randomization analysis of Lp(a) and the risk of cardiovascular diseases

Fig. 2

Causal estimates of genetically predicted Lp(a) level in cardiovascular diseases

Fig. 3

1 Associations of Lp(a) variants with Congestive Heart Failure in different methods. Fig. 3–2. Associations of Lp(a) variants with Ischemic Stroke in different methods. Fig. 3–3. Associations of Lp(a) variants with Atrial Fibrillation in different methods. Fig. 3–4. Associations of Lp(a) variants with Arrhythmia in different methods. Fig. 3–5. Associations of Lp(a) variants with Left Ventricular Mass Index in different methods. Fig. 3–6. Associations of Lp(a) variants with Left Ventricular Internal Dimension in Diastole in different methods. Fig. 3–7. Associations of Lp(a) variants with Left Ventricular Internal Dimension in Systole in different methods