Plasma lipid composition and risk of developing cardiovascular disease

Abstract

Aims: We tested whether characteristic changes of the plasma lipidome in individuals with comparable total lipids level associate with future cardiovascular disease (CVD) outcome and whether 23 validated gene variants associated with coronary artery disease (CAD) affect CVD associated lipid species.

Methods and results: Screening of the fasted plasma lipidome was performed by top-down shotgun analysis and lipidome compositions compared between incident CVD cases (n = 211) and controls (n = 216) from the prospective population-based MDC study using logistic regression adjusting for Framingham risk factors. Associations with incident CVD were seen for eight lipid species (0.21≤q≤0.23). Each standard deviation unit higher baseline levels of two lysophosphatidylcholine species (LPC), LPC16∶0 and LPC20∶4, was associated with a decreased risk for CVD (P = 0.024-0.028). Sphingomyelin (SM) 38∶2 was associated with increased odds of CVD (P = 0.057). Five triglyceride (TAG) species were associated with protection (P = 0.031-0.049). LPC16∶0 was negatively correlated with the carotid intima-media thickness (P = 0.010) and with HbA1c (P = 0.012) whereas SM38∶2 was positively correlated with LDL-cholesterol (P = 0.0*10(-6)) and the q-values were good (q≤0.03). The risk allele of 8 CAD-associated gene variants showed significant association with the plasma level of several lipid species. However, the q-values were high for many of the associations (0.015≤q≤0.75). Risk allele carriers of 3 CAD-loci had reduced level of LPC16∶0 and/or LPC 20∶4 (P≤0.056).

Conclusion: Our study suggests that CVD development is preceded by reduced levels of LPC16∶0, LPC20∶4 and some specific TAG species and by increased levels of SM38∶2. It also indicates that certain lipid species are intermediate phenotypes between genetic susceptibility and overt CVD. But it is a preliminary study that awaits replication in a larger population because statistical significance was lost for the associations between lipid species and future cardiovascular events when correcting for multiple testing.

Figure 1. Quantification by top-down lipidomics correlates with clinical parameters.

Linear regression analysis of A) the total triglyceride content or B) the total cholesterol content determined by MS versus the value obtained by traditional clinical chemistry analysis. The total triglyceride content measured by MS is obtained by summing the abundances of all the individual TAG species and the total cholesterol content by summing the abundances of free cholesterol and all cholesteryl esters.

Figure 2. Association between the lipid profile and the risk allele of 8 CAD-associated gene variants.

Heat map of regression coefficients obtained from linear regressions performed between the CAD-associated locus (with the CAD-associated allele coded) and the lipid species after log transformation adjusting for age and sex. *P<0.05, ^o P<0.01, ⁺ P<0.001.