Lp(a) is not associated with arterial stiffness: a Mendelian randomization study

Abstract Background Deeper understanding of the potential causal relationship between Lp(a) and vascular injury will provide further insight to related pathways to be monitored and targeted by emerging treatments. Accumulating evidence supports the causal association of lipoprotein(a) [Lp(a)] with cardiovascular disease and calcific aortic valve disease (AVD). Arterial stiffening is mechanistically linked with cardiovascular disease and AVD severity. We hypothesized that Lp(a) may be causally associated with pulse-wave velocity (PWV) as the gold-standard marker of arterial stiffness. Aim To investigate the potential causal association of Lp(a) levels with PWV. Methods We performed a two sample Mendelian randomization (MR) analysis of LP(a) on PWV by combining the summary data of two independent Genetic-Wide Association Study (GWASs). Genetic variants associated with Lp(a) were retrieved from the UK Biobank (N=220,497). A GWAS based on a cohort in Germany (N=7,000) was used to obtain genetic associations for PWV index (outcome). We assessed two different measures of arterial stiffness, brachial ankle (baPWV) and carotid femoral pulse (cfPWV) wave velocity. In total, we used 170 SNPs as Instrument Variables (IV's) and applied a two sample MR with the main technique of Inverse Variance Weighting method (IVW). We conducted sensitivity analyses (MR-Egger and Median based) to detect pleiotropy of the causal variants and to test for robustness of our findings. Results Our analyses based on all 170 SNP's did not find evidence for causal relationship between Lp(a) and PWV for neither measurement [bivw (baPWV) = −0.0005, CI (−0.0043, 0.0034), P=0.8 and bivw (cfPWV) = −0.006, CI (−0.013, 0.002), P=0.16 for brachial ankle and carotid-femoral PWV, respectively]. Sensitivity analyses, including weighted median and mode-based estimation, did not show significant association of Lp (a) with neither baPWV nor cfPWV. Conclusions Lp(a) is not causally associated with arterial stiffness. These findings suggest that arterial stiffening is not involved Lp(a)-mediated cardiovascular and aortic valve disease. Funding Acknowledgement Type of funding sources: None.