Contemporary perspectives on the genetics and clinical use of lipoprotein(a) in preventive cardiology.

Purpose of review The pathogenicity of lipoprotein(a) [Lp(a)] as a risk factor for atherosclerotic cardiovascular disease (ASCVD) is well evidenced and recognized by international consensus-based guidelines. However, the measurement of Lp(a) is not routine clinical practice. Therapeutic agents targeting Lp(a) are now progressing through randomised clinical trials, and it is timely for clinicians to familiarize themselves with this complex and enigmatic lipoprotein particle. Recent findings Recent developments in the understanding of genetic influences on the structure, plasma concentration and atherogenicity of Lp(a) have contextualized its clinical relevance. Mendelian randomization studies have enabled estimation of the contribution of Lp(a) to ASCVD risk. Genotyping individual patients with respect to Lp(a)-raising single nucleotide polymorphisms predicts ASCVD, but has not yet been shown to add value beyond the measurement of Lp(a) plasma concentrations, which should be done by Lp(a) isoform-independent assays capable of reporting in molar concentrations. Contemporary gene-silencing technology underpins small interfering RNA and antisense oligonucleotides, which are emerging as the leading Lp(a)-lowering therapeutic agents. The degree of Lp(a)-lowering required to achieve meaningful reductions in ASCVD risk has been estimated by Mendelian randomization, providing conceptual support. Summary Measurement of Lp(a) in the clinical setting contributes to the assessment of ASCVD risk, and will become more important with the advent of specific Lp(a)-lowering therapies. Knowledge of an individual patient's genetic predisposition to increased Lp(a) appears to impart little or not additional clinical value beyond Lp(a) particle concentration.