Genome-Wide Association Study and Identification of a Protective Missense Variant on Lipoprotein(a) Concentration : Protective Missense Variant on Lipoprotein(a) Concentration-Brief Report

Abstract

Objective: Lipoprotein(a) (Lp[a]) is associated with coronary artery disease (CAD) but also to LDL (low-density lipoprotein) cholesterol. The genetic architecture of Lp(a) remains incompletely understood, as well as its independence of LDL cholesterol in its association to CAD. We investigated the genetic determinants of Lp(a) concentrations in a large prospective multiethnic cohort. We tested the association for potential causality between genetically determined higher Lp(a) concentrations and CAD using a multivariable Mendelian randomization strategy. Approach and Results: We studied 371 212 participants of the UK Biobank with available Lp(a) and genome-wide genetic data. Genome-wide association analyses confirmed 2 known and identified 37 novel loci (P Conclusions: This study supports an LDL cholesterol-independent causal link between Lp(a) and CAD. A rare missense variant in the LPA gene locus appears to be protective in people with the Lp(a) increasing variant of rs10455872. In the search for therapeutic targets of Lp(a), future work should focus on understanding the functional consequences of this missense variant.