One in five individuals displays elevated lipoprotein (a) [Lp(a)], a highly atherogenic lipoprotein resembling low-density lipoproteins (LDL). Pathophysiological, epidemiological and genetic studies demonstrate that when circulating Lp(a) levels are high (above 125 nmol/L), cardiovascular event rates sharply increase. The major structural difference between Lp(a) and LDL is that Lp(a) contains a large signature protein, apolipoprotein (a) [apo(a)]. Apo(a) is extremely polymorphic in size as it contains 1 to more than 40 kringle-IV2 (KIV2) domains giving origin to more than 40 isoforms in humans. The size of apo(a) is inversely correlated with the circulating levels of Lp(a), but the exact molecular and metabolic pathways regulating Lp(a) plasma concentrations have not been clearly established yet. The goal of the present research project is to decipher these pathways. (1) For instance, the molecular mechanisms governing Lp(a) production are poorly understood. Short RNAs (miRs) control gene expression and have been shown to modulate lipoproteins homeostasis. miRs work by inducing RNA silencing and thereby reduce target genes expression. We will investigate the influence of these regulatory elements on the expression of the gene encoding apo(a). (2) In the population, Lp(a) levels can vary by up to 100-fold in carriers of identical apo(a) isoforms. We have recruited a large family in which several individuals present extremely high Lp(a) levels. We will determine the genetic causes on their apo(a) gene that are responsible for their extreme Lp(a) plasma concentrations leading to premature cardiovascular events. (3) Lp(a) levels are resistant to lifestyle changes and lipid lowering drugs such as statins, which poses a real challenge for clinical management. A novel class of lipid lowering agents, the PCSK9 inhibitors induce a 30% reduction in circulating Lp(a) levels. We will investigate the mechanisms by which PCSK9 inhibitors modulate Lp(a) plasma levels and the influence of the size of apo(a) on the response of patients to these novel therapies. (4) The gene encoding apolipoprotein E (apoE) is the only gene besides apo(a) and pcsk9 to have a significant association with circulating Lp(a) levels. Humans display three major apoE isoforms (e2/e3/e4) that differ by the presence of different amino acids at position 112 and 158. Carriers of the e2 allele display much lower Lp(a) than non-e2 carriers. We will study the pathway by which this particular apoE isoform lowers Lp(a) in humans. Taken together these studies have profound implications in terms of deciphering the genetic and metabolic pathways regulating plasma Lp(a) levels, and pave the way to enhanced diagnosis and therapeutics approaches for patients at high risk of Lp(a)-induced cardiovascular diseases.