LPA (lipoprotein(a); HGNC:6667, NCBI Gene ID 4018) is a human locus mapped to chromosome band 6q25.3-q26 that encodes polymorphic Apolipoprotein(a) glycoprotein (200 to >800 kDa; variable KIV-2 kringle repeats). LPA acts in hepatic assembly of Lipoprotein(a) via disulfide linkage to ApoB-100 & oxidized phospholipid transport, together with APOB (Apolipoprotein B Gene), Apolipoprotein B-100 Protein, and PCSK9 Gene. Encodes apolipoprotein(a), the polymorphic kringle-repeat glycoprotein covalently linked to ApoB-100 in atherogenic lipoprotein(a).
Hepatic assembly of Lipoprotein(a) via disulfide linkage to ApoB-100 & oxidized phospholipid transport
Clinical / Therapeutic Role
Causal monogenic risk factor for atherosclerotic CVD & calcific aortic valve stenosis; target of pelacarsen ASO & olpasiran/lepodisiran siRNAs
Gene Structure & Expression
Genomic Organization & Cytogenetic Locus: Evolved in Old World primates by duplication and remodeling of the adjacent plasminogen (PLG) gene at chromosome 6q25.3-q26; encodes 10 distinct kringle IV subtypes (KIV-1 through KIV-10, with KIV-2 tandemly repeated from 1 to >40 times per allele), one kringle V domain, and a catalytically inactive protease-like domain.
Cellular & Tissue Expression Profile: Synthesized exclusively by hepatic hepatocytes, where over 80–90% of inter-individual variance in plasma Lp(a) concentration is genetically determined by the KIV-2 copy-number variation and cis-acting SNPs (such as rs10455872 and rs3798220).
Molecular Function & Pathways
Biochemical & Physiological Mechanism: Forms a single covalent disulfide bond (between Cys4057 of Apo(a) KIV-9 and Cys4326 of hepatic ApoB-100) to assemble Lipoprotein(a) [Lp(a)], which acts as the primary plasma carrier of proinflammatory oxidized phospholipids (OxPL on KIV-10), infiltrates the arterial intima and aortic valve leaflets, and competitively impairs plasminogen activation and fibrinolysis.
Clinical & Therapeutic Significance
Human Genetic Variants & Disease Phenotypes: Mendelian randomization and genome-wide association studies establish elevated genetically predicted Lp(a) (>50 mg/dL or >125 nmol/L, present in ~20% of the global population) as an independent, causal driver of myocardial infarction, ischemic stroke, peripheral arterial disease, and calcific aortic valve stenosis, whereas biallelic LPA null carriers are healthy with reduced cardiovascular risk.
Therapeutic & Clinical Pharmacology: Because statins do not lower Lp(a), LPA mRNA is the premier target of hepatocyte-directed nucleic acid medicines: the GalNAc-conjugated antisense oligonucleotide pelacarsen and GalNAc-siRNAs olpasiran, zerlasiran, and lepodisiran achieve 80% to >95% sustained reductions in plasma Lp(a), alongside the oral small-molecule Apo(a)-ApoB assembly inhibitor muvalaplin.