title: Sortilin and the risk of cardiovascular disease.
abstract: Plasma low-density lipoprotein cholesterol (LDL-C) levels are a key determinant of the risk of cardiovascular disease, which is why many studies have attempted to elucidate the pathways that regulate its metabolism. Novel latest-generation sequencing techniques have identified a strong association between the 1p13 locus and the risk of cardiovascular disease caused by changes in plasma LDL-C levels. As expected for a complex phenotype, the effects of variation in this locus are only moderate. Even so, knowledge of the association is of major importance, since it has unveiled a new metabolic pathway regulating plasma cholesterol levels. Crucial to this discovery was the work of three independent teams seeking to clarify the biological basis of this association, who succeeded in proving that SORT1, encoding sortilin, was the gene in the 1p13 locus involved in LDL metabolism. SORT1 was the first gene identified as determining plasma LDL levels to be mechanistically evaluated and, although the three teams used different, though appropriate, experimental methods, their results were in some ways contradictory. Here we review all the experiments that led to the identification of the new pathway connecting sortilin with plasma LDL levels and risk of myocardial infarction. The regulatory mechanism underlying this association remains unclear, but its discovery has paved the way for considering previously unsuspected therapeutic targets and approaches.
authors.affiliation: Grupo de Investigação em Doenças Lisossomais de Sobrecarga, Unidade de I&D; Departamento de Genética Humana, INSA, Porto, Portugal; IPATIMUP, Porto, Portugal; Departamento de Biologia, Faculdade de Ciências, Universidade do Porto, Porto, Portugal. Electronic address: francisca_coutinho@yahoo.com.
authors.forename: Maria Francisca
authors.initials: MF
authors.lastname: Coutinho
authors.forename: Mafalda
authors.initials: M
authors.lastname: Bourbon
authors.forename: Maria João
authors.initials: MJ
authors.lastname: Prata
authors.forename: Sandra
authors.initials: S
authors.lastname: Alves
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D002318:Cardiovascular Diseases / Q000097:blood / Q000235:genetics*; D008078:Cholesterol, LDL / Q000097:blood; D055106:Genome-Wide Association Study; D006801:Humans; D009203:Myocardial Infarction / Q000097:blood / Q000235:genetics; D012307:Risk Factors; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D008078:Cholesterol, LDL; D000099183:Sortilin
keywords: C/EBP; CCAAT-enhancer binding protein; CT; Colesterol lipoproteína de baixa densidade; Coronary artery disease; DAC; DALYs; DCI; DCV; Doença das artérias coronárias; EAM; Functional genetics; GLUT4; GM2 activator protein; GM2AP; GWAS; Genome wide association studies; Genome-wide association studies; Genómica funcional; HDL; High-density lipoproteins; LDL; LPL; Lipoprotein metabolism; Low-density lipoprotein cholesterol; Low-density lipoproteins; Metabolismo das lipoproteínas; RAP; SAP; SNP; Sortilin; Sortilina; apo; apolipoproteína; colesterol total; disability-adjusted life years; doença cardíaca isquémica; doença cerebrovascular; doença das artérias coronárias; enfarte agudo do miocárdio; glucose transport isoform 4; lipoproteina lípase; receptor associated protein; single nucleotide polymorphism; sphingolipid activator protein