title: Role of six single nucleotide polymorphisms, risk factors in coronary disease, in OLR1 alternative splicing.
abstract: The OLR1 gene encodes the oxidized low-density lipoprotein receptor (LOX-1), which is responsible for the cellular uptake of oxidized LDL (Ox-LDL), foam cell formation in atheroma plaques and atherosclerotic plaque rupture. Alternative splicing (AS) of OLR1 exon 5 generates two protein isoforms with antagonistic functions in Ox-LDL uptake. Previous work identified six single nucleotide polymorphisms (SNPs) in linkage disequilibrium that influence the inclusion levels of OLR1 exon 5 and correlate with the risk of cardiovascular disease. Here we use minigenes to recapitulate the effects of two allelic series (Low- and High-Risk) on OLR1 AS and identify one SNP in intron 4 (rs3736234) as the main contributor to the differences in exon 5 inclusion, while the other SNPs in the allelic series attenuate the drastic effects of this key SNP. Bioinformatic, proteomic, mutational and functional high-throughput analyses allowed us to define regulatory sequence motifs and identify SR protein family members (SRSF1, SRSF2) and HMGA1 as factors involved in the regulation of OLR1 AS. Our results suggest that antagonism between SRSF1 and SRSF2/HMGA1, and differential recognition of their regulatory motifs depending on the identity of the rs3736234 polymorphism, influence OLR1 exon 5 inclusion and the efficiency of Ox-LDL uptake, with potential implications for atherosclerosis and coronary disease.
authors.affiliation: Centre de Regulació Genòmica, 08003 Barcelona, Spain Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: J Ramón
authors.initials: JR
authors.lastname: Tejedor
authors.affiliation: Centre de Regulació Genòmica, 08003 Barcelona, Spain Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Hagen
authors.initials: H
authors.lastname: Tilgner
authors.affiliation: Centre de Regulació Genòmica, 08003 Barcelona, Spain Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Camilla
authors.initials: C
authors.lastname: Iannone
authors.affiliation: Centre de Regulació Genòmica, 08003 Barcelona, Spain Universitat Pompeu Fabra, 08003 Barcelona, Spain.
authors.forename: Roderic
authors.initials: R
authors.lastname: Guigó
authors.affiliation: Centre de Regulació Genòmica, 08003 Barcelona, Spain Universitat Pompeu Fabra, 08003 Barcelona, Spain Institució Catalana de Recerca i Estudis Avançats, 08020 Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Valcárcel
mesh_terms: D017398:Alternative Splicing; D019295:Computational Biology / Q000379:methods; D003327:Coronary Disease / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease; D025741:HMGA1a Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007438:Introns; D015810:Linkage Disequilibrium; D008077:Lipoproteins, LDL / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D038621:Regulatory Sequences, Ribonucleic Acid; D012261:Ribonucleoproteins / Q000235:genetics / Q000378:metabolism*; D051127:Scavenger Receptors, Class E / Q000235:genetics* / Q000378:metabolism; D000068103:Serine-Arginine Splicing Factors
chemical_list: D008077:Lipoproteins, LDL; D009687:Nuclear Proteins; C495137:OLR1 protein, human; D016601:RNA-Binding Proteins; D038621:Regulatory Sequences, Ribonucleic Acid; D012261:Ribonucleoproteins; D051127:Scavenger Receptors, Class E; C099252:oxidized low density lipoprotein; D025741:HMGA1a Protein; C073288:SRSF2 protein, human; D000068103:Serine-Arginine Splicing Factors
keywords: OLR1; RRM; SNP; SR proteins; alternative splicing; coronary disease; linkage disequilibrium