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 (Lowand 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.

Integrative microRNA-gene expression network analysis in genetic hypercalciuric stone-forming rat kidney

“…Lpin2, which is associated with fatty acid, triacylglycerol, and ketone body metabolism ( Chen et al, 2015 ), also had a high degree of connectivity of 9. Olr1, a crucial regulator of lipid metabolism ( Tejedor et al, 2015 ), had a degree of connectivity of 8. Increasing numbers of studies are reporting a strong correlation between obesity/dyslipidemia and kidney stones ( De, Liu & Monga, 2014 ; Fujimura et al, 2014 ).…”

The roles of RNA processing in translating genotype to phenotype

“…There is a growing number of individual genes for which variant-specific splicing patterns have been directly linked with disease susceptibility, including splice variants of oxidized low-density lipoprotein receptor 1 ( OLR1 ) and low-density lipoprotein receptor ( LDLR ) that are linked with coronary artery disease and splice variants of interleukin-7 receptor ( IL7R ) that are linked with multiple sclerosis 37–39 . However, broad-based evidence for the role of pre-mRNA splicing in disease risk comes from GWAS that have identified common SNVs that affect splicing and disease trait loci.…”

Peer Review #3 of "Integrative microRNA-gene expression network analysis in genetic hypercalciuric stone-forming rat kidney (v0.1)"

“…Lpin2, which is associated with fatty acid, triacylglycerol, and ketone body metabolism (Chen et al 2015), also had a high degree of connectivity of 9. Olr1, a crucial regulator of lipid metabolism (Tejedor et al 2015), had a degree of connectivity of 8. Increasing numbers of studies are reporting a strong correlation between obesity/dyslipidemia and kidney stones (De SK et al 2014;Fujimura et al 2014).…”