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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.

SUBMITTER: Tejedor JR

PROVIDER: S-EPMC4436670 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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Role of six single nucleotide polymorphisms, risk factors in coronary disease, in OLR1 alternative splicing.

Tejedor J Ramón JR Tilgner Hagen H Iannone Camilla C Guigó Roderic R Valcárcel Juan J

RNA (New York, N.Y.) 20150422 6

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 ...[more]

PMID: 25904137

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Project description:BACKGROUND:Coronary artery disease (CAD) shares common risk factors with type 2 diabetes (T2DM). Variations in the transcription factor 7-like 2 (TCF7L2) gene, particularly rs7903146, increase T2DM risk. Potential links between genetic variants of the TCF7L2 locus and coronary atherosclerosis are uncertain. We therefore investigated the association between TCF7L2 polymorphisms and angiographically determined CAD in diabetic and non-diabetic patients. METHODOLOGY/PRINCIPAL FINDINGS:We genotyped TCF7L2 variants rs7903146, rs12255372, and rs11196205 in a cross-sectional study including 1,650 consecutive patients undergoing coronary angiography for the evaluation of established or suspected stable CAD. Significant CAD was diagnosed in the presence of coronary stenoses ?50%. Variant rs7903146 in the total study cohort was significantly associated with significant CAD (adjusted additive OR?=?1.29 [1.09-1.53]; p?=?0.003). This association was strong and significant in T2DM patients (n?=?393; OR?=?1.91 [1.32-2.75]; p?=?0.001) but not in non-diabetic subjects (OR?=?1.09 [0.90-1.33]; p?=?0.370). The interaction risk allele by T2DM was significant (p(interaction)?=?0.002), indicating a significantly stronger impact of the polymorphism on CAD in T2DM patients than in non-diabetic subjects. TCF7L2 polymorphisms rs12255372 and rs11196205 were also significantly associated with CAD in diabetic patients (adjusted additive OR?=?1.90 [1.31-2.74]; p?=?0.001 and OR?=?1.75 [1.22-2.50]; p?=?0.002, respectively). Further, haplotype analysis demonstrated that haplotypes including the rare alleles of all investigated variants were significantly associated with CAD in the whole cohort as well as in diabetic subjects (OR?=?1.22 [1.04-1.43]; p?=?0.013 and OR?=?1.67 [1.19-2.22]; p?=?0.003, respectively). CONCLUSIONS/SIGNIFICANCE:These results suggest that TCF7L2 variants rs7903146 rs12255372, and rs11196205 are significantly associated with angiographically diagnosed CAD, specifically in patients with T2DM. TCF7L2 therefore appears as a genetic link between diabetes and atherosclerosis.

Dataset Information

Role of six single nucleotide polymorphisms, risk factors in coronary disease, in OLR1 alternative splicing.

Publications

Role of six single nucleotide polymorphisms, risk factors in coronary disease, in OLR1 alternative splicing.

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