Association of single nucleotide polymorphisms in the oxidised LDL receptor 1 (OLR1) gene in patients with acute myocardial infarction.(Letter to JMG)

J Med Genet 2003;40:933-936

Acute myocardial infarction (AMI) is a significant cause of mortality and morbidity. Substantial data support a plausible role for oxidised LDL (oxLDL) in the aetiology of this disease. (1) (2) The human OLR1 (or LOX 1) gene encodes the endothelium derived lectin-like oxidised low density lipoprotein (oxLDL) receptor, which is involved in the binding, internalisation, and proteolytic degradation of oxLDL, suggesting that it may play a significant role in atherogenesis. (3) OLR1 is considered a good candidate for atherosclerosis and AMI since it is induced in vitro by inflammatory cytokines and in vivo by pro-atherogenic conditions like hypertension, hyperlipidaemia, and diabetes mellitus. (4) Recently, upregulation of OLR1 has been shown in ischaemia reperfusion injury in the rat. (5) OLR1 acts as a mediator of "endothelial dysfunction" favouring superoxide generation, inhibiting nitric oxide production, and enhancing endothelial adhesiveness for monocytes. (6-8) It is noteworthy that the versatile activities of OLR1 also include the ability to bind not only oxLDL, but also aged red blood cells, apoptotic cells, and activated platelets. (4) With this background, we sought to validate the hypothesis of OLR1 involvement in atherosclerosis and AMI by defining OLR1 genetic variation by an association study of intragenic SNPs.

METHODS

Study subjects

The study included 150 individuals with AMI who were referred to the Centre of Atherosclerosis at the Medical School of the Tor Vergata University of Rome. All cases were clinically evaluated and all underwent coronary angiography and left ventriculography. The diagnosis of AMI was based on typical electrocardiographic changes and increased serum activities of at least two enzymes, such as creatine kinase, aspartate aminotransferase, and lactate dehydrogenase. The diagnosis was confirmed by the presence of wall motion abnormality on left ventriculography and attendant stenosis (>50%) in any of the major coronary arteries or in the left main coronary artery on coronary angiography. One hundred and three control subjects were recruited from persons found to have at least one conventional risk factor for coronary artery disease (CAD), such as cigarette smoking (10 cigarettes daily), hypertension (systolic blood pressure of 140 mm Hg or diastolic blood pressure 90 mm Hg), diabetes mellitus (blood glucose level 126 mg per decilitre (6.93 mmol per litre)), hypercholesterolaemia (total serum cholesterol level 220 mg per decilitre (5.72 mmol per litre)). These subjects had no evidence of active myocardial ischaemia, but underwent left ventriculography and coronary angiography as part of valvular disease. All these control subjects were found to have normal coronary arteries. The mean age of the AMI patients was 64.4 (5.8 years) (mean (SD)) with a mean age at onset of symptoms 60.4 (4.5) years. The mean age of the control subjects was 63.4 (6.2) years. The study was approved by the Tor Vergata University Ethics Committee.

SNP discovery and genotyping

All six exons and intron/exon boundaries of OLR1 were screened using denaturing high performance liquid chromatography (DHPLC, Transgenomic, Crewe, UK) in 50 AMI patients and 50 controls …