Genetic Variation in Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1 (LOX1) Gene and the Risk of Coronary Artery Disease

Abstract

Background-We examined the association of 3 polymorphisms in the lectin-like oxidized LDL receptor-1 (LOX1 or OLR1) gene with coronary artery disease in the Women's Ischemia Syndrome Evaluation (WISE) study population. Methods and Results-The WISE sample comprised 589 white and 122 black women who underwent angiography for suspected ischemia. The sample was divided into 3 groups: Ͻ20% stenosis (38.7%), 20% to 49% stenosis (24.9%), and Ն50% stenosis (35.3%). The three LOX1 polymorphisms (intron 4/G3 A, intron 5/T3 G, and 3Ј UTR/T3 C) were in linkage disequilibrium and thus behaved as a single polymorphism. The frequency of the 3ЈUTR/T allele was significantly higher in whites than blacks (49% versus 19%; PϽ0.0001). Among white women, the frequency of the 3ЈUTR/T allele carriers (TCϩTT genotypes) increased gradually from 67.9% to 75.0% and 79.2% in the Ͻ20%, 20% to 49%, and Ն50% stenosis groups, respectively ( 2 trendϭ6.23; Pϭ0.013). Logistic regression analyses indicated that APOE (odds ratio, 1.90; Pϭ0.007) and LOX1 (odds ratio, 1.67; Pϭ0.025) genotypes were independently associated with the risk of disease and that there was no interaction between the two genes. The 3ЈUTR/T allele carriers also had significantly higher IgG anti-oxLDL levels than individuals carrying the CC genotype (0.94Ϯ0.20 versus 0.86Ϯ0.16; Pϭ0.032). Furthermore, our electrophoretic mobility shift assay data show that the 3ЈUTR polymorphic sequence affects the binding of a putative transcription factor in an allele-specific manner. Conclusions-Our data suggest that common genetic variation in the LOX1 gene may be associated with the risk of coronary artery disease in white women. (Circulation. 2003;107:3146-3151.)

On the association of the oxidised LDL receptor 1 (OLR1) gene in patients with acute myocardial infarction or coronary artery disease

“…No association of K167N and -73C4T SNPs with CAD was observed in women 9 (50 CAD vs 108 CAD-free; P ¼ 0.17, P ¼ 0.38, respectively).…”

“…Two studies reported a 3 0 UTR or a K167N association with CAD severity in non-Hispanic white women in the US population (CT þ TT: OR ¼ 0.61; CI: 0.41 -0.91) 9 and in the Japanese population (CC þ CG: OR ¼ 0.61; CI: 0.41 -0.92), 10 respectively. All CAD patients here described had severe coronary atherosclerosis, that is, lesions with greater than 50% luminal stenosis.…”

“…7,8 These polymorphisms have also been associated with CAD. 9,10 The aim of the present study was to confirm the association of the OLR1 gene with AMI or CAD in a novel, well phenotyped, and homogenous, population.…”

Complex Inheritance of the 5-Lipoxygenase Locus Influencing Atherosclerosis in Mice

“…Moreover, this gene has been found to be abundantly present in human (Kataoka et al 1999) and rabbit atherosclerotic lesions (Chen et al 2000). Several independent studies have also found evidence for association between OLR1 and acute myocardial infarction (Mango et al 2003;Tatsuguchi et al 2003) and coronary artery disease (Chen et al 2003b;Ohmori et al 2004). Perhaps the most direct evidence suggesting that Olr1 plays a role in the pathogenesis of atherosclerosis comes from the transgenic experiments.…”

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

“…Six single nucleotide polymorphisms (SNPs) in linkage disequilibrium have been identified within introns 4, 5 and the 3 ′ UTR of OLR1, which correlate with the risk of cardiovascular disease (Chen et al 2003;Mango et al 2003;Tatsuguchi et al 2003). Carriers of the Low-Risk allele series show equilibrated levels of both AS isoforms, while carriers of the High-Risk allele series display higher exon 5 inclusion (Mango et al 2005).…”