Severity of coronary artery stenosis is associated with a polymorphism in the CXCL16/SR‐PSOX gene

Abstract

Abstract. Lundberg GA, Kellin A, Samnegård A, Lundman P, Tornvall P, Dimmeler S, Zeiher AM, Hamsten A, Hansson GK, Eriksson P (Ö rebro University, Ö rebro and Karolinska Institute, Stockholm, Sweden; and University of Frankfurt, Frankfurt, Germany). Severity of coronary artery stenosis is associated with a polymorphism in the CXCL16/SR-PSOX gene. J Intern Med 2005; 257: 415-422.Objective. Enhanced expression of CXCL16 has been demonstrated in atherosclerotic plaques and several properties have been attributed to CXCL16 that could influence the atherosclerotic process. CXCL16 exists in transmembrane and soluble forms. The transmembrane form acts as a scavenger receptor for oxidised LDL whereas the soluble form acts a chemoattractant for mainly CD8+ T cells. In addition, the soluble form of CXCL16 influences human aortic smooth muscle cell proliferation in vitro. In the present work, a human molecular genetic approach employing a common polymorphism within exon 4 of CXCL16 (181 Ala>Val) was used to investigate whether CXCL16 may be involved in the development of coronary artery disease. The polymorphism is located within the spacer region between the chemokine and transmembrane region and potentially influences an Ala/Val cleavage site, a site commonly used for the release of chemokines by tumour necrosis factora converting enzyme. Design and subjects. We first genotyped 387 unselected survivors of a first myocardial infarction aged <60 years and 387 sex-and agematched controls. A subset of patients (n ¼ 236) was evaluated by quantitative coronary angiography. Secondly, a cohort of 468 patients undergoing percutaneous transluminal coronary angioplasty (PTCA) with stent implantation was genotyped.Results. No significant difference in allele frequency between patient and controls of the 181 A>V polymorphism was detected. However, the V-allele was associated with increased severity of coronary stenoses. Secondly, the V-allele was associated with smaller minimal luminal diameter in the coronary segment subjected to intervention in a second cohort of patients undergoing PTCA with stent implantation. Conclusions. The present work provides evidence that CXCL16 is involved in processes leading to enhanced stenosis in atherosclerotic coronary arteries.

CXCL16 Haplotypes in Patients with Human Carotid Atherosclerosis: Preliminary Results

“…All patients included in this study had an advanced phenotype of carotid atherosclerosis, with a high degree of carotid artery stenosis ( 70%). Therefore, our results are in agreement with those of Lundberg et al 16) . However, since this study had limited statistical power for the observed association, we consider our findings to be preliminary.…”

“…The role of CXCL16 in the onset of cardiovascular pathology was first documented when the levels of its soluble form were found to be positively and independently associated with acute coronary syndrome 27) . The A181V polymorphism was subsequently investigated in a few different populations in association with coronary artery disease [16][17][18] , but not carotid atherosclerosis. In one of these studies, a significant association between the V181V genotype and a high degree of coronary artery stenosis was found in Caucasian CAD patients 16) .…”

“…The A181V polymorphism was subsequently investigated in a few different populations in association with coronary artery disease [16][17][18] , but not carotid atherosclerosis. In one of these studies, a significant association between the V181V genotype and a high degree of coronary artery stenosis was found in Caucasian CAD patients 16) . In the present study, the missense allele haplotype, T123V181, was identified to be significantly more common in the patients than in the controls.…”

“…Although the importance of CXCL16 with respect to the pathogenesis of atherosclerosis is strongly supported by previous research, only a small number of studies have investigated the associations between CXCL16 gene variations and this disease. The first study of the effects of CXCL16 gene variations on the incidence of cardiovascular disease investigated the A181V polymorphism because this polymorphism has been suggested to influence the cleavage site within the transmembrane CXCL16, which is recognized by certain cell membrane sheddases, such as like ADAM17 16) , thus affecting the levels of soluble CXCL16. The role of CXCL16 in the onset of cardiovascular pathology was first documented when the levels of its soluble form were found to be positively and independently associated with acute coronary syndrome 27) .…”

“…Evidence of the association between CXCL16 gene polymorphisms and cardiovascular phenotypes is scarce [16][17][18] . In a recent study, the CXCL16 A181V polymorphism itself was not found to be associated with CHD among Indian Asian men and women 18) .…”