No Association of nineteen COX-2 gene variants to preclinical markers of atherosclerosis The Cardiovascular Risk in Young Finns Study

Backgroud: The role of cyclooxygenase-2 (COX-2) single nucleotide polymorphisms has mostly been studied in relation to advanced atherosclerosis, but little is known how they contribute to preclinical disease. In the present study we analyzed whether COX-2 gene variants associate independently with the early subclinical markers of atherosclerosis, carotid intima-media thickness and carotid artery distensibility in a population of young healthy Caucasian adults. Methods: SNPs for association analysis were collected from the COX-2 gene and 5 kb upand downstream of it. There were 19 SNPs available for analysis, four genotyped and fifteen imputed. Genotype data was available for 2442 individuals participating in the Cardiovascular Risk in Young Finns Study. Genotype imputation was performed using MACH 1.0 and HapMap II CEU (release 22) samples as reference. Association analysis was performed using linear regression with an additive model. PLINK was used for true genotyped SNPs and ProbABEL for imputed genotype dosages. False discovery rate was used to take into account multiple testing bias. Results: Two of the COX-2 variants (rs689470, rs689462) associated with distensibility (p = 0.005) under the linear regression additive model. After adjustment with gender, age, body mass index and smoking status, association between these SNPs and distensibility remained significant (p = 0.031). Subjects carrying the minor alleles had higher value of carotid artery distensibility compared to the major allele homozygotes. However, after correcting p-values for multiple testing bias using false discovery rate, association was lost. Another COX-2 variant rs4648261 associated with mean carotid intima-media thickness (p = 0.046) and maximal carotid intima-media thickness (p = 0.048) in the linear regression model. Subjects carrying the minor allele of rs4648261 had lower values of mean and maximal carotid intima-media thickness compared to subjects homozygote for major allele. After adjustments the associations were lost with both mean and maximal carotid intima-media thickness. Thus, no statistically significant associations of the studied COX-2 variants with carotid artery distensibility or carotid intima-media thickness were found. Conclusions: Our results suggest that in a Finnish population, there are no significant associations between COX-2 variants and early atherosclerotic changes in young adulthood. * Correspondence: seppo.nikkari@uta.fi Department of Medical Biochemistry, University of Tampere Medical School, Tampere, Finland Full list of author information is available at the end of the article © 2012 Lähteelä et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Lähteelä et al. BMC Medical Genetics 2012, 13:32 Page 2 of 6 http://www.biomedcentral. com/1471-2350/13/32 Background Atherosclerosis is the main pathologic process underlying cardiovascular disease. The chronic inflammatory reaction in vessel wall has an important role in disease initiation and progression [1]. Inflammation is partly regulated by prostaglandins which are produced through the enzyme cyclooxygenase (COX). Cyclooxygenase catalyzes the rate-limiting steps in prostaglandin production from arachidonic acid. COX-1 is constitutively expressed in most human tissues under basal conditions. COX-2 expression is primarily induced in response to inflammatory stimuli by growth factors, mitogens, and cytokines [2]. The important role of COX-1 expression in platelets leading to atherothrombosis has been clarified through its inhibition with acetosalicylic acid. However, the role of COX-2 activity in these events is still unclear [3]. COX-2 expression has been detected in endothelial cells, smooth muscle cells, monocytes, and macrophages within human atherosclerotic lesions [4,5]. Prostaglandins produced by the COX-2 route may have impact on the development of atherosclerosis by influencing inflammatory reaction, platelet function, leukocyte-endothelial cell adhesion and smooth muscle cell proliferation and migration [6]. The role of COX-2 has previously been studied in relation to advanced atherosclerosis with clinical complications, such as coronary artery disease [7,8] myocardial infarction and ischemic stroke [9]. However, atherosclerosis begins in childhood and progresses for decades until clinical complications such as myocardial infarction appear [10]. Contributions of genetic alterations would be expected to manifest themselves in younger rather than in older subjects. In fact, it has been suggested that low COX-2 level may enhance foam cell production and consequently, increase the risk of atherosclerosis and cardiovascular disease [11]. Functional studies have been made for only two of the tested SNPs (rs 20417, rs 5275), but this does not necessarily mean that the others are not functional [12-14]. There are 302 known SNPs in the COX-2 gene available from the NCBI dbSNP human database. In the present study we analyzed all the 19 COX-2 SNPs available from the HapMap II CEU (release 22) and their association with subclinical markers of carotid atherosclerosis, such as carotid intima-media thickness (CIMT) and carotid artery distensibility (Cdist).