Polymorphic variants in tenascin-C (TNC) are associated with atherosclerosis and coronary artery disease

Abstract

Tenascin-C (TNC) is an extracellular matrix protein implicated in biological processes important for atherosclerotic plaque development and progression, including smooth muscle cell migration and proliferation. Previously, we observed differential expression of TNC in atherosclerotic aortas compared with healthy aortas. The goal of this study was to investigate whether common genetic variation within TNC is associated with risk of atherosclerosis and coronary artery disease (CAD) in three independent datasets. We genotyped 35 single nucleotide polymorphisms (SNPs), including 21 haplotype tagging SNPs, in two of these datasets: human aorta tissue samples (n = 205) and the CATHGEN cardiovascular study (n = 1,325). Eleven of these 35 SNPs were then genotyped in a third dataset, the GENECARD family study of early-onset CAD (n = 879 families). Three SNPs representing a block of linkage disequilibrium, rs3789875, rs12347433, and rs4552883, were significantly associated with atherosclerosis in multiple datasets and demonstrated consistent, but suggestive, genetic effects in all analyses. In combined analysis rs3789875 and rs12347433 were statistically significant after Bonferroni correction for 35 comparisons, p = 2 × 10(-6) and 5 × 10(-6), respectively. The SNP rs12347433 is a synonymous coding SNP and may be biologically relevant to the mechanism by which tenascin-C influences the pathophysiology of CAD and atherosclerosis. This is the first report of genetic association between polymorphisms in TNC and atherosclerosis or CAD.

Fig. 1. Summary of overall study design employed

Fig. 2

TNC gene schematic and genotyped SNPs. TNC gene schematic showing the 35 SNPs genotyped across the TNC locus according to their physical location. Non-synonymous SNPs are denoted by a double solid arrow, synonymous SNPs are denoted by a double open arrow, intronic SNPs are denoted by a single solid arrow, and intergenic SNPs are denoted by a single open arrow. The TNC gene is located on the reverse strand of the reference assembly, and is hence drawn from 3′ to 5′ to reflect its physical orientation

Fig. 3

LD relationships between genotyped TNC SNPs. LD relationships (r² values) between genotyped SNPs are shown for CATHGEN Caucasian controls. The LD plot was visualized with the Haploview program (Barrett et al. 2005). The shading of the blocks indicates the strength of the LD relationship, with black blocks showing r² = 1.0 and white blocks showing r² = 0.0. The three most significant SNPs reported in this paper are highlighted by black boxes in the figure

Fig. 4

Graphical overview of TNC SNP associations. Graph showing the physical map location of each TNC SNP plotted against the −log₁₀ (p value) for each SNP in each analysis (see text for details). Data from the full model in CATHGEN and GENECARD probands are presented. Points above the horizontal dotted lines are significant at a threshold of p = 0.05 or 0.01. The gray, dashed, vertical lines highlight the p values for rs3789875 and rs12347433, the two significant SNPs from the meta-analysis