The present study is the first to report the relationship between LOX-1 gene polymorphisms and circulating sLOX-1 levels. We found that the 3′UTR-T allele was associated with lower sLOX-1 levels. These findings were surprising given that this allele has been positively associated with cardiovascular disease (Mango et al., 2003
;Chen et al., 2003
). While elevated sLOX-1 levels have been reported in patients with acute coronary syndromes (Hayashida et al., 2005
), the physiological significance of sLOX-1 is not known. Thus, the reasons for the discrepancy in these findings is not apparent, but may be related to the study population. We also found that the LOX-1 501GG genotype was associated with lower sLOX-1 levels. The association between the G501C polymorphism and cardiovascular disease is less clear, as published results have been largely inconsistent (Mango et al., 2003
;Tatsuguchi et al., 2003
;Ohmori et al., 2004
;Hattori et al., 2006
;Trabetti et al., 2006
). As such, determining the influence of LOX-1 polymorphisms on sLOX-1 levels may help to further elucidate the biological effects of LOX-1 gene variation on cardiovascular disease.
Both the 3′UTR and G501C polymorphisms may affect LOX-1 expression. Chen et al. reported that the 3′UTR-T allele has a 3-fold lower binding affinity for regulatory proteins compared with the C allele and proposed that the 3′UTR polymorphism may directly affect LOX-1 mRNA stability and/or translation (Chen et al., 2003
). Moreover, Mango et al. found that the 3′UTR polymorphism and five intronic polymorphisms comprise a linkage disequilibrium block that regulates the relative expression of two LOX-1 isoforms (Mango et al., 2005
). On the other hand, it has been suggested that the G501C polymorphism may alter gene expression by affecting LOX-1 binding activity (Tatsuguchi et al., 2003
). This polymorphism results in a non-conservative amino acid change (Lysine to Asparagine) in codon 167, which is located in the ligand-binding domain. Electrostatic interactions between basic residues in this domain and negatively charged residues in ox-LDL are critical for LOX-1 activity, and substitution of these residues may cause reduced ox-LDL binding and internalization (Chen et al., 2001
). Although more functional studies are needed to understand the impact of LOX-1 gene variation on the expression and activity of this receptor, our results suggest that common genetic variants in LOX-1 may affect plasma concentrations of sLOX-1.
As mentioned previously, Hayashida et al. found that serum sLOX-1 levels were significantly elevated in patients with acute coronary syndromes compared to individuals with normal coronary arteries and patients with stable CAD and non-cardiovascular diseases (Hayashida et al., 2005
). In patients with acute coronary syndromes, median sLOX-1 levels were 2,910 pg ml−1
(range, <500 to 170,000 pg ml−1
) compared to all other patient groups and controls, whose levels ranged from <500 to 14,000 pg ml−1
. It was concluded that sLOX-1 levels do not reflect general inflammation or lesion size, but rather the instability of atherosclerotic plaques, which is indicative of more prominent LOX-1 expression and enhanced protease activities. In vulnerable plaques, an increase in protease activities may serve to cleave LOX-1 from the cell surface, thereby increasing the circulating sLOX-1 levels. In our population of clinically healthy individuals, plasma sLOX-1 levels were substantially lower (median, 36.23 pg ml−1
; interquartile range, 24.63 to 54.15 pg ml−1
). Thus, the significance of elevated sLOX-1 levels in a disease-free population remains to be elucidated.
The main limitation in this study was the small sample size. With a 3′UTR/T-allele frequency of 46%, we had sufficient statistical power (~83%) to detect differences in sLOX-1 levels between the CC and TT genotype groups. However, given a 501C allele frequency of 10%, we had limited power to detect differences in sLOX-1 levels between the 501GG and GC genotype groups. Nevertheless, this is the first study to investigate the effects of the LOX-1 3′UTR-C/T and G501C polymorphisms on plasma sLOX-1 levels. Our findings demonstrate that LOX-1 gene variation may be important in the regulation of sLOX-1 levels in plasma. More studies are needed to clarify the significance of sLOX-1 in normal and pathological settings and the effect of genetic and behavioral factors on circulating sLOX-1 levels.