In the present study, we performed a systematic review of the associations between EL 584C/T polymorphism with HDL-C level, and the risk of CHD. Our meta-analysis concluded that there was no significant association between the EL 584C/T polymorphism and the risk of CHD. Nevertheless, the carriers of EL 584 T allele had a higher HDL-C level than non-carriers in Caucasian populations.
A growing body of evidence indicates that the EL might play a crucial role in the HDL-C metabolism[31–33] and in the pathogenesis of cardiovascular disease (CVD)[34, 35]. EL has a catalytic phospholipase activity and noncatalytic legend-bridging functions, which can hydrolyze the HDL-C and increase the clearance of HDL-C. As we know, the level of HDL-C correlated with the risk of CHD negatively. So the pro-atherosclerotic action of EL was probably partly caused by decreasing the level of HDL-C. The level of EL was regulated by several factors. Badellino et al. found the level of EL positively correlated with the level of high-sensitivity C-reactive protein, interleukin-6, soluble intercellular adhesion molecule-1, etc. but negatively correlated with the adiponectin level.
EL 584C/T gene variant is a missense polymorphism in exon 3, and was identified in 2002. To date, some studies have failed to validate the associations between EL 584C/T polymorphism and HDL-C level[13, 15], and the risk of CHD[14–17], whereas other studies found this variant was associated with HDL-C level[12, 17] and could also reduce the CHD susceptibility[12, 13]. By the prospective case–control study in EPIC-Norfolk, Vergeer et al. suggested that the minor allele of EL 584C/T was not associated with CHD. In our previous study, we didn’t find a statistically significant associations between the variant and HDL-C level, and the risk of CHD (OR = 0.92, 95% CI = 0.70-1.20, P = 0.528) either.
In 2008, Tang et al. carried out a study including 530 age- and sex-matched Chinese subjects to investigate the relationship between the common variant and the CHD risk. They concluded that the T allele could significantly reduce the CHD susceptibility. At the same time, they found the serum HDL-C level was significantly higher in the T allele carriers (CT + TT genotypes) than the wide-type CC carriers. In a case–control study of 214 Japanese individuals, Shimizu et al. also found the T allele was an independent protective factor to AMI (OR = 0.52, 95% CI: 0.28-0.98, P = 0.04).
In 2009, Jensen et al. performed a study to evaluate the relationship between the EL 584C/T polymorphism and the risk of CHD in three independent populations. Their study did not support an association between this variant and the risk of CHD in Caucasian populations. But only three independent Caucasian populations with 4140 individuals were included in their study and all studies were nested case–control studies. The statistical effect was limited because of the relatively small sample size. So we performed this meta-analysis including 13 independent populations. The results of the present meta-analysis were more convincing, as the statistical power increases. In this study, we found the EL 584C/T polymorphism was not significantly associated with the risk of CHD. Although the pooled effects indicated that the EL 584C/T polymorphism might be significantly associated with CHD in overall population (for the dominant model, OR = 0.829, 95% CI: 0.701-0.980, P = 0.028; for the allelic model, OR = 0.882, 95% CI: 0.779-0.999, P = 0.049). The sensitivity analysis found that the pooled effects changed after Tang’s study was excluded, which indicated that this study influenced the stability of the whole study. When Tang’s study was excluded, the conclusion changed completely (for the dominant model, OR = 0.908, 95% CI: 0.818-1.006, P = 0.066; for the allelic model, OR = 0.952, 95% CI: 0.883-1.027, P = 0.203). In our study, we found the significant heterogeneity among studies (I2 = 61.3%, Pheterogeneity = 0.008, for dominant model; I2 = 59.5%, Pheterogeneity = 0.011, for allelic model). So, we performed the meta-regression analysis to explore the sources of heterogeneity. The confounding factors, involving ethnicity, year of publication, RR and total sample size, were involved in meta-regression analysis. Total sample size (more than 600 or less than 600), but not other factors, could influence the initial heterogeneity (Pmeta-regression = 0.008, for allelic model; Pmeta-regression = 0.027, for dominant model), which could explain most heterogeneity. When we performed the subgroup analysis by total sample size, we found the association only existed in relatively small sample size subgroups, rather than larger sample size subgroups. In addition, when the stratified analysis was carried out by ethnicity, we found the protective effect only existed in the Asian subgroups. But, the sample size of each Asian study ranged from 214 to 623, which was relatively small. Especially, the Tang’s study involved both Asian subgroup and small sample size subgroup. We analyzed their study and found the frequency of T allele was significantly higher in their study than in others and the controls were not all confirmed by coronary angiography. These might partly influence the heterogeneity and the results. We calculated the pooled ORs again after excluding their study. The pooled ORs suggested that the EL 584C/T polymorphism was not associated with CHD risk. So, we should interpret the results cautiously.
In addition, our study concluded that the carriers of T allele had the higher HDL-C level than the non-carriers. The subgroup analysis suggested the positive result only existed in Caucasian populations. Because of the significant heterogeneity among studies, the subgroup analyses were carried out by ethnicity and the total of sample size. It was regrettable that the stratified analyses did not reduce the heterogeneity significantly. Individuals included in this study had different genetic background and environmental factors. At the same time, the sample size of each study varied and the age difference among the studies was also relatively large. All of these might contribute to the heterogeneity. The subgroup analyses suggested that the association between EL 584C/T polymorphism and HDL-C level existed in Caucasian populations and in subgroup of large sample size.
There were several inherent limitations in this meta-analysis. Firstly, the sample sizes of some studies were relatively small and they might not have an adequate power to detect the possible risk for the EL 584C/T polymorphism. Secondly, this meta-analysis only involved the published studies. As we all know, the papers having negative result were probably more difficult to be accepted for publication. So the inevitable publication bias may exist in the results, although the Egger’s tests indicated no remarkable publication bias in our meta-analysis. Thirdly, the populations only come from Asians and Caucasians. Other ethnic populations should be involved in the future studies, such as Africans.