The present findings consistently demonstrate that the T111I variant in the gene encoding EL is not associated with plasma lipids or lipoprotein measures. In addition, we found no consistent evidence that the T111I variant affects the risk of developing CHD during 7–10 years of follow-up.
We conducted our analyses in three independent cohorts of Caucasian men and women who were free from cardiovascular disease at baseline. Previously, the T111I variant allele has been associated with higher HDL-C among US patients with cardiovascular disease and among Japanese American and Chinese control samples.5,10,11
In contrast, T111I was not associated with HDL-C level in a healthy Canadian population and in a small Japanese sample.12,14
Overall, previous investigations were limited by small samples and already established cardiovascular disease among study participants. Because underlying cardiovascular disease and the treatment for this condition may affect plasma lipids, we believe it is important to investigate the association between genetic variants and plasma lipids in generally healthy population samples. Although our population cohorts were without CHD at baseline, a high proportion of especially the US participants reported a diagnosis of hypercholesterolaemia at baseline. In a subanalysis, we did not find materially different results when we excluded these participants (data not shown).
Few studies have attempted to determine whether the T111I variant is associated with cardiovascular endpoints. Two reports in Caucasian patients reported inconsistent results. The T111I variant was not associated with past history of MI or the progression of atherosclerosis during 2.5 years of follow-up in the Lipoprotein and Coronary Atherosclerosis Study of 371 patients with existing coronary artery disease, whereas the T111I variant allele occurred less frequently among participants in the ACCESS statin trial who had a history of MI compared with those without.9
Recently, the latter finding was supported by two small case–control studies from Japan and China.11,14
To our knowledge, no prospective studies have evaluated the role of T111I and genetic variation in LIPG
and risk of incident CHD in healthy Caucasian populations. It is difficult to reconcile discrepant findings when they originate from patients, healthy individuals, and populations of different ethnicities as different pathophysiological circumstances and different distributions of lifestyle characteristics may be of significance. However, by investigating the association between the T111I variant and risk of CHD in a prospective setting, we have avoided the potential survival bias that could be a problem in case-control studies including only survivors of recent cardiovascular events. In addition, with 1500 cases of CHD and a minor allele frequency of 30%, our estimated statistical power was greater than 80% for the detection of relative risk of 1.15 or greater.
Our results do not suggest that the T111I variant in the LIPG
gene plays a role for plasma lipids and lipoproteins and CHD. We explored the association of this genetic variant with other plasma lipids and lipoproteins because inhibition of EL has been shown to raise plasma levels of not only HDL-C but also apoB-containing lipoproteins.27
In accordance with our results, Edmondson et al
recently found that the lipolytic activity of the T111I variant was similar to the wildtype allele using in vitro
assays. The exploration of other variants in the EL gene in relation to lipid concentrations remains of great scientific interest. Because high EL mass has been inversely associated with HDL-C and positively associated with coronary artery calcification in 858 healthy individuals,6
the investigation of primarily loss-of-function variation in the EL gene, lifelong HDL-C concentrations, and risk of CHD may provide key insight into this protein as a potential new drug target.
We presented the results for women and men separately, although we did not have adequate statistical power to formally test for sex interactions. However, this allows for direct comparison between the estimates for each gender in the three cohorts. We did not observe any statistically significant lifestyle modification of the association between the T111I variant and risk of CHD, but we lacked statistical power to detect such heterogeneity when risk estimates were only modest. In-depth exploration of gene-environment interactions may be of interest for future investigations in larger studies.
In conclusion, our findings suggest that the common non-synonymous T111I variant in the EL gene is not associated with plasma lipids and risk of CHD in Caucasian population-based samples.