Gene-environment interaction in determining plasma lipids and dietary response: The effect of common mutations in the gene for lipoprotein lipase (D9N and N291S)

In understanding the genetics of polygenic disorders, the modifying effects of the different environmental factors experienced by individuals are particularly important. We have detected such an interaction between environmental modulation of the effect of two mutations in the lipoprotein lipase gene which alter amino acids (D9N and N291S) to result in a moderate reduction in the lipoprotein lipase activity and mass secreted from COS cells in transient expression assays. Each mutation occurs at a frequency of 2%-3% in the general population, and carriers for these mutations have slightly elevated plasma triglyceride and lower high-density lipoprotein cholesterol levels, as expected from the role of lipoprotein lipase in lipoprotein metabolism. However, when these individuals also are obese, the effect on plasma lipid levels is marked, such that the individuals are predicted to be at a significant risk of atherosclerosis. This increase in risk may be because obesity promotes overproduction of triglyceride-rich lipoproteins from the liver, which overwhelms the already partially deficient lipoprotein lipase in the adipose and muscle. Individuals with the lipoprotein lipase S291 variant have significantly greater postprandial lipemia, in support of this mechanism, and carriers of such mutations may have a distinct response to changes in dietary fat. An understanding of the mechanisms of these effects will help to identify individuals who may be particularly responsive to small dietary changes and to identify potential therapeutic targets.