Small genetic effects in complex diseases: A review of regulatory sequence variants in dyslipoproteinemia and atherosclerosis

Objective: Most reported mutations that affect lipoprotein metabolism are found within the coding sequences of genes. Recently, a few mutations that occur within promoter sequences have been detected. These promoter sequence variants are the topic of the present review. Methods: Some of these variants are fairly common genomic variants in the promoter regions for candidate genes in lipoprotein metabolism, such as APOA1, APOC3, LPA, and LPL. It is possible that such regulatory sequence variants can result in chronic, modestly altered levels of expression of qualitatively normal gene products. This might have a cumulative effect on quantitative phenotypes, such as plasma lipoprotein concentrations, over the long term. Such an effect might not be detected by existing clinical, biochemical, and/or physiological assays. Results: At present, the most consistent evidence from several lines of experiments indicates that genomic variation in the APOC3 promoter creates slightly elevated plasma triglyceride concentrations within the physiologic range. This altered expression appears to predispose to hypertriglyceridemia in the presence of secondary function might thus be one component of the predisposition to complex diseases. Conclusion: The aggregate of many small effects may create or contribute to a background of susceptibility that, under appropriate conditions, leads to development of frank dyslipidemia and atherosclerosis.