Combined hyperlipidemia: familial but not (usually) monogenic

Abstract

Purpose of review: Combined hyperlipidemia (CHL) is a complex phenotype that is commonly encountered clinically and is often associated with the expression of early heart disease. The affixed adjective 'familial' gives the impression that the trait is monogenic, like familial hypercholesterolemia. But despite significant efforts, genetic studies have yielded little evidence of single gene determinants of CHL.

Recent findings: Sophisticated linkage studies suggest that individual lipid components of the CHL phenotype - such as elevated LDL and triglyceride - each have several determinants that segregate independently in families. Furthermore, DNA sequencing shows that rare large-effect variants in genes such as LDL receptor (LDLR) and lipoprotein lipase are found in some CHL patients, explaining the elevated LDL cholesterol and triglyceride components, respectively. In addition, multiple common small-effect lipid-altering variants accumulate in an individual's genome, raising the LDL cholesterol and/or triglyceride components by multiple mechanisms. Finally, secondary factors, such as poor diet, obesity,fatty liver or diabetes further modulate the expression of the biochemically defined CHL phenotype.

Summary: Given the current state of genetic understanding, CHL may be best conceptualized as a syndrome with common clinical presentation but multigenic causes, similar to other common conditions such as type 2 diabetes.