Genetics of low-density lipoprotein subclasses

A predominance of small, dense LDL particles is associated with increased risk of coronary heart disease and an atherogenic lipoprotein profile. Using a variety of methods to characterize LDL heterogeneity, complex segregation analyses in studies based on large samples of families uniformly demonstrate a single major gene effect on LDL subclass distributions. Studies of twins in both men and women confirm genetic influences on LDL subclasses, but also demonstrate significant non-genetic influences. Although candidate gene linkage studies have implicated three different chromosomes in mapping the locus controlling the small, dense LDL phenotype, none of these results have been confirmed in independent samples of families. Small, dense LDL is associated with familial combined hyperlipidemia, but other genetic or environmental influences must also be involved in this disorder. In addition to genetic influences on LDL subclasses, there is accumulating evidence that age, sex, and environmental effects, including diet, are also important. This combination of genetic and non-genetic influences provides the potential for identifying genetically susceptible individuals and for developing effective, targeted intervention strategies to reduce risk of coronary heart disease.