Apolipoprotein A-II, genetic variation on chromosome 1q21-q24, and disease susceptibility

Apolipoprotein (apo) A-II is the second most abundant HDL apolipoprotein; however its function remains largely unknown. Owing to the lack of consequences of apoA-II deficiency in humans, it has long been considered an apolipoprotein of minor importance. Overexpression of apoA-II in transgenic mice, however, causes combined hyperlipidemia and, in some cases, insulin resistance. This, and the location of the apoA-II gene in chromosome 1q23, a hot region in the search for genes associated with familial combined hyperlipidemia, insulin resistance and type 2 diabetes mellitus, has greatly increased interest in this protein.

ApoA-II is biochemically and genetically linked to familial combined hyperlipidemia. Given that the chromosome 1q21-q24 region is associated with insulin resistance or type 2 diabetes, this region is a now a focus of interest in the study of these complex, often overlapping diseases. However, no polymorphisms that increase apoA-II levels have been identified to date in humans. Other nonstructural loci may regulate apoA-II plasma concentration. Further, plasma apoA-II concentration is increased by saturated fat intake. Several reports have added to our understanding of the relationship between apoA-II mutations and amyloidosis both in humans and mice.

An increased plasma concentration of apoA-II might contribute to familial combined hyperlipidemia or type 2 diabetes mellitus expression, which emphasizes the need to understand its function and metabolism. Genetic studies in well characterized patients and genomic and proteomic approaches in cell and mouse models may help to achieve this understanding.