Apoliporotein A5 (APOA5), a member of the apolipoprotein family, plays a key regulatory role in triglyceride (TG) metabolism.
Even though the exact biochemical background of its mechanism is not yet fully understood, diseases associated with this particular
gene highlighted its key role in the metabolism of triglycerides in humans. Naturally occurring functional variants of the gene and their
natural major haplotypes are known to associate with moderately elevated triglyceride levels, and are also known to confer risk or protection
for major polygenic diseases, like coronary heart disease, stroke, or metabolic syndrome. On the other hand, case reports and even
robust resequencing studies verified APOA5 mutations as underlying genetic defects behind extreme hypertriglyceridemic phenotype.
Soon after the recognition of the first cases, there were indications which suggest the existence of less frequent genetic variants which, in
combination with the common allelic variants of the gene, can define haplotypes that are associated with substantial triglyceride level increase.
In addition, it became evident, that there are rare mutations of the APOA5 gene which can be associated with specific complex
phenotypes and different types of hyperlipoproteinemia, which includes extremely high triglyceride levels with multiple organ pathology.
These rare mutations may cause inheritable hypertriglyceridemia, but they presented at a low frequency and could not be captured by
standard genotyping array screenings. The identification of new mutations still relies on the direct sequencing of APOA5 gene of patients
with hypertriglyceridemia with an unusual pattern, individually or in huge resequencing studies.