Sporadic publications refer to some other common polymorphisms, e.g. Val153>Met (rs3135507, G457A) and also suggest significant sex-dependent associations with plasma lipids. Rare variants within the APOA5 gene have been described in a couple of different populations. Among the “common mutations/rare SNPs”, one of the most characterised on a population level is the Ala315>Val exchange. Originally detected in patients with extreme TG levels over 10 mmo/L, it was also found in about 0.7% of the general population (mostly in individuals with normal TG values), which suggests a low penetrance of this variant. More than twenty other rare variants (mutations) have been described within the human APOA5 gene. They cover a wide spectrum that includes preliminary stop codons, amino acid changes as well as insertions and deletions. These mutations are generally associated with hypertriglyceridaemia, but penetration is usually not 100%. Individual mutations have been found mostly in one pedigree only. But not all the SNPs have a detrimental effect on TG levels. A recent report, showed that, in Sardinian population, the missense mutation Arg282Ser in APOA5 gene, correlates with a decrease in TG levels. The authors believe that this point mutation is a mayor modulatory of TG values in this population. Clinical significance In humans, plasma triglycerides such as triacylglycerols have been long debated as an important risk factor for not only cardiovascular disease but also for other relevant morbidities, such as cancer, renal disease, suicide, and all-cause mortality. The APOA5 gene was found by comparative sequencing of ~200 kbp of human and mice DNA as the last member of the gene cluster of apolipoproteins located on human chromosome 11 at 11q23. Two mouse transgenic mouse models (APOA5 transgenic and APOA5 knockout) confirmed the important role of this gene in plasma triglyceride levels of plasma triglycerides. Obesity and metabolic syndrome are both closely related to plasma triglyceride levels and APOA5. Recent meta-analyses suggest that the effect on metabolic syndrome development is more profound for rs662799 in Asian population and for rs3135506 for Europeans. Moreover, meta-analysis that focused on rs662799 and the risk of type 2 diabetes mellitus has suggested a significant association in Asian populations, but not in European populations. As a risk factor Even though plasma concentration of APOA5 is very low, some studies have focused on the analysis of the potential association of this biochemical parameter with cardiovascular disease (CVD). This relationship remains controversial, as higher plasma levels of APOA5