Hypertriglyceridemia in the genomic era: a new paradigm

Hypertriglyceridemia (HTG) is a highly prevalent condition that is associated with increased cardiovascular disease risk. HTG may arise as a result of defective metabolism of triglyceride-rich lipoproteins and their remnants, ie, impaired clearance, or increased production, or both. Current categorization of HTG segregates primary and secondary cases, implying genetic and nongenetic causes for each category. Many common and rare variants of the genes encoding factors involved in these pathways have been identified. Although monogenic forms of HTG do occur, most cases are polygenic and often coexist with nongenetic conditions. Cumulative, multiple genetic variants can increase the risks for HTG, whereas environmental and lifestyle factors can force expression of a dyslipidemic phenotype in a genetically susceptible person. HTG states are therefore best viewed as a complex phenotype resulting from the interaction of cumulated multiple susceptibility genes and environmental stressors. In view of the heterogeneity of the HTG states, the absence of a unifying metabolic or genetic abnormality, overlap with the metabolic syndrome and other features of insulin resistance, and evidence in some patients that accumulation of numerous small-effect genetic variants determines whether an individual is susceptible to HTG only or to HTG plus elevated low-density lipoprotein cholesterol, we propose that the diagnosis of primary HTG and further delineation of familial combined hyperlipidemia from familial HTG is neither feasible nor clinically relevant at the present time. The hope is that with greater understanding of genetic and environmental causes and their interaction, therapy can be intelligently targeted in the future.