Variation of candidate genes in triglyceride metabolism

After more than a decade of study, investigators are grappling for a consen sus regarding the relationship between variation in candidate genes and pla sma triglyceride concentration. Certain variants of LPL - both rare variant s, in the case of loss-of-function mutations in kindreds with chylomicronem ia, and common variants, in the case of the D9N and N291S variants - appear to be fairly consistently associated with an elevated plasma triglyceride level. In addition, the variation of the recognition site for Sstl within t he 3'-untranslated region of APOC3 has consistently shown an association wi th a variation in plasma triglycerides. The LPL and APOC3 variants thus hav e at least a chance in future clinical applications, but this will require more study. Common variants of some other promising candidate genes, such a s HL, have not shown as consistent an association with the variation in pla sma triglyceride level. Finally, studies of variants of newer candidates, s uch as the mitochondrial genome, LMNA, and IL-6, indicate that many differe nt genes might be important determinants of plasma triglyceride concentrati on in the general population. As always, the associations of genes with a c omplex intermediate trait such as plasma triglyceride level depend upon int eractions with modulatory factors such as genetic background and/or seconda ry genetic effects, in addition to the effects of gender, age, hormone repl acement, and postprandial status. A key attribute for increasing confidence in the biologic or potential clinical validity of the associations of cand idate gene variation with plasma triglyceride will be the development of as says that will provide a more direct mechanistic link between the genetic v ariant and the elevated plasma triglyceride. (C) 2000 Lippincott Williams & Wilkins.