A COMMON DELETION POLYMORPHISM IN THE APOLIPOPROTEIN A4 GENE AND ITS SIGNIFICANCE IN LIPID-METABOLISM

Apolipoprotein A-IV (apoA-IV, protein;APOA4, gene) is a major constitu ent of high-density lipoprotein (HDL) and triglyceride-rich lipoprotei n particles, but its precise function in lipid metabolism is still unc ertain. We have determined APOA4 genetic polymorphism in 285 randomly selected Melanesians from the Solomon Islands and have evaluated its s ignificance in lipid metabolism. By using isoelectric focusing and imm unoblotting techniques, a variant pattern, indistinguishable from the APOA42 allele uniquely found in white populations at a frequency of a bout 8%, was detected at a relatively high frequency (19%) in the Mela nesian sample. Polymerase chain reaction (PCR) amplification and DNA s equencing of the 3' end of the APOA4 gene revealed that the Melanesian mutation is distinct from the known APOA42 mutation and that it invo lves a four-amino acid deletion in the evolutionarily conserved carbox yl-terminal region in the apoA-IV protein, which consists of four repe ats of four amino acids each. After adjustment for concomitant variabl es, we investigated the impact of the deletion polymorphism on plasma levels of cholesterol, triglycerides, apoA-I, apoA-II, and apoE. A sig nificant (P=.02) and gene-dosage effect was observed on the plasma lev els of apoA-I and apoA-II: these levels were lowest in individuals hom ozygous for the deletion allele (D), intermediate in heterozygotes (ND ), and highest in homozygous individuals for the normal allele (N). Th e average effect of the APOA4D allele was to lower apoA-I and apoA-II by 8 mg/dL and 2 mg/dL, respectively, and the APOA4 polymorphism acco unted for about 3% of the phenotypic variance in bath cases. A gene-do sage effect was also noted on the cholesterol and triglyceride levels, but the intergenotype difference was not statistically significant. T hese data suggest that the deletion polymorphism may play an important role in HDL metabolism.