INCOMPLETE DOMINANCE OF TYPE-III HYPERLIPOPROTEINEMIA IS ASSOCIATED WITH THE RARE APOLIPOPROTEIN E2 (ARG136-]SER) VARIANT IN MULTIGENERATIONAL PEDIGREE STUDIES

In the process of screening apolipoprotein (apo) E genotypes in a popu lation of subjects with lipid abnormalities, we have identified five s ubjects (one homozygote and four heterozygotes) with an abnormal 109 b ase pairs band following apo E restriction isotyping of amplified DNA with the restriction endonuclease CfoI. The polymerase chain reaction (PCR) products were cloned and their sequencing revealed a C-->A subst itution at the first nucleotide of codon 136. This mutation resulted i n an amino acid substitution Arg to Ser, previously described as apo E 2 Christchurch. Family studies were carried out for four of the proban ds. In these kindreds, stepwise multiple regression analyses indicated that 78% of the cholesterol variability in men was predicted by body mass index, age and the rare apo E2 (Arg136-->Ser) variant. In women, age and the apo E2 (Arg136-->Ser) variant predicted 54.9% of the varia bility in cholesterol levels. Linkage analysis suggested that the pres ence of the apo E2 (Arg136-->Ser) variant was linked with the occurren ce of cholesterol enriched triglyceride rich lipoproteins and with an incomplete dominance of type III hyperlipoproteinemia. Our data indica tes that this mutation may be a relatively common cause of dyslipidemi a in the Spanish population.