SEX-SPECIFIC EFFECTS OF THE GLUTAMINE HISTIDINE POLYMORPHISM IN APO A-IV ON HDL METABOLISM

In Caucasians, a histidine for glutamine substitution (Gln-->His) at r esidue 360 in apolipoprotein (ape) A-IV leads to an electrophoreticall y detectable polymorphism whose contribution to lipid metabolism regul ation is controversial. In this study of 426 male and 188 female coron ary heart disease patients, we analyzed the impact of this polymorphis m on lipid metabolism, particularly high-density lipoprotein (HDL). Th e frequency of the rarer apo A-IV (360:His) allele was .069. This poly morphism exerted opposite effects in men and women in terms of serum c oncentrations of total cholesterol; triglycerides; HDL cholesterol; LD L cholesterol; lipoprotein (Lp) A-I; and ape A-I, A-II, and B. Only th e difference in Lp A-I levels between male ape A-IV (360:Gln/Gln) homo zygotes and apo A-IV (360:Gln/His) heterozygotes was significant (P<.0 5). In randomly selected subgroups of 38 male and 15 female ape A-IV ( 360:Gln/His) heterozygotes and 104 male and 15 female ape A-IV (360:Gl n) homozygotes, heterozygosity for ape A-IV (360:Gln/His) in both sexe s was associated with lower plasma cholesteryl ester transfer protein (CETP) activity (P<.05) and higher serum apo A-IV concentrations (P<.0 1 in men). Moreover, only men had significantly higher mean plasma act ivity levels of lecithin :cholesterol acyltransferase (LCAT) (P<.01). Multivariate analysis of the effects of age, diabetes mellitus, intake of lipid-lowering drugs, body mass index, smoking, and apo A-IV polym orphism revealed that the apo A-IV polymorphism contributed 1%, 3% to 4%, 6% to 7%, and 5% to 18% of the variation in serum concentrations a nd plasma activities of Lp A-I, ape A-IV, LCAT, and CETP, respectively . In men, univariate and multivariate regression analyses revealed sig nificant interrelationships between concentrations and activities of H DL cholesterol, Lp A-I, ape A-IV, LCAT, and CETP. We conclude that the 360:Gln/His ape A-IV polymorphism influences HDL metabolism via ape A -IV concentration and/or plasma activities of LCAT and CETP. However, these effects appear to be strongly modulated by other factors, includ ing gender, and do not contribute importantly to cardiovascular risk.