GENETIC-CONTROL OF APOLIPOPROTEIN-A-I DISTRIBUTION AMONG HDL SUBCLASSES

We conducted genetic analyses to determine the components of variation for size distributions of apolipoprotein (apo) A-I among human plasma lipoproteins resolved on the basis of size. Analyses used data for 71 7 individuals in 26 pedigrees. Apo A-I distributions among lipoprotein size classes were measured by nondenaturing gradient gel electrophore sis (GGE) and immunoblotting procedures. Curves were fitted to apo A-I absorbance profiles to estimate fractional absorbance in each of five high-density lipoprotein (HDL) subclasses. Multivariate regression an alyses revealed several covariates (sex, age, diabetes, and apo A-I co ncentrations) that were significantly associated with variation in one or more HDL subclasses. Female gender and elevated apo A-I concentrat ions were associated with increases in proportion of apo A-I in larger HDLs, while increasing age and diabetes were associated with decrease s. The analyses showed significant heritabilities, h(2), for each vari able representing the different HDL subclasses. Both genetic and nonge neric effects on apo A-I size distributions were generally exerted acr oss the range of lipoprotein sizes, as suggested by high genetic and e nvironmental correlations between HDL subclass variables. Decompositio n of total overall variance showed that unidentified environmental fac tors accounted for 48% of variation in apo A-I size distribution, whil e genetic factors explained about 36% and the identified covariates ex plained the remaining 16%. When considered separately, apo A-I concent ration explained only 5% of the total variation in apo A-I size distri bution, indicating that apo A-I concentration is a poor predictor of a po A-I size distribution. In summary, the data suggest that there are significant genetic and environmental effects on apo A-I size distribu tion in humans, and that they are general metabolic effects rather tha n effects on specific HDL subclasses.