Genetic control of the HDL proteome

Nathalie Pamir; Calvin Pan; Deanna L. Plubell; Patrick M. Hutchins; Chongren Tang; Jake Wimberger; Angela Irwin; Thomas Q. de Aguiar Vallim; Jay W. Heinecke; Aldons J. Lusis

We report the analysis of the HDL proteome across a set of 93 inbred strains of mice exhibiting common genetic variation. The genetic variation across this mouse panel resembles that in human populations, based on the number of common SNPs (about 4 million). Previous studies in mice have revealed genetic variations in the levels of HDL-cholesterol, HDL apoproteins, and HDL composition (Lusis et al., 1983) . Our results are consistent with a high level of heritability of HDL proteins, including the identification of a number of novel pQTLs. One significant conclusion that has emerged is that certain proteins cluster together in response to genetic perturbations, presumably reflecting physical or regulatory interactions. These clusters then help define the heterogeneity of HDL particles, although our analyses do not address lipid heterogeneity. Another important conclusion is evidence of a relationship between protein composition and HDL function. Finally, we have identified potential links between HDL proteins and various clinical or molecular traits studied previously in the HMDP strains. We discuss each of these points in turn below.