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

A total of 19 HDL proteins showed significant evidence of local regulation of hepatic transcript levels or protein levels (Table 2) . With the exception of Apoc3, all of the significant pQTL also exhibited significant eQTL, indicating that genetic variation in protein levels was largely due to regulation of gene expression. In the case of Apoc3, while there was no significant eQTL in liver, there was a highly significant eQTL in adipose tissue (P=1.8 x 10 -7 ) (Supplemental Table 3 ). Apoa2 and Saa2 exhibited much more significant pQTL than eQTL (P=1.324e-22, effect size = -0.413 vs. P=1.276e-4, effect size = 0.0210 for Apoa2, and P=2.559e-10, effect size = 0.0780 and P=1.533e-6, effect size = 0.780 for Saa2 respectively), suggesting that the pQTL were due to coding rather than regulatory variations. In the case of Apoa2, our previous studies indicated that structural variation affecting translation efficiency was largely responsible for the differences in protein levels among several common inbred strains (Bennett et al., 2010) . Also, common coding variants are present among the HMDP strains for both Apoe3 and Saa2 (www.informatics.jax.org). As shown in Table 2 , many variants significantly affecting HDL protein expression did not exhibit corresponding variations in protein levels. A likely explanation in the case of HDL is that, for some proteins, only a limited amount of the protein can be incorporated into the HDL lipid-protein complex, the remainder presumably being degraded.