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

Mice have 85% of their HDL cholesterol distributed in the 7.6-9.8nm range (medium size) in a monodispersed peak (Pamir et al, 2016) , and therefore medium size HDL represents the majority of HDL cholesterol. This latter cluster is associated with APOA2 levels ( Figure 3 ). Further, proteins that participate in immune responses, including serum amyloids SAA1, SAA2, histocompatibility complexes H2-Q4 and H2-Q10 associated strongly and formed a distinct cluster with other immune response proteins CD97, C4BPA and APOE. All of the hemoglobin proteins, HBBA, HBB1, HBBT1 formed a distinct cluster. Lipid metabolism proteins, APOC1, APOA5, APOA4, PLTP, and GPLD1 clustered together. Most interestingly, APOC3 correlated negatively with 39 proteins on HDL. Among these were proteins with roles in immune response such as APOE, PON1, SAA1, SAA4 (Supplementary Table 5 ). insulin like growth factor binding protein, IGFALS clustered strongly but negatively with APOC3 (r=-0.53, P=0.002). Recent studies suggest a role for APOC3 in beta cell insulin resistance (Ã…vall et al, 2015) and according to proteome interactome by Harmonizome (a tool curated from 100 public databases (Rouillard et al, 2016) ) APOC3 is one of the 73 proteins found to interact with IGFALS. We observed significant correlations between HDL-C levels and GM94, ITGB1, APOC1, APOC2 (positive) and APOA2, SERPINA1A, ALB, and TFRC (negative) regardless of PSM normalization method used (Supplemental Table 5 ). All the New Zealand strains studied (NZB BIN/J, NZW LAC/J, KKHI/J) were in the top quintile of HDL-C distribution and bottom quintile of APOA2 distribution. The QTL analysis indicated the same genomic regions for regulation of APOA2 and HDL-C levels (Supplemental Figure 8) . APOA2 seems to be the main genetic regulator of plasma HDL-C levels in mice.