The Genetic Architecture of the Cardiovascular Risk Proteome
Background—We recently identified 156 proteins in human plasma that were each associated with the net Framingham Cardiovascular Disease (CVD) Risk Score (FRS) using an aptamer-based proteomic platform in Framingham Heart Study (FHS) Offspring participants. Here, we hypothesized that performing genome-wide association studies and exome array analyses on the levels of each these 156 proteins might identify genetic determinants of risk-associated circulating factors and provide insights into early cardiovascular pathophysiology.
Methods—We studied the association of genetic variants with the plasma levels of each of the 156 FRS-associated proteins using linear mixed effects models in two population-based cohorts. We performed discovery analyses in 759 participants of the FHS Offspring cohort, an observational study of the adult children of the original FHS participants, and validated these findings in 1421 participants of the Malmö Diet and Cancer Study. To evaluate the utility of this strategy in identifying new biological pathways relevant to CVD pathophysiology, we performed studies in a cell-model system to experimentally validate the functional significance of an especially novel genetic association with circulating apolipoprotein E (ApoE) levels.
Results—We identified 120 locus-protein associations in genome-wide analyses and 41 associations in exome array analyses, the majority of which have not been described previously. These loci explained up to 66% of inter-individual plasma protein level variation and, on average, accounted for three times the amount of variation explained by common clinical factors, such as age, sex, and diabetes status. We described overlap between many of these loci and CVD genetic risk variants. Finally, we experimentally validated a novel association between circulating ApoE levels and the transcription factor phosphatase 1G (PPM1G). Knockdown of PPM1G in a human liver cell model resulted in decreased ApoE transcription and ApoE protein levels in cultured supernatants.
Conclusions—We identified dozens of novel genetic determinants of proteins associated with the FRS and experimentally validated a new role for PPM1G in lipoprotein biology. Further, genome-wide and exome array data for each protein has been made publicly available as a resource for CVD research.
- Received May 16, 2017.
- Revision received October 2, 2017.
- Accepted November 6, 2017.