부산대학교 도서관

Introduction: Using an aptamer-based proteomics platform, we recently identified 156 plasma proteins associated with the Framingham Risk Score (FRS) in Framingham Heart Study (FHS) Offspring participants. Here we hypothesized that integrating genetic and proteomic data would highlight novel determinants of circulating levels of the FRS-associated cardiovascular disease (CVD) risk proteome and pathways that may contribute to disease biology.Methods: We performed GWAS and exome chip (EC) studies of the 156 plasma proteins linked to the FRS in 759 participants of the FHS Offspring cohort with replication in 554 participants of the Malmö Diet and Cancer Study (MDCS). For functional validation, we used siRNA for genetic knockdown in the Hep G2 human hepatocyte cell line and measured mRNA levels by RT-PCR and protein accumulation in the culture media by ELISA.Results: We identified 120 locus-protein associations in GWAS (P < 5 x 10) and 41 associations in EC analyses (P < 6 x 10) that explained up to 65.6% of plasma protein heritability, the majority of which were novel and validated in MDCS. We identified cis associations (<1 Mb) for key proteins involved in extracellular matrix homeostasis (e.g., cathepsin S, extracellular matrix protein 1) and inflammation (e.g., interleukin-18 receptor 1, soluble advanced glycosylation end product-specific receptor), as well as a trans association that included a nonsense mutation in the coding region of macrophage scavenger receptor type I protein strongly associated with galectin-3 levels. We experimentally validated a trans association of particular interest between circulating ApoE levels and phosphatase 1G (PPM1G), a regulator of transcription linked to circulating cholesterol levels through an unknown mechanism in GWAS consortium analyses. Knockdown of PPM1G in Hep G2 cells resulted in a specific 36% reduction in ApoE expression (N = 6; P = 6.0 x 10) and 18% reduction in ApoE protein in the culture media (N = 12; P = 1.1 x 10).Conclusions: We identified dozens of novel genetic determinants of proteins associated with the Framingham Risk Score and experimentally validated a role for PPM1G in ApoE biology. All GWAS and EC proteomic data have been made publicly available as a resource for future CVD research.