Shared genetic regulatory networks for cardiovascular disease and type 2 diabetes in multiple populations of diverse ethnicities in the United States

PLoS Genet. 2017 Sep 28;13(9):e1007040. doi: 10.1371/journal.pgen.1007040. eCollection 2017 Sep.

Abstract

Cardiovascular diseases (CVD) and type 2 diabetes (T2D) are closely interrelated complex diseases likely sharing overlapping pathogenesis driven by aberrant activities in gene networks. However, the molecular circuitries underlying the pathogenic commonalities remain poorly understood. We sought to identify the shared gene networks and their key intervening drivers for both CVD and T2D by conducting a comprehensive integrative analysis driven by five multi-ethnic genome-wide association studies (GWAS) for CVD and T2D, expression quantitative trait loci (eQTLs), ENCODE, and tissue-specific gene network models (both co-expression and graphical models) from CVD and T2D relevant tissues. We identified pathways regulating the metabolism of lipids, glucose, and branched-chain amino acids, along with those governing oxidation, extracellular matrix, immune response, and neuronal system as shared pathogenic processes for both diseases. Further, we uncovered 15 key drivers including HMGCR, CAV1, IGF1 and PCOLCE, whose network neighbors collectively account for approximately 35% of known GWAS hits for CVD and 22% for T2D. Finally, we cross-validated the regulatory role of the top key drivers using in vitro siRNA knockdown, in vivo gene knockout, and two Hybrid Mouse Diversity Panels each comprised of >100 strains. Findings from this in-depth assessment of genetic and functional data from multiple human cohorts provide strong support that common sets of tissue-specific molecular networks drive the pathogenesis of both CVD and T2D across ethnicities and help prioritize new therapeutic avenues for both CVD and T2D.

MeSH terms

  • Adipocytes / metabolism
  • Amino Acids, Branched-Chain / metabolism
  • Animals
  • Cardiovascular Diseases / genetics*
  • Caveolin 1 / genetics
  • Caveolin 1 / metabolism
  • Diabetes Mellitus, Type 2 / genetics*
  • Disease Models, Animal
  • Ethnic Groups / genetics*
  • Extracellular Matrix Proteins / genetics
  • Extracellular Matrix Proteins / metabolism
  • Gene Expression Regulation
  • Gene Regulatory Networks*
  • Genome-Wide Association Study
  • Glucose / metabolism
  • Glycoproteins / genetics
  • Glycoproteins / metabolism
  • Humans
  • Hydroxymethylglutaryl CoA Reductases / genetics
  • Hydroxymethylglutaryl CoA Reductases / metabolism
  • Insulin-Like Growth Factor I / genetics
  • Insulin-Like Growth Factor I / metabolism
  • Lipid Metabolism
  • Male
  • Mice
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Reproducibility of Results
  • United States

Substances

  • Amino Acids, Branched-Chain
  • Cav1 protein, mouse
  • Caveolin 1
  • Extracellular Matrix Proteins
  • Glycoproteins
  • Pcolce protein, mouse
  • insulin-like growth factor-1, mouse
  • Insulin-Like Growth Factor I
  • Hydroxymethylglutaryl CoA Reductases
  • Glucose