Shared Molecular Pathways and Gene Networks for Cardiovascular Disease and Type 2 Diabetes in Women across Diverse Ethnicities
Background—While cardiovascular disease (CVD) and type 2 diabetes (T2D) share many common risk factors, potential molecular mechanisms that may also be shared for these two disorders remain unknown.
Methods and Results—Using an integrative pathway and network analysis, we carried out genome-wide association studies (GWAS) in 8,155 African American (AA), 3,494 Hispanic American (HA), and 3,697 Caucasian American (CA) women who participated in the national Women's Health Initiative SNP Health Association Resource (WHI-SHARe) and the Genomics and Randomized Trials Network (WHI-GARNET). Eight top pathways and gene networks related to cardiomyopathy, calcium signaling, axon guidance, cell adhesion, and extracellular matrix appeared to be commonly shared between CVD and T2D across all three ethnic groups. We also identified ethnicity-specific pathways, such as cell cycle (specific for HA and CA) and tight junction (CVD and combined CVD and T2D in HA). In network analysis of gene-gene or protein-protein interactions, we identified key drivers that included COL1A1, OL3A1, and ELN in the shared pathways for both CVD and T2D. These key driver genes were cross-validated in multiple mouse models of diabetes and atherosclerosis.
Conclusions—Our integrative analysis of American women of three ethnicities identified multiple shared biological pathways and key regulatory genes for the development of CVD and T2D. These prospective findings also support the notion that ethnicity-specific susceptibility genes and process are involved in the pathogenesis of CVD and T2D.
- pathway and network analysis
- genome-wide association studies
- diabetes mellitus
- cardiovascular disease
- Received March 18, 2014.
- Revision received September 4, 2014.
- Accepted September 23, 2014.