Shared Molecular Pathways and Gene Networks for Cardiovascular Disease and Type 2 Diabetes Mellitus in Women Across Diverse Ethnicities

Abstract

It has long been known that cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) share many common risk factors and pathophysiological intermediaries including obesity, dyslipidemia, insulin resistance, and proinflammatory and prothrombotic states. [1][2][3] However, the key molecular drivers underlying these highly correlated phenotypes as well as the potential regulatory networks shared in the pathogenesis of CVD and T2D remain poorly understood. Clinical Perspective on p 919Of the ≈60 genetic loci identified for CVD and T2D in large-scale genome-wide association studies (GWAS), 5 only 2 significant loci (TCF7L2 and VEGFA) are shared between the 2 diseases. There are ≥3 fundamentally important questions that remain to be answered. First, are there additional genetic risks, either alone or concentrated in specific regulatory networks that may explain the pathophysiological connections between CVD and T2D? Second, are there any ethnicityspecific genetic mechanisms for these 2 common vascular diseases, given that there are drastic ethnicity-specific differences in their risk and linkage disequilibrium patterns. [6][7][8] Third, although common genetic loci have been detected across different populations (eg, the Chr9p21 locus for CVD and the TCF7L2 locus for T2D) supporting the presence of common pathological paths across ethnicity, to what degree molecular mechanisms are shared across ethnicities?To answer these 3 questions, we performed 2 GWAS for both CVD and T2D using an integrative pathway and network analysis in the national Women's Health Initiative SNP Health Association Resource (WHI-SHARe) and the Genomics and Background-Although cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D) share many common risk factors, potential molecular mechanisms that may also be shared for these 2 disorders remain unknown. Methods and Results-Using an integrative pathway and network analysis, we performed genome-wide association studies in 8155 blacks, 3494 Hispanic American, and 3697 Caucasian American women who participated in the national Women's Health Initiative single-nucleotide polymorphism (SNP) Health Association Resource and the Genomics and Randomized Trials Network. Eight top pathways and gene networks related to cardiomyopathy, calcium signaling, axon guidance, cell adhesion, and extracellular matrix seemed to be commonly shared between CVD and T2D across all 3 ethnic groups. We also identified ethnicity-specific pathways, such as cell cycle (specific for Hispanic American and Caucasian American) and tight junction (CVD and combined CVD and T2D in Hispanic American). In network analysis of gene-gene or protein-protein interactions, we identified key drivers that included COL1A1, COL3A1, and ELN in the shared pathways for both CVD and T2D. These key driver genes were cross-validated in multiple mouse models of diabetes mellitus and atherosclerosis. Conclusions-Our integrative analysis of American women of 3 ethnicities identified multiple shared biological pathways and key regulatory ge...

Soluble CD93 Is Involved in Metabolic Dysregulation but Does Not Influence Carotid Intima-Media Thickness

“…Leaky vessels and endothelial damage would permit insulin diffusion into the interstitial space, leading to suboptimal insulin delivery to distal tissues. These results are the first direct evidence for the recently proposed role for CD93 in T2D (12). …”

“…More recently, the CD93 gene has been identified as a potential regulator of pathways common to both T2D and CVD (12). Interestingly, CD93 expression is upregulated by conditions relevant to diabetes or its complications, for example, flow-related shear stress (13) due to endothelial dysfunction; during the development of new but leaky blood vessels (14), as observed in retinopathy; and during ischemia-related inflammation of cerebral vascular endothelium (15), thus reflecting myocardial infarction.…”

Identification of polycystic ovary syndrome potential drug targets based on pathobiological similarity in the protein-protein interaction network

“…As shown in a series of recent publications [16, 65] in developing new findings and approaches, user-friendly and publicly accessible web-servers will significantly enhance their impacts [20], we shall make efforts in our future work to provide a web-server to displaying findings that can be manipulated by users according to their need.…”

“…For example, disease genes and drug targets of coronary heart disease (CAD) and T2D could be identified effectively by systems biology approaches [18, 19]. Chan KH et al identified key drivers that included COL1A1, COL3A1, and ELN in the shared pathways for both CAD and T2D based on the protein-protein interaction network (PPIN) and genome-wide association studies [20]. In addition, the highly central importance proteins in core networks or sub-networks are globally or locally important nodes which could act as functional modules or pathways or key role genes to uncover the pathogenesis and therapeutic ways of disease [21].…”

“…In addition, the highly central importance proteins in core networks or sub-networks are globally or locally important nodes which could act as functional modules or pathways or key role genes to uncover the pathogenesis and therapeutic ways of disease [21]. For example, Li H et al presented a novel PPI knowledge-based approach that identified functional modules and hub genes for CAD, revealing several novel pathogenic mechanisms [20]. Wan Li et al developed a method using combined centrality indices on the systems level to identify essential cancer-related motifs in central roles, which provided a clue for the study of signal transduction in biological pathways [22].…”