Abstract
The insulin-like growth factors (IGFs)/insulin resistance (IR) axis is the major metabolic hormonal pathway mediating the biologic mechanism of several complex human diseases, including type 2 diabetes (T2DM) and cancers. The genomewide association study (GWAS)-based approach has neither fully characterized the phenotype variation nor provided a comprehensive understanding of the regulatory biologic mechanisms. We applied systematic genomics to integrate our previous GWAS data for IGF-I and IR with multi-omics datasets, e.g., whole-blood expression quantitative loci, molecular pathways, and gene network, to capture the full range of genetic functionalities associated with IGF-I/IR and key drivers (KDs) in gene-regulatory networks. We identified both shared (e.g., T2DM, lipid metabolism, and estimated glomerular filtration signaling) and IR-specific (e.g., mechanistic target of rapamycin, phosphoinositide 3-kinases, and erb-b2 receptor tyrosine kinase 4 signaling) molecular biologic processes of IGF-I/IR axis regulation. Next, by using tissue-specific gene–gene interaction networks, we identified both well-established (e.g., IRS1 and IGF1R) and novel (e.g., AKT1, HRAS, and JAK1) KDs in the IGF-I/IR-associated subnetworks. Our results, if validated in additional genomic studies, may provide robust, comprehensive insights into the mechanisms of IGF-I/IR regulation and highlight potential novel genetic targets as preventive and therapeutic strategies for the associated diseases, e.g., T2DM and cancers.
Highlights
The insulin-like growth factors (IGFs)/insulin resistance (IR) axis has been considered one of the major metabolic hormonal pathways that mediate the biologic mechanism of several complex human diseases, such as type 2 diabetes (T2DM), metabolic syndrome, cardiovascular disease, and cancers [1,2,3,4,5,6,7,8,9,10,11]
The IGFs/IR axis can be associated with carcinogenesis by aberrantly regulating multiple downstream cell-signaling cascades involved in the promitogenic, proinflammatory, and antiapoptotic signals, creating a proneoplastic environment for tumor growth and development in particular cells [6,13,14,15,16,17]
estimated glomerular filtration rate (EGFR) signaling is associated with insulin-like growth factor-I (IGF-I) receptor (IGF-IR) expression and IGF-I secretion in cancer cells [54,55], contributing to cancer cell growth and poor survival; dual targeting at EGFR and the IGF/IR axis has been suggested to be a promising therapeutic strategy for overcoming drug-acquired resistance in several cancer types, such as lung adenocarcinoma, head and neck squamous cell and colorectal carcinomas, and glioblastoma [55,56,57,58]
Summary
The insulin-like growth factors (IGFs)/insulin resistance (IR) axis has been considered one of the major metabolic hormonal pathways that mediate the biologic mechanism of several complex human diseases, such as type 2 diabetes (T2DM), metabolic syndrome, cardiovascular disease, and cancers [1,2,3,4,5,6,7,8,9,10,11]. The IGFs/IR axis can be associated with carcinogenesis by aberrantly regulating multiple downstream cell-signaling cascades involved in the promitogenic, proinflammatory, and antiapoptotic signals, creating a proneoplastic environment for tumor growth and development in particular cells [6,13,14,15,16,17]. Despite advances in the understanding of genetic variance in relation to those biomarkers, common genetic variants from genomewide association studies (GWASs) explain a moderate proportion of the phenotype variation. GWASs [23] have so far identified more than 83 loci for one or more glycemic traits, together explaining about 20% of the genetic heritability [24]; this suggests that more than two thirds of heritability is still to be discovered
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