Convergence of genetic influences in comorbidity

McEachin, Richard C.; Sannareddy, Keerthi; Cavalcoli, James D.; Karnovsky, Alla; Vink, Jacqueline M.; Sartor, Maureen A.

doi:10.1186/1471-2105-13-s2-s8

Cited by 3 publications

(2 citation statements)

References 12 publications

(18 reference statements)

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“…One of the outcomes of this recent work suggests the hypothesis that the OVOLs have roles in regulating MET in multiple cancers. This hypothesis is also consistent with our earlier work [ 4 - 8 ], where we found common underlying genetic etiology for related disease phenotypes. We also found in earlier work [ 6 , 7 , 9 ] that exploring this common underlying genetic etiology using a systems biology approach can lead to improved understanding of the related phenotypes and interactions among the genetic influences on them, and may point out potential clinically significant biomarkers or drug targets.…”

Section: Introductionsupporting

confidence: 94%

A bioinformatics approach reveals novel interactions of the OVOL transcription factors in the regulation of epithelial – mesenchymal cell reprogramming and cancer progression

et al. 2014

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BackgroundMesenchymal to Epithelial Transition (MET) plasticity is critical to cancer progression, and we recently showed that the OVOL transcription factors (TFs) are critical regulators of MET. Results of that work also posed the hypothesis that the OVOLs impact MET in a range of cancers. We now test this hypothesis by developing a model, OVOL Induced MET (OI-MET), and sub-model (OI-MET-TF), to characterize differential gene expression in MET common to prostate cancer (PC) and breast cancer (BC).ResultsIn the OI-MET model, we identified 739 genes differentially expressed in both the PC and BC models. For this gene set, we found significant enrichment of annotation for BC, PC, cancer, and MET, as well as regulation of gene expression by AP1, STAT1, STAT3, and NFKB1. Focusing on the target genes for these four TFs plus the OVOLs, we produced the OI-MET-TF sub-model, which shows even greater enrichment for these annotations, plus significant evidence of cooperation among these five TFs. Based on known gene/drug interactions, we prioritized targets in the OI-MET-TF network for follow-on analysis, emphasizing the clinical relevance of this work. Reflecting these results back to the OI-MET model, we found that binding motifs for the TF pair AP1/MYC are more frequent than expected and that the AP1/MYC pair is significantly enriched in binding in cancer models, relative to non-cancer models, in these promoters. This effect is seen in both MET models (solid tumors) and in non-MET models (leukemia). These results are consistent with our hypothesis that the OVOLs impact cancer susceptibility by regulating MET, and extend the hypothesis to include mechanisms not specific to MET.ConclusionsWe find significant evidence of the OVOL, AP1, STAT1, STAT3, and NFKB1 TFs having important roles in MET, and more broadly in cancer. We prioritize known gene/drug targets for follow-up in the clinic, and we show that the AP1/MYC TF pair is a strong candidate for intervention.

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Section: Introductionsupporting

confidence: 94%

A bioinformatics approach reveals novel interactions of the OVOL transcription factors in the regulation of epithelial – mesenchymal cell reprogramming and cancer progression

et al. 2014

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“…The search for genetic associations has typically been for specific disorders, although some have begun to investigate shared genetic pathways related to comorbidities [63]. One way to consider genetic predisposition is to consider mutations that either prevent the synthesis of a functional protein or more often provide for the synthesis of a protein with suboptimal function.…”

Section: Molecular Players As Shared Biological Substrate For Causationmentioning

confidence: 99%

Sex-dependent pathophysiology as predictors of comorbidity of major depressive disorder and cardiovascular disease

Tobet

Goldstein

2013

Pflugers Arch - Eur J Physiol

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There is a strong and growing literature showing that key aspects of brain development may be critical antecedents of adult physiology and behavior, or lead to physiological and psychiatric disorders in adulthood. Many are significantly influenced by sex-dependent factors. Neurons of the paraventricular nucleus of the hypothalamus (PVN) occupy a key position in regulating homeostatic, neuroendocrine, and behavioral functions. This brain area is a critical link for our understanding of the etiology of a number of disorders with components ranging from mood, to feeding and energy balance, and autonomic nervous system regulation. Thus based on common brain circuitry, the PVN may be a critical anatomical intersection for understanding comorbidities among depression, obesity, and cardiovascular risk. Historically, the majority of approaches to brain development examine neuronal, glial, and vascular factors independently, with notably less emphasis on vascular contributions. The realization that the PVN undergoes a unique vascular developmental process places added value on discerning the cellular and molecular mechanisms that drive its late onset angiogenesis and further implications for neuronal differentiation and function. This has ramifications in humans for understanding chronic, and sometimes fatal, comorbidities that share sex-dependent biological bases in development through functional and anatomical intersections with the hypothalamus.

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Interaction of Depression and Anxiety in the Development of Mixed Anxiety/Depression Disorder. Experimental Studies of the Mechanisms of Comorbidity (review)

Galyamina

Kovalenko

Smagin

et al. 2017

Neurosci Behav Physi

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Convergence of genetic influences in comorbidity

Cited by 3 publications

References 12 publications

A bioinformatics approach reveals novel interactions of the OVOL transcription factors in the regulation of epithelial – mesenchymal cell reprogramming and cancer progression

A bioinformatics approach reveals novel interactions of the OVOL transcription factors in the regulation of epithelial – mesenchymal cell reprogramming and cancer progression

Sex-dependent pathophysiology as predictors of comorbidity of major depressive disorder and cardiovascular disease

Interaction of Depression and Anxiety in the Development of Mixed Anxiety/Depression Disorder. Experimental Studies of the Mechanisms of Comorbidity (review)

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