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Shared (epi)genomic background connecting neurodegenerative diseases and type 2 diabetes.

ABSTRACT: The progressive aging of populations has resulted in an increased prevalence of chronic pathologies, especially of metabolic, neurodegenerative and movement disorders. In particular, type 2 diabetes (T2D), Alzheimer's disease (AD) and Parkinson's disease (PD) are among the most prevalent age-related, multifactorial pathologies that deserve particular attention, given their dramatic impact on patient quality of life, their economic and social burden as well the etiopathogenetic mechanisms, which may overlap in some cases. Indeed, the existence of common triggering factors reflects the contribution of mutual genetic, epigenetic and environmental features in the etiopathogenetic mechanisms underlying T2D and AD/PD. On this subject, this review will summarize the shared (epi)genomic features that characterize these complex pathologies. In particular, genetic variants and gene expression profiles associated with T2D and AD/PD will be discussed as possible contributors to determine the susceptibility and progression to these disorders. Moreover, potential shared epigenetic modifications and factors among T2D, AD and PD will also be illustrated. Overall, this review shows that findings from genomic studies still deserves further research to evaluate and identify genetic factors that directly contribute to the shared etiopathogenesis. Moreover, a common epigenetic background still needs to be investigated and characterized. The evidences discussed in this review underline the importance of integrating large-scale (epi)genomic data with additional molecular information and clinical and social background in order to finely dissect the complex etiopathogenic networks that build up the "disease interactome" characterizing T2D, AD and PD.

SUBMITTER: Caputo V

PROVIDER: S-EPMC7243483 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Shared (epi)genomic background connecting neurodegenerative diseases and type 2 diabetes.

Caputo Valerio V Termine Andrea A Strafella Claudia C Giardina Emiliano E Cascella Raffaella R

World journal of diabetes 20200501 5

The progressive aging of populations has resulted in an increased prevalence of chronic pathologies, especially of metabolic, neurodegenerative and movement disorders. In particular, type 2 diabetes (T2D), Alzheimer's disease (AD) and Parkinson's disease (PD) are among the most prevalent age-related, multifactorial pathologies that deserve particular attention, given their dramatic impact on patient quality of life, their economic and social burden as well the etiopathogenetic mechanisms, which ...[more]

PMID: 32477452

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Project description:BACKGROUND:Pancreatic Islets of Langerhans are heterogeneous tissues consisting of multiple endocrine cell types that carry out distinct yet coordinated roles to regulate blood glucose homeostasis. Islet dysfunction and specifically failure of the beta cells to secrete adequate insulin are known precursors to type 2 diabetes (T2D) onset. However, the exact genetic, (epi)genomic, and environmental mechanisms that contribute to islet failure, and ultimately to T2D pathogenesis, require further elucidation. SCOPE OF REVIEW:This review summarizes efforts and advances in dissection of the complex genetic underpinnings of islet function and resilience in T2D pathogenesis. In this review, we will highlight results of the latest T2D genome-wide association study (GWAS) and discuss how these data are being combined with clinical measures in patients to uncover putative T2D subtypes and with functional (epi)genomic studies in islets to understand the genetic programming of islet cell identity, function, and adaptation. Finally, we discuss new and important opportunities to address major knowledge gaps in our understanding of islet (dys)function in T2D risk and progression. MAJOR CONCLUSIONS:Genetic variation exerts clear effects on the islet epigenome, regulatory element usage, and gene expression. Future (epi)genomic comparative analyses between T2D and normal islets should incorporate genetics to distinguish patient-specific from disease-specific differences. Incorporating genotype information into future analyses and studies will also enable more precise insights into the molecular genetics of islet deficiency and failure in T2D risk, and should ultimately contribute to a stratified view of T2D and more precise treatment strategies. Islet cellular heterogeneity continues to remain a challenge for understanding the associations between islet failure and T2D development. Further efforts to obtain purified islet cell type populations and determine the specific genetic and environmental effects on each will help address this. Beyond observation of islets at steady state conditions, more research of islet stress and stimulation responses are needed to understand the transition of these tissues from a healthy to diseased state. Together, focusing on these objectives will provide more opportunities to prevent, treat, and manage T2D.

Project description:BackgroundConsidered as the representatives of neurodegenerative diseases, Alzheimer's disease (AD) and glaucoma are complex progressive neuropathies affected by both genetic and environmental risk factors and cause irreversible damages. Current research indicates that there are common features between AD and glaucoma in terms of epidemiology and pathophysiology. However, the understandings and explanations of their comorbidity and potential genetic overlaps are still limited and insufficient.MethodGenetic pleiotropy analysis was performed using large genome-wide association studies summary statistics of AD and glaucoma, with an independent cohort of glaucoma for replication. Conditional and conjunctional false discovery rate methods were applied to identify the shared loci. Biological function and network analysis, as well as the expression level analysis were performed to investigate the significance of the shared genes.ResultsA significant positive genetic correlation between AD and glaucoma was identified, indicating that there were significant polygenetic overlaps. Forty-nine shared loci were identified and mapped to 11 shared protein-coding genes. Functional genomic analyses of the shared genes indicate their modulation of critical physiological processes in human cells, including those occurring in the mitochondria, nucleus, and cellular membranes. Most of the shared genes indicated a potential modulation of metabolic processes in human cells and tissues. Furthermore, human protein-protein interaction network analyses revealed that some of the shared genes, especially MTCH2, NDUFS3, and PTPMT1, as well as SPI1 and MYBPC3, may function concordantly. The modulation of their expressions may be related to metabolic dysfunction and pathogenic processes.ConclusionOur study identified a shared genetic architecture between AD and glaucoma, which may explain their shared features in epidemiology and pathophysiology. The potential involvement of these shared genes in molecular and cellular processes reflects the "inter-organ crosstalk" between AD and glaucoma. These results may serve as a genetic basis for the development of innovative and effective therapeutics for AD, glaucoma, and other neurodegenerative diseases.

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Shared (epi)genomic background connecting neurodegenerative diseases and type 2 diabetes.

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Shared (epi)genomic background connecting neurodegenerative diseases and type 2 diabetes.

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