Abstract
Type 1 and 2 diabetes (T1/2D) are complex metabolic diseases caused by absolute or relative loss of functional β-cell mass, respectively. Both diseases are influenced by multiple genetic loci that alter disease risk. For many of the disease-associated loci, the causal candidate genes remain to be identified. Remarkably, despite the partially shared phenotype of the two diabetes forms, the associated loci for T1D and T2D are almost completely separated. We hypothesized that some of the genes located in risk loci for T1D and T2D interact in common pancreatic islet networks to mutually regulate important islet functions which are disturbed by disease-associated variants leading to β-cell dysfunction. To address this, we took a dual systems genetics approach. All genes located in 57 T1D and 243 T2D established genome-wide association studies (GWAS) loci were extracted and filtered for genes expressed in human islets using RNA sequencing data, and then integrated with; (1) human islet expression quantitative trait locus (eQTL) signals in linkage disequilibrium (LD) with T1D- and T2D-associated variants; or (2) with genes transcriptionally regulated in human islets by pro-inflammatory cytokines or palmitate as in vitro models of T1D and T2D, respectively. Our in silico systems genetics approaches created two interaction networks consisting of densely-connected T1D and T2D loci genes. The “T1D-T2D islet eQTL interaction network” identified 9 genes (GSDMB, CARD9, DNLZ, ERAP1, PPIP5K2, TMEM69, SDCCAG3, PLEKHA1, and HEMK1) in common T1D and T2D loci that harbor islet eQTLs in LD with disease-associated variants. The “cytokine and palmitate islet interaction network” identified 4 genes (ASCC2, HIBADH, RASGRP1, and SRGAP2) in common T1D and T2D loci whose expression is mutually regulated by cytokines and palmitate. Functional annotation analyses of the islet networks revealed a number of significantly enriched pathways and molecular functions including cell cycle regulation, inositol phosphate metabolism, lipid metabolism, and cell death and survival. In summary, our study has identified a number of new plausible common candidate genes and pathways for T1D and T2D.
Highlights
Type 1 (T1D) and 2 diabetes (T2D) are complex metabolic traits characterized by complete or relative insulin deficiency, respectively, due to destruction or failure of the β-cells in the pancreatic islets of Langerhans
During the process of immunemediated β-cell killing, the β-cells are not just passive bystanders but actively participate in their own demise through the interface with the immune system via e.g., MHC class I expression and production of chemokines favoring islet infiltration of immune cells, and through their inherent “fragility” to immune damage (Soleimanpour and Stoffers, 2013; Mallone and Eizirik, 2020). β-cell failure in T2D may be caused by prolonged metabolic stress exerted by e.g., free fatty acids (FFA) such as palmitate, and by the persistent increased demand for insulin production due to peripheral insulin resistance leading to β-cell failure (Prentki and Nolan, 2006; Oh et al, 2018; Wysham and Shubrook, 2020)
We aimed to take current knowledge of T1D and T2D genetics a step further by applying a systems genetics approach integrating genome-wide association studies (GWAS) data with human islet expression quantitative trait locus (eQTL) and in vitro pathogenesis models to identify plausible causal risk genes, networks, and pathways shared between T1D and T2D at the pancreatic islet level
Summary
Type 1 (T1D) and 2 diabetes (T2D) are complex metabolic traits characterized by complete or relative insulin deficiency, respectively, due to destruction or failure of the β-cells in the pancreatic islets of Langerhans. Different mechanisms lead to β-cell failure in T1D and T2D, the loss of functional β-cell mass is a common key mechanism and, in both cases the β-cells seem to play an active role (Eizirik et al, 2020). Both T1D and T2D are polygenetic and disease risk is influenced by multiple genetic variants. Among the few known common risk genes that have been functionally validated is GLIS3 which plays an important role in the β-cells by regulating proliferation and apoptosis (Nogueira et al, 2013; Wen and Yang, 2017). Better insight into the differences and putative commonalities of diabetes genetics may shed new light onto the pathogeneses of both diabetes forms
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