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Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study.

ABSTRACT: Background: The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n?=?789) and without (n?=?2127) T2D from the IMI-DIRECT cohorts to describe the co-expression structure of whole blood that mainly reflects processes and cell types of the immune system, and how it relates to metabolically relevant clinical traits and T2D.

Methods: Clusters of co-expressed genes were identified in the non-diabetic IMI-DIRECT cohort and evaluated with regard to stability, as well as preservation and rewiring in the cohort of individuals with T2D. We performed functional and immune cell signature enrichment analyses, and a genome-wide association study to describe the genetic regulation of the modules. Phenotypic and trans-omics associations of the transcriptomic modules were investigated across both IMI-DIRECT cohorts.

Results: We identified 55 whole blood co-expression modules, some of which clustered in larger super-modules. We identified a large number of associations between these transcriptomic modules and measures of insulin action and glucose tolerance. Some of the metabolically linked modules reflect neutrophil-lymphocyte ratio in blood while others are independent of white blood cell estimates, including a module of genes encoding neutrophil granule proteins with antibacterial properties for which the strongest associations with clinical traits and T2D status were observed. Through the integration of genetic and multi-omics data, we provide a holistic view of the regulation and molecular context of whole blood transcriptomic modules. We furthermore identified an overlap between genetic signals for T2D and co-expression modules involved in type II interferon signaling.

Conclusions: Our results offer a large-scale map of whole blood transcriptomic modules in the context of metabolic disease and point to novel biological candidates for future studies related to T2D.

SUBMITTER: Gudmundsdottir V

PROVIDER: S-EPMC7708171 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study.

Gudmundsdottir Valborg V Pedersen Helle Krogh HK Mazzoni Gianluca G Allin Kristine H KH Artati Anna A Beulens Joline W JW Banasik Karina K Brorsson Caroline C Cederberg Henna H Chabanova Elizaveta E De Masi Federico F Elders Petra J PJ Forgie Ian I Giordano Giuseppe N GN Grallert Harald H Gupta Ramneek R Haid Mark M Hansen Torben T Hansen Tue H TH Hattersley Andrew T AT Heggie Alison A Hong Mun-Gwan MG Jones Angus G AG Koivula Robert R Kokkola Tarja T Laakso Markku M Løngreen Peter P Mahajan Anubha A Mari Andrea A McDonald Timothy J TJ McEvoy Donna D Musholt Petra B PB Pavo Imre I Prehn Cornelia C Ruetten Hartmut H Ridderstråle Martin M Rutters Femke F Sharma Sapna S Slieker Roderick C RC Syed Ali A Tajes Juan Fernandez JF Thomas Cecilia Engel CE Thomsen Henrik S HS Vangipurapu Jagadish J Vestergaard Henrik H Viñuela Ana A Wesolowska-Andersen Agata A Walker Mark M Adamski Jerzy J Schwenk Jochen M JM McCarthy Mark I MI Pearson Ewan E Dermitzakis Emmanouil E Franks Paul W PW Pedersen Oluf O Brunak Søren S

Genome medicine 20201201 1

<h4>Background</h4>The rising prevalence of type 2 diabetes (T2D) poses a major global challenge. It remains unresolved to what extent transcriptomic signatures of metabolic dysregulation and T2D can be observed in easily accessible tissues such as blood. Additionally, large-scale human studies are required to further our understanding of the putative inflammatory component of insulin resistance and T2D. Here we used transcriptomics data from individuals with (n = 789) and without (n = 2127) T2D ...[more]

PMID: 33261667

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Project description:Aims/hypothesis: It is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cycle hypothesis (TC) provides a mechanistic basis for impairment in glycaemic control through the interactions of substrate availability, substrate metabolism and abdominal ectopic fat accumulation. Here, we hypothesise that the effect of physical activity in glucose regulation is mediated by the twin-cycle. We aimed to examine this notion in the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) Consortium cohorts comprised of participants with normal or impaired glucose regulation (cohort 1: N???920) or with recently diagnosed type 2 diabetes (cohort 2: N???435).Methods: We defined a structural equation model that describes the TC and fitted this within the IMI DIRECT dataset. A second model, twin-cycle plus physical activity (TC-PA), to assess the extent to which the effects of physical activity in glycaemic regulation are mediated by components in the twin-cycle, was also fitted. Beta cell function, insulin sensitivity and glycaemic control were modelled from frequently sampled 75 g OGTTs (fsOGTTs) and mixed-meal tolerance tests (MMTTs) in participants without and with diabetes, respectively. Abdominal fat distribution was assessed using MRI, and physical activity through wrist-worn triaxial accelerometry. Results are presented as standardised beta coefficients, SE and p values, respectively.Results: The TC and TC-PA models showed better fit than null models (TC: ?2?=?242, p?=?0.004 and ?2?=?63, p?=?0.001 in cohort 1 and 2, respectively; TC-PA: ?2?=?180, p?=?0.041 and ?2?=?60, p?=?0.008 in cohort 1 and 2, respectively). The association of physical activity with glycaemic control was primarily mediated by variables in the liver fat cycle.Conclusions/interpretation: These analyses partially support the mechanisms proposed in the twin-cycle model and highlight mechanistic pathways through which insulin sensitivity and liver fat mediate the association between physical activity and glycaemic control.

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Dataset Information

Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study.

Publications

Whole blood co-expression modules associate with metabolic traits and type 2 diabetes: an IMI-DIRECT study.

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