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Type 2 Diabetes Development Linked to GWAS-Informed Regulatory Modules

NEW YORK – With analyses that included gene expression, genetic risk, and functional data, researchers at Vanderbilt University, the University of Michigan at Ann Arbor, and elsewhere have started to tease out the gene regulatory networks behind type 2 diabetes (T2D), highlighting a key role for the transcription factor-coding gene RFX6.

"By integrating diverse modalities, we show that early-stage T2D is characterized by beta cell-intrinsic defects that can be proportioned into gene regulatory modules with enrichment in signals of genetic risk," co-corresponding authors Marcela Brissova, with Vanderbilt University Medical Center; Alvin Powers, with Vanderbilt University School of Medicine, Vanderbilt University Medical Center, and the VA Tennessee Valley Healthcare System; Stephen Parker, with the University of Michigan at Ann Arbor; and their colleagues wrote.

As they reported in Nature on Monday, the researchers relied on transcriptome profiling on cell-sorted pancreatic islet cells — together with pancreatic tissue imaging and islet cell functional assays — to profile pancreatic samples from 20 genotyped individuals with early-stage T2D and 19 unaffected individuals, setting the results against genetic signals linked to T2D risk through prior genome-wide association studies.

Using this approach, the team tracked down regulatory modules that were enriched for T2D-related risk variants, including modules regulating a subset of insulin-producing islet cells known as beta cells.

The results prompted the investigators to take a closer look at one of these modules, which centered on the transcription factor gene RFX6, using short hairpin RNA-based knockdown of the gene in pseudoislet cell samples from seven donor individuals.

Consistent with previous studies pointing to a role for rare RFX6 coding variants in early-onset diabetes risk, their single-nucleus RNA sequencing and single-nucleus ATAC-seq experiments suggested that islet cells lacking the RFX6 gene lead to beta cells with altered chromatin accessibility in parts of the genome containing T2D risk variants flagged in previous GWAS.

Likewise, the team's analyses on available UK Biobank data pointed to an apparent rise in T2D risk in the presence of noncoding genetic variants that are expected to dial down RFX6 expression.

"Overall, our results and prior information reveal multiple layers of genetic convergence on RFX6 and its regulatory network," the authors wrote, adding that "three different classes of genetic variations all converge on RFX6 biology in diabetes."

The investigators speculated that altered RFX6 activity during islet cell development or beta cell maintenance may manifest over time via interactions with environmental, nutritional, and age-related factors. They noted that additional research will be needed to distinguish that possibility from a model in which the beta cell effects stem from cumulative genetic effects of many common T2D genetic risk variants impacting RFX6-containing regulatory modules.

"[P]recisely what underlies the initial RFX6 dysregulation and whether it can be targeted to prevent or reverse early-stage molecular and functional defects in the beta cell should be an active area of investigation," the authors wrote.

More broadly, they suggested that a similar strategy may be used to dig into the regulatory underpinnings of other traits or conditions that have been analyzed by GWAS.

"Understanding the molecular mechanisms of complex, systemic diseases necessitates integration of signals from multiple molecules, cells, organs, and individuals," the authors reasoned, "and thus we anticipate that this approach will be a useful template to identify and validate key regulatory networks and master hub genes for other diseases and traits using GWAS data."