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Functional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation - Nature Communications

Functional characterization of T2D-associated SNP effects on baseline and ER stress-responsive β cell transcriptional activation - Nature Communications

Source :

https://www.nature.com/articles/s41467-021-25514-6

Identifying causal variants at GWAS loci is important to understand disease mechanisms. Here the authors use massively parallel reporter assays to identify type 2 diabetes-associated variants that alter cis-regulatory activity, narrowing in on the causal variants and genetic mechanisms behind the disease.

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    Key Points
    • Conclusion/Relevance: “In this study, we tested 13,252 sequences containing alleles of 6,621 SNPs for their ability to activate and modulate transcription in MIN6 β cells under standard culture conditions and after ER [endoplasmic reticulum] stress or paired solvent control exposures. In total, 29.9% of elements (n = 1982/6621) exhibited increased β cell transcriptional activity from a minimal promoter. SNP alleles in 44.3% of these elements altered MPRA [massively parallel reporter assays] activity (n = 879/1982), including 220 SNPs associated with T2D risk by GWAS.”
    • In the aggregate, the researchers identified elements mediating β cell steady state and ER stress-responsive transcriptional activation, proposed causal T2D SNPs, and elucidated possible roles for repetitive elements in β cell transcriptional stress response and the genetics of type 2 diabetes.
    • MPRA are functional genomic tools used to test the transcription activating potential of thousands of sequences at the same time. The impact of naturally occurring variants in the human population with regard to MPRA activity can be uncovered by introducing nucleotide changes in a given sequence. Current studies have used MPRA to isolate functional SNPs linked to different conditions such as red blood cell traits, adiposity, osteoarthritis, and gene expression levels {eQTLs}.
    • Regardless of the limitations of cross-species testing of human species involving episomal assays’, various lines of research suggest that MPRA in MIN6 mouse β cells can identify features of β cell transcription activation of human sequences and the associated allelic effects of SNPs.
    • “It is possible that SNPs with low T2D association posterior probabilities identified as functional by MPRA may not be causal, and that technical limitations such as MPRA design, fragment size, cell line used, and conditions tested, may preclude the identification of some true causal SNPs,” wrote the authors. They recommended comprehensive testing of T2D credible set SNPs via MPRA across multiple metabolic cell types and relevant pathophysiologic states to modify probabilities and indicate functional T2D variants.