ABSTRACT
Type 1 diabetes is characterized by the autoimmune destruction of insulin secreting beta-cells. Genetic variations upstream at the insulin (INS) locus contribute to ~10% of type 1 diabetes heritable risk. Multiple studies showed an association between rs3842753 C/C genotype and type 1 diabetes susceptibility. Three small studies have reported an association between the rs3842753 C allele and increased whole pancreas INS expression. To date, no large-scale studies have looked at the effect of those genetic variations on insulin expression at the single cell level. We aligned all human islet single cell RNA sequencing datasets available to us in 2020 to the reference genome GRCh38.98 and genotyped rs3842753. We integrated 2315 beta-cells from 13 A/A donors, 23 A/C heterozygous donors, and 35 C/C at-risk donors. The donors included adults without diabetes and with type 2 diabetes. INS expression mean and variance were significantly higher in single β cells from females compared with males. Comparing across all β cells, we found that rs3842753 C containing cells (either homozygous or heterozygous) had the highest INS expression. We also found that β cells with the rs3842753 C allele had significantly higher ER stress marker gene expression compared to the A/A homozygous genotype. These findings support the emerging concept that inherited risk of type 1 diabetes may be associated with elevated insulin production at the mRNA level which may lead to β cell ER stress and fragility.
KEY MESSAGES
The type 1 diabetes at risk allele at rs3842753 is associated with increased INS gene expression and ER stress in single human beta-cells.
Single beta-cells from female donors and donors with type 2 diabetes exhibit a wider range of INS gene expression.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
AUTHOR DISCLOSURES: No conflicts of interest relevant to this study.