A New Hypothesis for Type 1 Diabetes Risk: The At-Risk Allele at rs3842753 Associates With Increased Beta-Cell INS Messenger RNA in a Meta-Analysis of Single-Cell RNA-Sequencing Data.

OBJECTIVES: Type 1 diabetes is characterized by the autoimmune destruction of insulin-secreting beta cells. Genetic variants upstream at the insulin (INS) locus contribute to ∼10% of type 1 diabetes heritable risk. Previous studies showed an association between rs3842753 C/C genotype and type 1 diabetes susceptibility, but the molecular mechanisms remain unclear. To date, no large-scale studies have looked at the effect of genetic variation at rs3842753 on INS mRNA at the single-cell level. METHODS: We aligned all human islet single-cell RNA sequencing data sets available to us in year 2020 to the reference genome GRCh38.98 and genotyped rs3842753, integrating 2,315 ß cells and 1,223 ß-like cells from 13 A/A protected donors, 23 A/C heterozygous donors and 35 C/C at-risk donors, including adults without diabetes and with type 2 diabetes. RESULTS: INS expression mean and variance were significantly higher in single ß cells from females compared with males. On comparing across ß cells and ß-like cells, we found that rs3842753 C‒containing cells (either homozygous or heterozygous) had the highest INS expression. We also found that ß cells with the rs3842753 C allele had significantly higher endoplasmic reticulum stress marker gene expression compared with the A/A homozygous genotype. CONCLUSIONS: These findings support the emerging concept that inherited risk of type 1 diabetes may be associated with inborn, persistent elevated insulin production, which may lead to ß-cell endoplasmic reticulum stress and fragility.