A noncoding variant confers pancreatic differentiation defect. A noncoding variant confers pancreatic differentiation defect

GWAS provided many β cell function-associated single nucleotide polymorphisms (SNPs) without clearly pathogenic mechanism. Stepwise differentiation of pancreatic β cells provide the promise to study developmental genetic disorders. Here, we focused on SNP rs6048205 (A/G) located in downstream noncoding region of FOXA2, which was annotated with fast glucose and β cell function risk. We introduced the mutation into human pluripotent stem cells, directed pancreatic differentiation revealed that risk G mutation reduce the percentage of PDX1+NKX6-1+ progenitor cells at pancreatic progenitor 2 stage (PP2), and then defect the function of β cells in-vitro. Mechanistically, risk allele G variant could alter the upstream factor RXRA binding to ectopically promote the expression of FOXA2, which is an important transcription factor in pancreatic development. Overall design: Comparative gene expression profiling analysis of RNA-seq data for human PDX1+/NKX6-1+ pancreatic progenitor cells with different genotypes (A/A, G/G, FOXA2-control, FOXA2 conditional overexpressed during pancreatic progenitor cells).