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. 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).