Disease allele-dependent small-molecule sensitivities in blood cells from monogenic diabetes

Even as genetic studies identify alleles that influence human disease susceptibility, it remains challenging to understand their functional significance and how they contribute to disease phenotypes. Here, we describe an approach to translate discoveries from human genetics into functional and therapeutic hypotheses by relating human genetic variation to small-molecule sensitivities. We use small-molecule probes modulating a breadth of targets and processes to reveal disease allele-dependent sensitivities, using cells from multiple individuals with an extreme form of diabetes (maturity onset diabetes of the young type 1, caused by mutation in the orphan nuclear receptor HNF4 alpha). This approach enabled the discovery of small molecules that show mechanistically revealing and therapeutically relevant interactions with HNF4 alpha in both lymphoblasts and pancreatic beta-cells, including compounds that physically interact with HNF4 alpha. Compounds including US Food and Drug Administration-approved drugs were identified that favorably modulate a critical disease phenotype, insulin secretion from beta-cells. This method may suggest therapeutic hypotheses for other non-blood disorders.