Mycophenolic acid response biomarkers: a cell line model system-based genome-wide screen

Abstract

Mycophenolic acid (MPA) is commonly used to treat patients with solid organ transplants during maintenance immunosuppressive therapy. Response to MPA varies widely, both for efficacy and drug-induced toxicity. A portion of this variation can be explained by pharmacokinetic and pharmacodynamic factors, including genetic variation in MPA-metabolizing UDP-glucuronyltransferase isoforms and the MPA targets, inosine monophosphate dehydrogenase 1 and 2. However, much of the variation in MPA response presently remains unexplained. We set out to determine whether there might be additional genes that modify response to MPA by performing a genome-wide association study between basal gene mRNA expression profiles and an MPA cytotoxicity phenotype using a 271 human lymphoblastoid cell line model system to identify and functionally validate genes that might contribute to variation in MPA response. Our association study identified 41 gene expression probe sets, corresponding to 35 genes, that were associated with MPA cytotoxicity as a drug response phenotype (p<1×10(-6)). Follow-up siRNA-mediated knockdown-based functional validation identified four of these candidate genes, C17orf108, CYBRD1, NASP, and RRM2, whose knockdown shifted the MPA cytotoxicity curves in the direction predicted by the association analysis. These studies have identified novel candidate genes that may contribute to variation in response to MPA therapy and, as a result, may help make it possible to move toward more highly individualized MPA-based immunosuppressive therapy.