Exome sequencing and array-based comparative genomic hybridisation analysis of preferential 6-methylmercaptopurine producers
Abstract
Preferential conversion of azathioprine or 6-mercaptopurine into methylated metabolites is a major cause of thiopurine resistance. To seek potentially Mendelian causes of thiopurine hypermethylation, we recruited 12 individuals who exhibited extreme therapeutic resistance while taking azathioprine or 6-mercaptopurine and performed whole-exome sequencing (WES) and copy-number variant analysis by array-based comparative genomic hybridisation (aCGH). Exome-wide variant filtering highlighted four genes potentially associated with thiopurine metabolism (ENOSF1 and NFS1), transport (SLC17A4) or therapeutic action (RCC2). However, variants of each gene were found only in two or three patients, and it is unclear whether these genes could influence thiopurine hypermethylation. Analysis by aCGH did not identify any unusual or pathogenic copy-number variants. This suggests that if causative mutations for the hypermethylation phenotype exist they may be heterogeneous, occurring in several different genes, or they may lie within regulatory regions not captured by WES. Alternatively, hypermethylation may arise from the involvement of multiple genes with small effects. To test this hypothesis would require recruitment of large patient samples...Continue Reading
References
Next-generation sequencing of pharmacogenes: a critical analysis focusing on schizophrenia treatment
Citations
Related Concepts
Related Feeds
Autoimmune Hepatitis
Autoimmune hepatitis formerly called lupoid hepatitis, is a chronic, autoimmune disease of the liver that occurs when the body's immune system attacks liver cells causing the liver to be inflamed. Discover the latest research on autoimmune hepatitis here.