Association between genetically predicted expression of TPMT and azathioprine adverse events.

BACKGROUND

Polymorphisms thiopurine-S-methyltransferase (TPMT) and nudix hydrolase 15 (NUDT15) can increase the risk of azathioprine myelotoxicity, but little is known about other genetic factors that increase risk for azathioprine-associated side effects. PrediXcan is a gene-based association method that estimates the expression of individuals’ genes and examines their correlation to specified phenotypes. To interrogate the utility of using PrediXcan as a tool for detecting associations between genetic factors and azathioprine side effects, we aimed to determine whether the genetically predicted expression of TPMT or NUDT15 was associated with leukopenia or other known side effects of azathioprine.

METHODS

This is a retrospective cohort study of 1,364 new users of azathioprine (patients taking azathioprine with an organ transplant indication were excluded) with electronic health record (EHR)-reported White race. We used PrediXcan to impute expression in liver tissue, tested its association with pre-specified phecodes representing known side effects (e.g. skin cancer), and completed chart review to confirm cases.

RESULTS

Among confirmed cases, patients in the lowest tertile of TPMT predicted expression had significantly higher odds of developing leukopenia (OR = 3.30, 95%CI: 1.07–10.20, p = 0.04) versus those in the highest tertile; no other side effects were significant.

CONCLUSION

The results suggest that this methodology could be deployed on a larger scale to uncover associations between genetic factors and drug side effects for more personalized care.