Azathioprine (AZA) is a
thiopurine prodrug commonly used in triple-immunosuppressive therapy following
liver transplantation. Approximately 1 in 10 patients suffers side effects in response to the
drug, the most problematic being bone marrow toxicity. There is evidence that polymorphisms in the genes encoding
thiopurine methyltransferase (TPMT) and
inosine triphosphate pyrophosphatase (
ITPase) predict
adverse drug reactions to AZA
therapy. Furthermore, common genetic polymorphisms in the gene encoding
methylenetetrahydrofolate reductase (MTHFR) may have an indirect impact on
thiopurine drug methylation by influencing levels of the methyl donor
S-adenosylmethionine (SAM). The aim of this study was to determine whether polymorphisms in these candidate pharmacogenetic loci predict
adverse drug reactions to AZA immunosuppressive therapy in
liver transplant patients. A series of 65
liver transplant recipients were recruited to the study from the
Liver Transplant Out-Patient clinic at The Royal Infirmary of Edinburgh. Clinical response to AZA was retrospectively correlated against TPMT activity, TPMT*2, *3A, and *3A genotypes,
inosine triphosphatase (ITPA) 94C>A and IVS2+21A>C genotypes, and MTHFR 677C>T and 1298A>C genotypes. Variant TPMT, ITPA, and MTHFR genotypes were not significantly associated with
adverse drug reactions to AZA, including bone marrow suppression. However, the 2 patients who suffered nodular regenerative
hyperplasia (NRH) were both heterozygous for the TPMT*3A mutation. In conclusion, our findings suggest that TPMT, ITPA, and MTHFR genotypes do not predict
adverse drug reactions, including bone marrow suppression, in
liver transplant patients. However, the possible association between NRH and a heterozygous TPMT genotype should be investigated further.