Genotype and Phenotype Correlation of the TPMT∗8 Allele in Thiopurine Metabolism

Abstract

Thiopurine 6-mercaptopurine (6-MP) is metabolized by thiopurine methyl transferase (TPMT). TPMT genetic variation results in some individuals having reduced or absent TPMT enzyme activity. If these individuals take a full thiopurine dose, life-threatening adverse events can occur. Testing identifies patients with reduced or absent TPMT activity and is recommended prior to initiation of therapy. The TPMT*8 allele, defined by c.644G>A (p.Arg215His), is common among individuals of African ancestry (∼2.3% minor allele frequency), but is not included in genotyping recommendations due to its uncertain function. Here, a clinical TPMT enzyme activity assay was used to assess TPMT activity in red blood cells from 982 patients, including those with *1/*8 (n=22), *3A/*8 (n=1), and *3C/*8 (n=1) TPMT diplotypes. The average 6-MMP production (primary TPMT product measured clinically) was 3.08 ± 0.16 nmol/mL/hr for *1/*8 individuals, compared to 3.77 ± 0.03 nmol/mL/hr for normal metabolizers (p=0.0001) and 2.39 ± 0.06 nmol 6-MMP/mL/hr for intermediate metabolizers (p<0.0001). Individuals with a TPMT*1/*8 diplotype demonstrated reduced 6-MP metabolism between that of normal metabolizers and intermediate metabolizers, suggesting that TPMT*8 is a reduced function allele.