Black Americans are More Likely to have Intermediate TPMT Enzyme Levels than White Americans

Abstract

Purpose: Thiopurine methyltransferase (TPMT) metabolizes azathioprine (AZA) and mercaptopurine (6MP) into active and inactive metabolites. Optimal therapeutic effect is achieved at 6-thioguanine levels (6TG) between 230-400. Achieving therapeutic levels of 6TG is limited by the concurrent production of the inactive hepatotoxic metabolite 6-methylmercaptopurine (6MMP). A patient's TPMT enzyme activity is related to the ratio of production of these metabolites. Black Americans and Caucasians have differing frequencies of mutant alleles resulting in similar phenotypes of low, intermediate and normal levels. It is unclear whether there are racial differences in TPMT levels. Such differences could affect both medication choices and dosage regimens in the management of patients with inflammatory bowel disease. We sought to investigate ethnic variations in TMPT levels. Methods: We performed a retrospective chart review of patients who underwent TPMT level or genetic testing at our institution from June 2004 to June 2009. TPMT testing was performed at Prometheus Laboratories (San Diego, CA). Results: We identified 272 patients who had TPMT levels drawn (96 males, 176 females). Of the patients with quantitative TPMT levels available for review, 80 were self-described black American, 133 Caucasian, and 18 other. These levels are categorized into low, intermediate and normal (with less than 6.0 EU being low, 6.0- 21.0 EU intermediate and greater than 21.0 EU normal). The mean TPMT level for black Americans was 23.2 EU (SD 8.1), for Caucasians 27.7 EU (SD 9.4) and for other patients 25.7 EU (SD 8.7) (p=0.002). The mean levels are all within the normal range. Categorization of these levels into low, intermediate and normal showed that 0/80 (0.0%) of black Americans, 1/133 (0.8%) of Caucasians and 0/18 (0.0%) of others had low enzyme levels. 31/80 (38.8%) of black Americans, 26/133 (19.6%) of Caucasians and 5/18 (27.3%) of others had intermediate levels. 49/80 (61.3%) of black Americans, 106/133 (79.7%) of Caucasians and 13/18 (72.2%) of others had normal levels. The difference among the three categories is statistically significant (Fisher exact test p-value=0.017). Conclusion: Significant racial differences exist in mean TPMT enzyme levels among different American ethnic groups. While mean levels fall within the normal enzyme range, there was a statistically significant difference in the distribution of patients who fall into the intermediate versus the normal enzyme level between black and white Americans with a higher percentage of black Americans in the intermediate range and higher percentage of Caucasians in the normal range. Such differences may have important clinical implications insofar as ability to achieve therapeutic levels of 6TG.