SEGREGATION ANALYSIS OF HUMAN RED-BLOOD-CELL THIOPURINE METHYLTRANSFERASE ACTIVITY

Thiopurine methyltransferase (TPMT) catalyzes thiopurine S-methylation , an important metabolic pathway for drugs such as 6-mercaptopurine (6 -MP). Inherited differences in the activity of this enzyme are related to individual differences in the therapeutic efficacy and toxicity of 6-MP and other thiopurine drugs. Variation of TPMT activity in the re d blood cell (RBC) has been found to reflect activity differences in l ess accessible tissues. Previously reported qualitative analyses of in heritance of RBC TPMT in families suggested that a major gene plays a role in the regulation of activity of this enzyme. In the present stud y we completed complex segregation analyses of RBC TPMT activity of 21 3 individuals in 49 families that were randomly ascertained through ch ildren in the Rochester, MN, public school system. We found clear evid ence of a major gene effect on RBC TPMT activity. Both transformed and untransformed data supported the segregation of a Mendelian major gen e with frequency of 0.94 for the allele conferring high enzyme activit y. The genotype distributions of individuals who were homozygous for t he low activity allele, heterozygous, and homozygous for the high acti vity allele accounted for approximately 0.3%, 11.2%, and 88.5%, respec tively, of the individuals in the sample. This major locus accounted f or 66% of the total variance in untransformed RBC TPMT activity. Altho ugh there were significant residual family correlations among probable high activity homozygotes, there was insufficient power to detect add itional major locus ol polygenic inheritance effects on the residual v ariance. (C) 1995 Wiley-Liss, Inc.