Thiol methylation pharmacogenetics: Heritability of human erythrocyte thiol methyltransferase activity

Thiol methylation of aliphatic sulfhydryl drugs is catalyzed by thiol methyltransferase (TMT), an enzyme activity that can be measured in the human erythrocyte (RBC) membrane. As a first step toward determining the possible role of inheritance in the regulation of individual variations in the S-methylation of drugs in man, the heritability of human RBC membrane TMT activity was determined. RBC TMT activity was measured in blood samples from 231 first-degree relatives in 47 randomly selected families. The frequency distribution of enzyme activities was unimodal, with a fivefold variation within ±2 SDs. RBC TMT activity did not correlate with either age or sex. Heritability in the "narrow" sense (h²) was estimated by comparing correlations of RBC TMT activities in first-degree relatives with theoretical values expected for a trait under total additive genetic control. The correlation between RBC TMT activities in mothers and fathers in these families was only 0.04, a finding that made shared environment a less likely explanation for significant correlations among other family members. However, sibling-sibling (S-S), parent-offspring (P-O), and midparent (average of two parental values) -offspring (M-O) correlations were 0.49, 0.49, and 0.69. Theoretical expected values for a trait with a heritability of 1.0 (100%), for these same correlations would be 0.5, 0.5, and 0.71. Estimates of h² calculated from the observed correlations were 0.98 (S-S), 0.98 (P-O), and 0.98 (M-O). None of the calculated values for heritability differed significantly from the theoretical maximum value of 1.0. These results suggested that inheritance was the primary factor- regulating the fivefold variation in RBC TMT activity.