The Coriell personalized medicine collaborative pharmacogenomics appraisal, evidence scoring and interpretation system

Table 8 Genotype-phenotype drug response interpretations of the Pharmacogenomics Advisory Group-approved drug-gene pairs: thiopurines and TPMT ^a

Common Diplotypes^b	Expected population frequency, %^c			PK/PD phenotype	Clinical phenotype	FDA guidelines
Common Diplotypes^b	Caucasian ancestry	African ancestry	East Asian ancestry	PK/PD phenotype	Clinical phenotype	FDA guidelines
TPMT1/1	94	81	97	EM: normal enzymatic function and normal drug elimination	Expected to respond to a standard dose of thiopurine drugs. Not at increased risk of drug toxicity	–
TPMT1/2, TPMT1/3A*, and other rare diplotypes (see Additional file 1: Table S24)	6	18	3	IM: reduced enzymatic function, leading to reduced drug elimination and greater drug exposure	At increased risk of drug toxicity such as myelosuppression when taking standard dose of thiopurine drugs. Risk of side effects can be reduced by reducing standard dose by 50 to 70%	Heterozygous patients with low or intermediate TPMT activity are more likely to experience toxicity
Rare in Caucasians, The following are more common in African ancestry: TPMT3A/3A, TPMT3B/3B	0.1	1	0	PM: very low or absent enzymatic function, leading to greatly reduced drug elimination and increased drug exposure	At increased risk of drug toxicity such as myelosuppression when taking thiopurine drugs. Should consider alternative medication	Homozygous-deficient patients (two non-functional TPMT alleles) given usual dose of thiopurines are at increased risk of toxicity

Abbreviations: EM Extensive metabolizer, FDA Food and Drugs Administration, IM intermediate metabolizer, PD pharmacodynamic, PK pharmacokinetic, PM poor metabolizer.
^aSupporting evidence may be found in Additional file 2: Section S6.0 to 6.7 and Additional file 1: Tables S22 to S24. These include summaries of the PhAESIS evaluation and referenced publications supporting the drug-gene clinical phenotypes.
^bDiplotypes with frequencies of less than 0.4% in Caucasians are included above. Other rare diplotypes that fall under the same phenotype category can be found in the genotype-phenotype Punnett table (see Additional file 1: Table S24). Diplotypes above and in the genotype-phenotype Punnett table include both clinically validated genetic results (those that include variants with evidence code 1) and results that include variants with evidence scores 2 to 7 (potentially clinically relevant). The latter require further validation to support their inclusion for clinical reporting.
^aPopulation frequencies are estimated based on reported gene variant allele frequencies (see Additional file 1: Table S23) and Hardy-Weinberg principles.

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