TPMT genotyping

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(Joint with the Biochemistry department at ORC)

TPMT (Thiopurine S-Methyltransferase) catalyses the rate-limiting enzymatic step in the breakdown and excretion of immunosuppressive and chemotherapeutic drugs including Azathioprine and 6-Mercaptopurine.  Drugs based on these compounds are used in the treatment of conditions including autoimmune disorders such as Crohn’s disease and rheumatoid arthritis, organ transplant recipients, and in acute lymphoblastic leukaemia.

1 in 300 Caucasians are deficient in TPMT activity and are thus prone to life-threatening myelosuppression if treated with standard thiopurine drug doses. A further 10% of the population have intermediate TPMT activity and are also prone to thiopurine drug side effects, requiring lower dosing.

Various clinical guidelines advocate determination of TPMT status of a patient prior to administration of thiopurine drugs in order to limit the number of adverse drug reactions.

In the majority of cases, TPMT activity is determined for each referral by a biochemical assay and only those with intermediate or deficient TPMT activity will subsequently be referred for TPMT genotyping analysis.

The majority of the variation in TPMT activity is accounted for by the presence of one or more non-synonymous SNPs; in those with intermediate TPMT activity these are present on one allele only, whilst those with deficient TPMT activity are either homozygotes or compound heterozygotes for such changes.

Whilst many different TPMT genotypes have been described, 85-95% of TPMT genetic variations are accounted for by the genotypes TPMT*3A, *3B, *3C and *2, characterized by SNPs within three exons of TPMT. The standard test for TPMT genotyping test detects these common variants only.

If deficient TPMT activity is not described by one of the common SNPs clinicians may choose, at additional cost, for full TPMT gene analysis by DNA sequencing. Normally this approach should be applied after confirmatory TPMT activity testing has been performed.

Patients for which TPMT activity analysis is inappropriate, for example those that have had a recent blood transfusion, can be genotyped as a front line test in order to exclude the presence of the common TPMT variants.

Note that the referral route for TPMT genotyping is normally via Biochemistry so that the appropriate TPMT activity assay can be performed, and samples triaged for onward referral to the MDC for genotyping, where indicated.

(Last reviewed October 2018)