Significance and application of individualized detection of thiopurine S-methyltransferase in patients with chronic actinic dermatitis

Abstract

Objective To investigate correlations of thiopurine S-methyltransferase (TPMT) activity (phenotype) and genotype with adverse reactions after oral azathioprine treatment in patients with chronic actinic dermatitis, and to explore optimal azathioprine dose for the treatment of chronic actinic dermatitis. Methods Totally, 70 patients with chronic actinic dermatitis treated with oral azathioprine were enrolled into this study and served as patient group, of whom, 12 had adverse reactions to azathioprine. In addition, 50 health checkup examinees were enrolled as the control group. EDTA-anticoagulated blood samples were collected from the patients and controls, and erythrocytes lysates were prepared. High performance liquid chromatography (HPLC) was performed to evaluate the activity of TPMT. Genome-wide DNA was extracted from the blood samples, and TPMT genotypes were detected by allele-specific PCR and PCR-restriction fragment length polymorphism (RFLP) analysis. Results There was no significant difference in the TPMT activity between the patient group and control group ([25.80 ± 8.34]U/ml vs. [23.58 ± 5.70]U/ml, t= 0.782, P > 0.05) . However, the TPMT activity was significantly lower in patients with adverse reactions than those without ([18.86 ± 9.22]U/ml vs.[27.27 ± 6.72]U/ml, t= 3.437, P < 0.05) . TPMT genotypes were detected among 120 samples, and a heterozygous mutation TPMT*3C (A719G) was found in the TPMT gene in 7 samples, including 5 in the patient group and 2 in the control group. The frequencies of the mutant genotype and allele were 5.8% (7/120) and 2.9% respectively. No significant difference in the frequency of TPMT*3C mutation was observed between the patient group and control group (χ2= 0.108, P= 0.742) . The TPMT*3C mutation was found in 3 of the 12 patients with adverse reactions, as well as in 2 of 58 patients without adverse reactions. Additionally, the frequency of TPMT*3C mutation was significantly higher in patients with adverse reactions than in those without (χ2= 40.093, P < 0.05) . Conclusion Adverse reactions after oral azathioprine treatment are associated with TPMT mutations and decreased TPMT activity in patients with chronic actinic dermatitis, so appropriately adjusting the azathioprine dose in patients with low-activity and mutant-type TPMT can facilitate safe treatment. Key words: Dermatitis, photoallergic; Azathioprine; Drug toxicity; DNA mutational analysis; Thiopurine methyltransferase