Thiopurine S-Methyltransferase Pharmacogenetics in a Large-Scale Healthy Italian–Caucasian Population: Differences in Enzyme Activity

Abstract

Aims: To investigate the influence of genotype, age and gender on the thiopurine S-methyltransferase (TPMT) phenotype in healthy Italian–Caucasian subjects. Materials & methods: The study investigated the TPMT genotype and the TPMT phenotype of 943 healthy Italian–Caucasian subjects of different age and gender (age range: 0.08–68 years; 623 males 320 females). TPMT red blood cell activity was measured in all samples and genotype was determined for the TPMT alleles *2, *3A, *3B and *3C. Results: TPMT activity levels in our whole population ranged from 1.6 up to 75.2 U/gHb. Significant TPMT activity differences between wild-type and heterozygous subjects were observed. We divided our TPMT activity into four categories according to our frequency distribution: low (0.1%), intermediate (32.9%), normal (60%) and high (7%), with arbitrary cut-off values of 8.0, 19.4 and 37.0 U/gHb, respectively. The whole population had a total of 94.5% of homozygous wild-type subjects, 5.4% heterozygous variants and one (0.1%) compound heterozygous variant TPMT*3B/*3C. The overall concordance rate between TPMT genotypes and phenotypes was 71.6%. The TPMT activity was significantly higher in wild-type children (0.08–17 years) than in wild-type adults (aged 18–68 years). Moreover, it was noted that wild-type infants from 0.08 to 5 years had a 9% higher average TPMT activity than the other wild-type groups, and only in children from 0.08 to 2 years was the TPMT activity higher in males than in females. Conclusion: The data obtained in this study show that genetic factors seem to be the major aspect in TPMT phenotype variability in adults, whilst, in children, other physiological factors should be taken into consideration when assessing the TPMT phenotype, such as age and gender.

KEYWORDS::

• age
• gender
• genotype
• phenotype
• TPMT

Acknowledgments

We wish to thank Prof. William E Evans from the Department of Pharmaceutical Sciences, St Jude Children‘s Research Hospital, Memphis, TN, USA, for kindly providing the genomic DNA with TPMT*2/*2 mutation as a control sample and Norbert Erb from the Department of Paediatric Hematology and Oncology, Children‘s University Hospital, Hamburg, Germany for his valuable HPLC technical advice. We are indebted to the nurses in the Blood Bank, of San Giovanni Battista Hospital, Torino, Italy, and all the physicians for their contributions to this research, as well as all the volunteers for their participation in the research program. We also thank Prof. Carlo Ferretti from the Department of Anatomy, Pharmacology and Forensic Medicine, University of Torino, Italy, for his technical support and Mrs Barbara Wade for her linguistic advice.

Financial & competing interests disclosure

This work was supported by grants from the Piemonte Regional Government and from the Fondazione IBD Onlus, with a project funded by Compagnia di San Paolo, Torino, Italy. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Ethical conduct of research

The authors state that they have obtained appropriate institutional review board approval or have followed the principles outlined in the Declaration of Helsinki for all human or animal experimental investigations. In addition, for investigations involving human subjects, informed consent has been obtained from the participants involved.

Additional information

Funding

This work was supported by grants from the Piemonte Regional Government and from the Fondazione IBD Onlus, with a project funded by Compagnia di San Paolo, Torino, Italy. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.