Thiopurine S-methyltransferase activity in three major Asian populations: a population-based study in Singapore.
OBJECTIVE
The distribution of thiopurine methyltransferase (TPMT) activity in Asian populations has not been well documented. We studied the TPMT phenotype in three major Asian ethnic groups in Singapore, namely the Chinese (Ch), Malays (Mal) and Indians (Ind), with the aim of carrying out a comprehensive survey of the distribution of TPMT activity in Asians.


METHODS
A radiochemical assay was used to measure the enzymatic activity of TPMT in the red blood cells (RBCs) of 479 healthy adults (Ch=153, Mal=163 and Ind=163). Cut-off points for intermediate TPMT activity were validated using a receiver operating curve (ROC) analysis. PCR-based methods were used to screen for the TPMT*3C, TPMT*3A and TPMT*6 variants.


RESULTS
The histogram of the combined population cohort showed a bimodal distribution of TPMT activity, with no subject having low TPMT activity (<5 units). In total, TPMT variants were detected in 14 subjects (*1/*3C in 13 subjects; *1/*3A in one subject). We observed significant inter-ethnic differences in terms of TPMT activity (p<0.001), with the Malays showing a higher median activity than the Chinese or Indians (17.8 units vs 16.4 units). The Malays also showed a higher methylation rate--with a cut-off point for intermediate TPMT activity of 11.3 units--than the Chinese (9.9 units) or Indians (9.4 units). A high phenotype-genotype correlation of >97% was observed in all three races. We also genotyped 418 childhood leukaemias. The combined analysis of subjects participating in this and a previous study--1585 subjects--showed that 4.7% of Chinese (n=30/644), 4.4% of Malays (n=24/540) and 2.7% of Indians (n=11/401) were heterozygous at the TPMT gene locus.


CONCLUSIONS
This is the first comprehensive TPMT phenotype and genotype study in Asian populations, particularly in the Malays and Indians.
Kham
Shirley Kow Yin
SK
Department of Paediatrics, National University of Singapore, and Department of Haematology-Oncology, National University Hospital, Singapore City, Republic of Singapore.
Soh
Chin Kok
CK
Liu
Te Chih
TC
Chan
Yiong Huak
YH
Ariffin
Hany
H
Tan
Poh Lin
PL
Yeoh
Allen Eng Juh
AE
D000293:Adolescent; D000328:Adult; D044466:Asian People; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005006:Ethnicity; D005260:Female; D005838:Genotype; D006801:Humans; D007194:India / Q000453:epidemiology / Q000208:ethnology; D007223:Infant; D007938:Leukemia / Q000201:enzymology / Q000235:genetics; D008297:Male; D008780:Methyltransferases / Q000378:metabolism*; D008875:Middle Aged; D010641:Phenotype; D012372:ROC Curve; D015203:Reproducibility of Results; D012846:Singapore / Q000453:epidemiology
D008780:Methyltransferases; C022745:thiopurine methyltransferase