[Association between metabolic enzyme genotype of azathioprine and drug tolerance in patients with rheumatic diseases].
OBJECTIVE
To discuss the relationship between the genotype of thiopurine methyltransferase (TPMT) and azathioprine tolerance in the patients with rheumatic diseases.


METHODS
Four common mutation alleles of TPMT in 200 patients with rheumatic diseases [TPMT*2 (G238C), TPMT*3A (A719G/G460A), TPMT*3B (G460A), TPMT*3C (A719G)] were detected by allele specific polymerase chain reaction (AS-PCR) and polymerase chain reaction-restriction fragment length polymorphism (PCR-PFLP). 194 patients who had used azathioprine finished the 3 months' follow-up.


RESULTS
In the 200 patients with rheumatic diseases, 4 cases of heterozygote of TPMT*3C were detected, but no mutation of TPMT*2, TPMT*3B or TPMT*3A was found. The genotypic frequency of wild-type homozygote was 98%, and that of heterozygote (TPMT*1/TPMT*3C) was 2%. Mutation allele frequency in these patients was 1%. Average of TPMT activity of the 4 cases of heterozygote was (2.4 +/- 1.2) U/ml red blood cells, significantly lower than that of the 196 cases of homozygote which was (12.2 +/- 6.8) U/ml RBC. In the 194 patients who had used azathioprine, bone marrow suppression occurred in 18 patients, 2 of which suffered severe crisis of hematopoietic system, and 6 of which were complicated with impaired liver function. In the 4 patients with heterozygote, 3 had used azathioprine, and bone marrow suppression occurred within 1 month of using the drug, including 2 cases of severe crisis of hematopoietic system.


CONCLUSIONS
Patients with mutation alleles of TPMT are intolerant to azathioprine, and likely to have severe crisis of hematopoietic system. To detect the TPMT genotype before using azathioprine is significant to improve the therapeutic safety.
Zhan
Zhong-ping
ZP
Department of Rheumatology, First Affiliated Hospital of Sun Yat-sen University, Guangzhou 510080, China.
Liang
Liu-qin
LQ
Yang
Xiu-yan
XY
Wang
Yi-xi
YX
Huang
Min
M
Li
Hao
H
D000293:Adolescent; D000328:Adult; D000704:Analysis of Variance; D001379:Azathioprine / Q000378:metabolism / Q000627:therapeutic use*; D004351:Drug Resistance; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D007166:Immunosuppressive Agents / Q000378:metabolism / Q000627:therapeutic use; D008297:Male; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D012216:Rheumatic Diseases / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism
D007166:Immunosuppressive Agents; D008780:Methyltransferases; C022745:thiopurine methyltransferase; D001379:Azathioprine