title: Polymorphisms of the thiopurine S-methyltransferase gene among the Libyan population.
abstract: Thiopurine S-methyltransferase (TPMT) is a cytosolic enzyme that catalyses the S-methylation of 6-mercaptopurine and azathioprine. Low activity phenotypes are correlated with polymorphism in the TPMT gene. Patients with low or undetectable TMPT activity could develop severe myelosuppression when they are treated with standard doses of thiopurine drugs. Since ethnic differences in the TPMT gene polymorphism have been demonstrated worldwide, assessing it in the Libyan population is worthwhile.
  
  
  
  We investigated TPMT gene polymorphism in a total of 246 Libyan healthy adult blood donors from three different Libyan regions (Tripoli, Yefren, and Tawargha) and 50 children with acute lymphoblastic leukaemia (ALL). We used polymerase chain reaction restriction length polymorphism (PCR-RFLP) and allele-specific PCR-based assays to analyse the TPMT gene for the variants *2 c.238 G>C, *3A (c.460 G>A and c.719 A>G), *3B (c.460 G>A), and *3C (c.719 A>G).
  
  
  
  Our results show that the TPMT variants associated with low enzymatic activity were detected in 3.25% (8 in 246) of adult Libyan individuals and the frequency of total mutant alleles was 1.63%. Heterozygous genotypes were TPMT*3A in three subjects (0.61%) and TPMT*3C in five subjects (1.02%). No TPMT*2 and TPMT*3B allelic variants and no homozygous or compound heterozygous mutant alleles were detected. The normal allele (wild-type) was found in 98.4% of the adult individuals studied. No mutant alleles were detected among the 50 children who had ALL.
  
  
  
  We report on the presence of the TPMT*3C and *3A mutant alleles in the Libyan population. Therefore, monitoring the patients to be treated with doses of thiopurine drugs for TPMT variants is worthwhile to avoid the development of severe myelosuppression.
authors.affiliation: Department of Genetic Engineering, Biotechnology Research Center (BTRC), Twisha, Tripoli, Libya.
authors.forename: Hamza Ben
authors.initials: HB
authors.lastname: Zeglam
authors.affiliation: Department of Genetic Engineering, Biotechnology Research Center (BTRC), Twisha, Tripoli, Libya.
authors.forename: Abdrazak
authors.initials: A
authors.lastname: Benhamer
authors.affiliation: Department of Genetic Engineering, Biotechnology Research Center (BTRC), Twisha, Tripoli, Libya.
authors.forename: Adel
authors.initials: A
authors.lastname: Aboud
authors.affiliation: Department of Genetic Engineering, Biotechnology Research Center (BTRC), Twisha, Tripoli, Libya.
authors.forename: Haitem
authors.initials: H
authors.lastname: Rtemi
authors.affiliation: Department of Genetic Engineering, Biotechnology Research Center (BTRC), Twisha, Tripoli, Libya.
authors.forename: Meftah
authors.initials: M
authors.lastname: Mattardi
authors.affiliation: Department of Genetic Engineering, Biotechnology Research Center (BTRC), Twisha, Tripoli, Libya.
authors.forename: Saleh Suleiman
authors.initials: SS
authors.lastname: Saleh
authors.affiliation: Department of Biochemistry, Faculty of Medicine, University of Tripoli, Tripoli, Libya.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Bashein
authors.affiliation: Department of Genetic Engineering, Biotechnology Research Center (BTRC), Twisha, Tripoli, Libya; nabil.enattah@btrc.ly; nabil.enattah@yahoo.com.
authors.forename: Nabil
authors.initials: N
authors.lastname: Enattah
mesh_terms: D000328:Adult; D000483:Alleles; D001782:Blood Donors / Q000706:statistics & numerical data*; D017931:DNA Primers; D005260:Female; D005787:Gene Frequency; D018740:Genetic Heterogeneity; D005819:Genetic Markers; D006801:Humans; D008002:Libya / Q000453:epidemiology; D008297:Male; D008780:Methyltransferases / Q000032:analysis / Q000235:genetics*; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
chemical_list: D017931:DNA Primers; D005819:Genetic Markers; D008780:Methyltransferases; C022745:thiopurine methyltransferase
keywords: TPMT gene; acute lymphoblastic leukaemia; polymorphisms; thiopurine drugs
references.citation: Clin Pharmacol Ther. 1997 Jul;62(1):60-73
references.pmid: 9246020
references.citation: Hum Mol Genet. 1999 Feb;8(2):367-70
references.pmid: 9931345
references.citation: Hum Mol Genet. 1999 Feb;8(2):371-6
references.pmid: 9931346
references.citation: Pharmacogenetics. 1999 Feb;9(1):37-42
references.pmid: 10208641
references.citation: J Clin Pharm Ther. 2005 Oct;30(5):491-6
references.pmid: 16164497
references.citation: Med Oncol. 2008;25(1):56-62
references.pmid: 18188716
references.citation: Rev Med Chil. 2009 Feb;137(2):185-92
references.pmid: 19543639
references.citation: Clin Res Hepatol Gastroenterol. 2012 Apr;36(2):178-84
references.pmid: 22225964
references.citation: J Natl Cancer Inst. 1999 Dec 1;91(23):2001-8
references.pmid: 10580024
references.citation: Pharmacogenetics. 1999 Oct;9(5):641-50
references.pmid: 10591545
references.citation: Pharmacogenetics. 1999 Dec;9(6):773-6
references.pmid: 10634140
references.citation: Leukemia. 2000 Apr;14(4):567-72
references.pmid: 10764140
references.citation: Pharmacology. 2000 Sep;61(3):136-46
references.pmid: 10971199
references.citation: Clin Chem. 2001 Mar;47(3):548-55
references.pmid: 11238310
references.citation: Drug Metab Dispos. 2001 Apr;29(4 Pt 2):601-5
references.pmid: 11259360
references.citation: Pharmacogenetics. 2001 Apr;11(3):275-8
references.pmid: 11337944
references.citation: Eur J Clin Pharmacol. 2001 Apr;57(1):51-4
references.pmid: 11372592
references.citation: Clin Pharmacol Ther. 2001 Aug;70(2):183-8
references.pmid: 11503013
references.citation: Pharmacogenetics. 2002 Apr;12(3):191-5
references.pmid: 11927834
references.citation: Pharmacogenomics. 2002 Jan;3(1):89-98
references.pmid: 11966406
references.citation: J Pediatr Hematol Oncol. 2002 Jun-Jul;24(5):353-9
references.pmid: 12142782
references.citation: Br J Clin Pharmacol. 2003 Jun;55(6):560-9
references.pmid: 12814450
references.citation: Pharmacogenomics J. 2003;3(3):178-82
references.pmid: 12815366
references.citation: Ann Clin Biochem. 2003 Jul;40(Pt 4):388-93
references.pmid: 12880540
references.citation: Methods Find Exp Clin Pharmacol. 2003 Jul-Aug;25(6):423-9
references.pmid: 12949626
references.citation: Ther Drug Monit. 2003 Oct;25(5):631-6
references.pmid: 14508387
references.citation: Science. 2003 Oct 24;302(5645):588-90
references.pmid: 14576416
references.citation: Clin Chem. 2004 Feb;50(2):288-95
references.pmid: 14656901
references.citation: Eur J Clin Pharmacol. 2004 Apr;60(2):89-96
references.pmid: 15022030
references.citation: Br J Clin Pharmacol. 2004 Jul;58(1):66-70
references.pmid: 15206995
references.citation: Pharmacogenetics. 2004 Jul;14(7):407-17
references.pmid: 15226673
references.citation: Br J Clin Pharmacol. 2004 Aug;58(2):163-8
references.pmid: 15255798
references.citation: J Pediatr. 1991 Dec;119(6):985-9
references.pmid: 1960624
references.citation: Dev Pharmacol Ther. 1991;17(1-2):16-23
references.pmid: 1811918
references.citation: Eur J Clin Pharmacol. 1992;43(4):329-39
references.pmid: 1451710
references.citation: Lancet. 1993 Feb 13;341(8842):436
references.pmid: 8094196
references.citation: Lancet. 1993 May 1;341(8853):1151
references.pmid: 8097831
references.citation: Mol Pharmacol. 1993 Jun;43(6):878-87
references.pmid: 8316220
references.citation: Pharmacogenetics. 1992 Aug;2(4):148-59
references.pmid: 1306116
references.citation: Clin Pharmacol Ther. 1994 Jan;55(1):15-20
references.pmid: 8299312
references.citation: Proc Natl Acad Sci U S A. 1995 Feb 14;92(4):949-53
references.pmid: 7862671
references.citation: Drug Metab Dispos. 1995 Mar;23(3):398-405
references.pmid: 7628307
references.citation: Am J Hum Genet. 1996 Apr;58(4):694-702
references.pmid: 8644731
references.citation: Clin Pharmacol Ther. 1996 Jul;60(1):68-74
references.pmid: 8689814
references.citation: Br J Clin Pharmacol. 1996 Nov;42(5):638-41
references.pmid: 8951198
references.citation: Ann Intern Med. 1997 Apr 15;126(8):608-14
references.pmid: 9103127