title: Genetic determinants of the thiopurine methyltransferase intermediate activity phenotype in British Asians and Caucasians.
abstract: OBJECTIVE
  Polymorphisms in the TPMT gene open reading frame (ORF) are associated with reduced TPMT activity. Variable number tandem repeats (VNTR*3 to VNTR*9) in the promoter region of the gene consisting of combinations of Type A, B and C repeat units, may modulate TPMT activity. Here we present the allele frequencies of genetic modifiers of TPMT activity in a British Asian population, as well as the concordance between intermediate TPMT activity and ORF and VNTR genotypes in a predominantly Caucasian population.
  
  
  METHODS
  VNTR type and ORF mutations were determined in two selected TPMT activity ranges, intermediate activity (4-8 U, 108 patients), normal (12-15 U, 53 patients) and in 85 British Asians.
  
  
  RESULTS
  In British Asians, TPMT*3C was the prevalent mutant allele (four heterozygotes). One patient was heterozygous for TPMT*3A. Overall VNTR frequencies did not differ from Caucasians. Three new VNTR alleles were designated VNTR*6c, VNTR*6d, and VNTR*7c. Forty-one percent of patients with intermediate activity were heterozygous for a TPMT ORF mutation (3A, 2B, 1C). Marked linkage disequilibrium was noted between VNTR*6b - TPMT*3A (D' = 1), VNTR*4b - TPMT*3C (D' = 0.67) and VNTR*6a - TPMT*1 (D' = 1) alleles. As a result, significant differences (P < 0.05) in the distribution of Type A, B or the total number of repeats summed for both alleles, were found between the ORF heterozygous intermediate activity group and the wild-type intermediate or normal activity groups. No significant difference was found between the two wild-type groups.
  
  
  CONCLUSIONS
  Our results suggest that TPMT gene VNTRs do not significantly modulate enzyme activity.
authors.affiliation: Purine Research and Department of Gastroenterology, Guy's and St Thomas' Hospital, London SE1 9RT, UK. tony.marinaki@kcl.ac.uk
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Marinaki
authors.forename: Monica
authors.initials: M
authors.lastname: Arenas
authors.forename: Zubair H
authors.initials: ZH
authors.lastname: Khan
authors.forename: Cathryn M
authors.initials: CM
authors.lastname: Lewis
authors.forename: El-Monsor
authors.initials: el-M
authors.lastname: Shobowale-Bakre
authors.forename: Emilia
authors.initials: E
authors.lastname: Escuredo
authors.forename: Lynette D
authors.initials: LD
authors.lastname: Fairbanks
authors.forename: John F
authors.initials: JF
authors.lastname: Mayberry
authors.forename: Antony C
authors.initials: AC
authors.lastname: Wicks
authors.forename: Azhar
authors.initials: A
authors.lastname: Ansari
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sanderson
authors.forename: John A
authors.initials: JA
authors.lastname: Duley
mesh_terms: D000483:Alleles; D005006:Ethnicity / Q000235:genetics; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008780:Methyltransferases / Q000235:genetics* / Q000378:metabolism; D018598:Minisatellite Repeats / Q000235:genetics; D016366:Open Reading Frames / Q000235:genetics; D010641:Phenotype; D011110:Polymorphism, Genetic; D006113:United Kingdom / Q000453:epidemiology; D044465:White People / Q000235:genetics
chemical_list: D008780:Methyltransferases; C022745:thiopurine methyltransferase