Genetic determinants of the thiopurine methyltransferase intermediate activity phenotype in British Asians and Caucasians.
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.
Marinaki
Anthony M
AM
Purine Research and Department of Gastroenterology, Guy's and St Thomas' Hospital, London SE1 9RT, UK. tony.marinaki@kcl.ac.uk
Arenas
Monica
M
Khan
Zubair H
ZH
Lewis
Cathryn M
CM
Shobowale-Bakre
El-Monsor
el-M
Escuredo
Emilia
E
Fairbanks
Lynette D
LD
Mayberry
John F
JF
Wicks
Antony C
AC
Ansari
Azhar
A
Sanderson
Jeremy
J
Duley
John A
JA
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
D008780:Methyltransferases; C022745:thiopurine methyltransferase