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Thiopurine methyltransferase polymorphic tandem repeat: Genotype‐phenotype correlation analysis
Author(s) -
Yan Lan,
Zhang Shuichen,
Eiff Bianca,
Szumlanski Carol L.,
Powers Melody,
O'Brien John F.,
Weinshilboum Richard M.
Publication year - 2000
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1067/mcp.2000.108674
Subject(s) - thiopurine methyltransferase , genotype , genetics , biology , allele , methyltransferase , variable number tandem repeat , tandem repeat , microbiology and biotechnology , methylation , dna , gene , azathioprine , medicine , disease , pathology , genome
Background Thiopurine methyltransferase (TPMT) is a genetically polymorphic enzyme that catalyzes the S ‐methylation of thiopurine drugs such as 6‐mercaptopurine. Recently, a variable number tandem repeat (VNTR) within the TPMT promoter has been reported to “modulate” levels of this enzyme activity. Methods We set out to perform genotype‐phenotype correlation analysis for the polymorphic TPMT tandem repeat in 1211 clinical laboratory samples in which red blood cell (RBC) TPMT activity had been measured and to compare those results with data for 279 control DNA samples. Results TPMT VNTR length varied from three to nine repeats ( *V3 to *V9 ), but the most common alleles were *V4 and *V5 , with frequencies in the control samples of 0.54 and 0.36, respectively. The clinical laboratory samples were then stratified into those with “low,” “intermediate,” or “high” levels of RBC TPMT activity; that is, samples presumed to be homozygous for open reading frame (ORF)–based variant alleles, heterozygous for those alleles, or homozygous for the “wild‐type” ORF sequence, respectively. TPMT VNTR genotype *V4/*V5 was associated with significantly higher RBC TPMT activity than were *V4/*V4 or *V5/*V5 . Lowest activity levels were associated with genotypes that included an allele with more than 5 repeat elements. However, all of these effects were quantitatively small. Finally, there was linkage disequilibrium between VNTR allele *V5 and TPMT*3A , the most common ORF‐based polymorphism associated with very low TPMT activity in white persons. Conclusions These observations suggest that, in addition to the striking effects of ORF‐based single nucleotide polymorphisms on TPMT activity, the VNTR within the 5′‐flanking region of the TPMT gene also may modulate levels of RBC TPMT activity. Clinical Pharmacology & Therapeutics (2000) 68 , 210–219; doi: 10.1067/mcp.2000.108674