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Genetic Variation in the MTHFR Gene Influences Thiopurine Methyltransferase Activity

¹ Purine Research Laboratory, Department of Chemical Pathology, and³ Department of Gastroenterology, Guy’s and St. Thomas’ Hospital NHS Trust, London, United Kingdom;² Department of Medical and Molecular Genetics, GKT School of Medicine, King’s College, London, United Kingdom

^aaddress correspondence to this author at: Purine Research Laboratory, Department of Chemical Pathology, 5th Floor Thomas Guy House, Guy’s Hospital, London SE1 9RT, United Kingdom; fax 44-207-188-1280, e-mail tony.marinaki@kcl.ac.uk

The first 300 words of the full text of this article appear below.

The immunosuppressive drug 6-mercaptopurine (6-MP) and its prodrug azathioprine are used in the treatment of inflammatory bowel disease and other disorders of immune regulation (1). Thiopurine methyltransferase (TPMT) inactivates 6-MP by methylation. The genetic variants TPMT*2 to *19 are associated with decreased TPMT activity (2), and TPMT*3A, *3C, and *2 are the most common deficiency-associated variants (1). A heterozygous TPMT genotype (1 in 10 individuals from the general population) is associated with an increased risk of myelosuppression with standard-dose azathioprine therapy (3) and a favorable response to reduced-dose thiopurine therapy (1). Patients with complete TPMT deficiency (1 in 300 individuals from the general population) are at high risk for myelosuppression (4).

The erythrocyte TPMT activity distribution is continuous, and concordance between genotype and phenotype in the carrier range varies, depending on where the cutoff is established between the ranges for carriers and noncarriers. We propose that genetic variation in folate metabolism influences TPMT activity and contributes to the lack of concordance between genotype and phenotype in the carrier range.

TPMT irreversibly transfers a methyl group from S-adenosylmethionine (SAM) to 6-MP, forming 6-methylmercaptopurine (6-MeMP) and S-adenosylhomocysteine (SAH). The adenosyl moiety of SAH is subsequently cleaved, and homocysteine is remethylated to methionine. The methyl donor for this folate-dependent remethylation cycle is 5-methyltetrahydrofolate, which is formed from 5,10-methylenetetrahydrofolate (MTHF) in a reaction catalyzed by 5,10-MTHF reductase (MTHFR). The MTHFR 677C>T (A222V) thermolabile variant (5) and the 1298A>C (E429A) variant (6) are associated with decreased MTHFR activity. The homozygous MTHFR 677TT genotype occurs in 8%–10% of the population (7), shows 30%–50% of wild-type activity in lymphocytes (8)(9), and is associated with hyperhomocysteinemia (10), DNA . . . [Full Text of this Article]

The following articles in journals at HighWire Press have cited this article:

				N. B. Y. Tsui Multiple Thiopurine S-Methyltransferase Variation Detection: A Step toward Personalized Medicine Clin. Chem., October 1, 2008; 54(10): 1598 - 1599. [Full Text] [PDF]