Ansari, A.; Marinaki, A.; Arenas, M.; Shobowale-Bakre, E.M.; Lewis, C.L.; Duley, J.; Sanderson, J.D.
April 2003
Gut;Apr2003 Supplement 1, Vol. 52, pA65
Academic Journal
Background: Polymorphisms in the thiopurine methyl transferase (TPMT) gene only explain a proportion of side effects on azathioprine (AZA). S-adenosylmethionine (SAM) is the methyl donor for methylation by TPMT and is converted to S-adenosyl-homocysteine (SAH). The adenosyl moiety of SAH is cleaved and homocysteine can be remethylated to methionine in a folate dependent pathway. A common polymorphism in the methylene tetrahydrofolate reductase (MTHFR) gene, the 677C>T variant is associated with decreased MTHFR enzyme activity and thus may indirectly affect TPMT activity. Aim: To investigate whether MTHFR gene polymorphism influences erythrocyte TPMT activity and might be associated with adverse drug reactions to azathioprine (AZA). Methods: MTFHR TT genotype frequency was assessed in 52 patients with wild type TPMT genotype but intermediate TPMT activity (4-8U) and compared to 55 patients with normal TPMT activity and genotype (in the range 12-15U). MTHFR genotype frequencies were then compared between 57 IBD patients with adverse drug reactions to AZA therapy and 71 patients tolerant to AZA. Results: MTHFR TT genotype was significantly underrepresented in the normal compared to the intermediate activity group (7.3% v 23% (p=0.0296). Despite this, MTHFR genotype was not significantly associated with an increase in overall side effects to AZA. The MTHFR 677C>T allele was less frequent amongst those with hepatitis and pancreatitis on AZA (4/16(25%) v 35/71 (49%) but this association did not reach statistical significance (p=0.6). Conclusions: MTFHR genotype influences TPMT activity such that wildtype MTHFR genotype is associated with high methylation capacity. High TPMT activity has been suggested as a cause of pancreatic and hepatic side effects but could not be confirmed in this study. Larger studies are needed to explore this relationship further.


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