An inosine 5 '-monophosphate dehydrogenase 2 single-nucleotide polymorphism impairs the effect of mycophenolic acid

作者：Winnicki W; Weigel G^*; Sunder Plassmann G; Bajari T; Winter B; Herkner H; Sengoelge G

来源：The Pharmacogenomics Journal, 2010, 10(1): 70-76.

DOI：10.1038/tpj.2009.43

• IMPDH2
• inosine 5 '-monophosphate dehydrogenase activity
• lymphocyte proliferation
• mycophenolic acid
• SNP

Mycophenolic acid (MPA) is a selective inhibitor of inosine 5'-monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme of de novo synthesis of guanine nucleotides. The isoenzyme IMPDH2 predominates in activated lymphocytes, and its inhibition by MPA is part of standard immunosuppressive regimens. Yet, there are significant unexplained differences in efficacy and tolerability among patients. The objective of this study was to analyze whether frequent variants in the IMPDH2 gene lead to changes in IMPDH activity and to differences in responsiveness to MPA therapy. All 14 exons and intron-exon boundary regions of IMPDH2 were sequenced from genomic DNA probes from 100 healthy individuals. Two novel exonic single-nucleotide polymorphisms were identified in 1% and one intronic polymorphism (rs11706052) in 19% of the study population. Lymphocyte IMPDH activity and proliferation under three MPA concentrations (2.5, 10 and 25 mu mol l(-1)) were compared in rs11706052 carriers and wild-type individuals. The presence of rs11706052 polymorphism reduced the antiproliferative effect of MPA on lymphocytes by approximately 50% compared with the IMPDH2 wild-type form at therapeutic relevant concentrations of 10 mu mol l(-1) and 25 mu mol l(-1). We conclude that a poorer response to MPA therapy can be explained in some individuals by the presence of the rs11706052 polymorphism. The Pharmacogenomics Journal (2010) 10, 70-76; doi: 10.1038/tpj.2009.43; published online 22 September 2009

• 出版日期2010-2
• 单位河北医科大学