Genetic Variations in the HGPRT, ITPA, IMPDH1, IMPDH2, and GMPS Genes in Japanese Individuals

Abstract

Thiopurines (such as azathioprine and 6-mercaptopurine) are widely used for the treatment of patients suffering from malignancies, rheumatic disease, inflammatory bowel disease and solid organ transplant rejection. These drugs are activated and eliminated by a number of enzymes in the human body. This analyzes all the exons and exon-intron junctions of 5 enzyme genes (hypoxanthine-guanine phosphoribosyltransferase, HGPRT; inosine triphosphate pyrophosphatase, ITPA; inosine monophosphate dehydrogenases 1 and 2, IMPDH1 and IMPDH2 and guanosine monophosphate synthetase, GMPS) involved in the metabolism of thiopurine drugs. Twelve novel single nucleotide polymorphisms (SNPs) (HGPRT: IVS6-12C>A (frequency:0.003); ITPA: 569T>C (Phe189Phe, 0.003); IMPDH1: IVS8-15C>A (0.003), IVS9+227A>G (0.003), IVS17+115C>T (0.003), and 930C>T (Thr310Thr, 0.005); IMPDH2: IVS1+50G>T (0.003), IVS2+15G>A (0.010), IVS3-20G>A (0.003), 609C>T (Arg203Arg, 0.003), and 1534C>T (Arg512Trp, 0.003); and GMPS: 1563T>C (Gly521Gly, 0.003)) and 7 known SNPs (ITPA: 94C>A (Pro32Thr, 0.005), 138G>A (Gln46Gln, 0.586), and 563G>A (Glu187Glu, 0.433); IMPDH1: 987G>C (Leu329Leu, 0.113) and 1575A>G (Ala525Ala, 0.620) and GMPS: IVS5-7T>C (0.153), 993A>G (Thr331Thr, 0.153)) were identified in 200 Japanese subjects. These data should provide useful information for thiopurine therapy in the Japanese and as well as other Asian populations.

RNA‐seq‐based quanitative transcriptome analysis of meat color and taste from chickens administered by eucalyptus leaf polyphenols extract

“…Here, we showed that ITPA and IMPDH2 were both upregulated DEGs related and may be related to the observed trend of increased IMP. ITPA functions in nucleotide binding, Nicotinamide adenine dinucleotide pyrophosphatase activity, and deoxyinosine triphosphate diphosphatase activity, and also participates in deoxyribonucleoside triphosphate catabolic processes, nucleoside triphosphate catabolic processes, and ITP catabolic processes (Kudo et al., 2009; Sakumi et al., 2010). Additionally, IMPDH2 is a key gene in the rate‐limiting step of de novo guanine nucleotide synthesis.…”

Review article: recent advances in pharmacogenetics and pharmacokinetics for safe and effective thiopurine therapy in inflammatory bowel disease

“…In normal cells, inosine diphosphate and inosine triphosphate are produced from inosine monophosphate by kinases, and ITPA preferentially catalyses hydrolysis of inosine triphosphate back to inosine monophosphate and pyrophosphate, to prevent the accumulation of 6‐thioinosine triphosphate (6‐TITP), rogue nucleotides, which would be otherwise incorporated into DNA and RNA, or compete with nucleotides . Recently, SNPs in the ITPA gene, some of which are accompanied by decreased enzyme activity, have been reported . The most frequent SNPs related with deficient ITPA activity are 94C>A and IVS2 + 21A>C .…”

Pharmacogenetic studies of thiopurine methyltransferase genotype-phenotype concordance and effect of methotrexate on thiopurine metabolism

“…When this PhD project started, a few studies concerning varying enzyme activity or the connection between varying genotypes and adverse reactions in other thiopurine metabolizing enzymes had been published. Throughout these years, the complexity of thiopurine metabolism has been more extensive with reports of several polymorphisms within the metabolism of thiopurines (ITPA [166,167], HGPRT [142,168], IMPDH [168][169][170], XO [60,171], GST [172][173][174], GMPS [168], Rac1 [175], NT5C2 [176,177], PACSIN2 [178], genes in the mismatch repair system (MMR) [179], folate cycle [152][153][154] and transporters [56,175,[180][181][182]) and recently, pharmacogenetic testing of NUDT15, whose variants are more common in Asian populations, has been implemented in the guidelines of the Clinical Pharmacogenetics Implementation Consortium (CPIC) for thiopurine treatment [19,183] . Otherwise, so far, no other polymorphism has had the same extensive effect on thiopurine treatment as the genetic variants of TPMT.…”