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

Summary: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: 569 T > 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: 1563 T > 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 – 7 T > 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.