The Nudix Hydrolase 15 (NUDT15) Gene Variants among Jordanian Arab Population

Background: Nudix Hydrolase 15 gene (NUDT15) encodes nucleotide triphosphate diphosphatase which metabolizes the purine analog drugs, such as anticancer thiopurine and anti-gout allopurinol. Genetic variants on Nudix Hydrolase 15 gene (NUDT15) gene effects the drug’s hydrolyses and hence increases the susceptibility to drug-induced toxicity. The NUDT15 gene has been genotyped in various ethnic groups, however, it has not been genotyped among the Middle Eastern Arab Jordanian population. Aim: The current study aimed to identify NUDT15 genetic variants among Jordanian Arab population. Method: The DNA samples were isolated from leukocytes of 85 unrelated Jordanian Arab volunteers. The coding regions of NUDT15 gene; Exon 1,2 and 3, in addition to some regions of intron 1,2 and 3’UTR, were amplified using polymerase chain reaction (PCR). the PCR products were then subjected to purification and sequenced using Applied Biosystems Model (ABI3730x1). Results: Six NUDT15 genetic variants were found among the volunteers.The results were as followed: A novel synonymous variant 36A>G on exon 1 (6%, 95%CI= 3- 9%), the intronic IVS1 +116C>T variant on intron 1 (0.6%, 95%CI= 0-2%), the non-synonymous variant on exon 3; 415C>T (0.6%, 95%CI= 0-2%), A novel non-synonymous variant on exon 3; 404C>A (0.6%, 95%CI= 0-2%) , and two novel variants on 3’UTR ;502G>A (2%, 95%CI= 0.5-4%) and 588T>C (0.6%, 95%CI= 0-2%). NUDT15 36A>G wasfound to be the most common allele among Jordanians was. In silico softwares predicted that the novel NUDT15 404C>A was harmful and affected NUDT15 enzyme’sstability and function. Furthermore, the frequency of NUDT15 IVS1 +116C>T , among Jordanians, showed to be significantly lower from what was reported in other ethnicities with ap value > 0.05 on the other hand, the frequency of 415C>T variant showed to be similar to Europeans in contrast to Asians and Indians that showed to be significantly lower (p value > 0.05). Conclusions: The frequency of NUDT15 genetic variants is low among the Jordanian volunteers and significantly lower than other ethnic groups. The findings of this study may increase our understanding of the inter-individual variation in the response to purine analog drugs. Further clinical studies are needed to investigate the influence of novel NUDT15 404C>A on drug metabolism and response.