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

Abstract

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