Novel Deleterious Dihydropyrimidine Dehydrogenase Variants May Contribute to 5-Fluorouracil Sensitivity in an East African Population

T. Elraiyah, C. R. Jerde, S. Shrestha, R. Wu, Q. Nie, N. H. Giama, V. Sarangi, L. R. Roberts, S. M. Offer, R. B. Diasio

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Clinical studies have identified specific genetic variants in dihydropyrimidine dehydrogenase (DPD; DPYD gene) as predictors of severe adverse toxicity to the commonly used chemotherapeutic 5-fluorouracil (5-FU); however, these studies have focused on European and European-American populations. Our laboratory recently demonstrated that additional variants in non-European haplotypes are predictive of 5-FU toxicity. The objective of this study was to identify potential risk variants in an understudied East African population relevant to our institution's catchment area. The DPYD protein-coding region was sequenced in 588 individuals of Somali or Kenyan ancestry living in central/southeast Minnesota. Twelve novel nonsynonymous variants were identified, seven of which significantly decreased DPD activity in vitro. The commonly reported toxicity-associated variants, *2A, D949V, and I560S, were not detected in any individuals. Overall, this study demonstrates a critical limitation in our knowledge of pharmacogenetic predictors of 5-FU toxicity, which has been based on clinical studies conducted in populations of limited diversity.

Original languageEnglish (US)
Pages (from-to)382-390
Number of pages9
JournalClinical pharmacology and therapeutics
Volume101
Issue number3
DOIs
StatePublished - Mar 1 2017

Bibliographical note

Funding Information:
The authors wish to thank Abdirashid Shire, Essa Mohamed, and Hassan Shaleh for facilitating the collection of specimens. This study was funded by the Mayo Clinic Cancer Center grant number CA15083 and was supported by the National Institutes of Health training grant number T32 GM008685. The collection of specimens was supported in part by funding from Gilead Sciences. T.E. presented this study at the ASCPT 2016 meeting and was the recipient of an ASCPT Presidential Trainee Award.

Publisher Copyright:
© 2016 American Society for Clinical Pharmacology and Therapeutics

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