Novel deleterious dihydropyrimidine dehydrogenase variants may contribute to 5-fluorouracil sensitivity in an East African population

Tarig Elraiyah; Calvin R. Jerde; Shikshya Shrestha; Rentian Wu; Qian Nie; Nasra H. Giama; Vivekananda Sarangi; Lewis R. Roberts; Steven M. Offer; Robert B. Diasio

doi:10.1002/cpt.531

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Novel deleterious dihydropyrimidine dehydrogenase variants may contribute to 5-fluorouracil sensitivity in an East African population

Journal article

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Novel deleterious dihydropyrimidine dehydrogenase variants may contribute to 5-fluorouracil sensitivity in an East African population

Tarig Elraiyah, Calvin R. Jerde, Shikshya Shrestha, Rentian Wu, Qian Nie, Nasra H. Giama, Vivekananda Sarangi, Lewis R. Roberts, Steven M. Offer and Robert B. Diasio

Clinical pharmacology and therapeutics, Vol.101(3), pp.382-390

03/2017

DOI: 10.1002/cpt.531

PMCID: PMC5309195

PMID: 27727460

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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; however, these studies have focused on European and European-American populations. Our lab 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 under-studied 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 non-synonymous 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.

Details

Title: Subtitle: Novel deleterious dihydropyrimidine dehydrogenase variants may contribute to 5-fluorouracil sensitivity in an East African population
Creators: Tarig Elraiyah - Mayo Clinic
Calvin R. Jerde - Mayo Clinic
Shikshya Shrestha - Mayo Clinic
Rentian Wu - Mayo Clinic
Qian Nie - Mayo Clinic
Nasra H. Giama - Mayo Clinic
Vivekananda Sarangi - Mayo Clinic
Lewis R. Roberts - Mayo Clinic
Steven M. Offer - Mayo Clinic
Robert B. Diasio - Mayo Clinic
Resource Type: Journal article
Publication Details: Clinical pharmacology and therapeutics, Vol.101(3), pp.382-390
DOI: 10.1002/cpt.531
PMID: 27727460
PMCID: PMC5309195
ISSN: 0009-9236
eISSN: 1532-6535
Grant note: DOI: 10.13039/100000002, name: National Institutes of Health, award: T32 GM008685; DOI: 10.13039/100005564, name: Gilead Sciences
Language: English
Date published: 03/2017
Academic Unit: Pathology
Record Identifier: 9984618645102771

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