Potential Impact of DPYD Variation on Fluoropyrimidine Drug Response in sub-Saharan African Populations.

Autor:	da Rocha JEB; Faculty of Health Sciences, Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa.; Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Lombard Z; Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa., Ramsay M; Faculty of Health Sciences, Sydney Brenner Institute for Molecular Bioscience, University of the Witwatersrand, Johannesburg, South Africa.; Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
Jazyk:	angličtina
Zdroj:	Frontiers in genetics [Front Genet] 2021 Mar 09; Vol. 12, pp. 626954. Date of Electronic Publication: 2021 Mar 09 (Print Publication: 2021).
DOI:	10.3389/fgene.2021.626954
Abstrakt:	Cancer is a critical health burden in Africa, and mortality rates are rising rapidly. Treatments are expensive and often cause adverse drug reactions (ADRs). Fluoropyrimidine treatments can lead to severe toxicity events which have been linked to variants within the dihydropyrimidine dehydrogenase ( DPYD ) gene. There are clinical guidelines to improve safety outcomes of treatment, but these are primarily based on variants assessed in non-African populations. Whole genome sequencing data from the 1000 Genomes Project and the African Genome Variation Project were mined to assess variation in DPYD in eight sub-Saharan African populations. Variant functional annotation was performed with a series of bioinformatics tools to assess potential likelihood of deleterious impact. There were 29 DPYD coding variants identified in the datasets assessed, of which 25 are rare, and some of which are known to be deleterious. One African-specific variant (rs115232898-C), is common in sub-Saharan Africans (1-4%) and known to reduce the function of the dihydropyrimidine dehydrogenase enzyme (DPD), having been linked to cases of severe toxicity. This variant, once validated in clinical trials, should be considered for inclusion in clinical guidelines for use in sub-Saharan African populations. The rs2297595-C variant is less well-characterized in terms of effect, but shows significant allele frequency differences between sub-Saharan African populations (0.5-11.5%; p = 1.5 × 10 -4 ), and is more common in East African populations. This study highlights the relevance of African-data informed guidelines for fluorouracil drug safety in sub-Saharan Africans, and the need for region-specific data to ensure that Africans may benefit optimally from a precision medicine approach. Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 da Rocha, Lombard and Ramsay.)
Databáze:	MEDLINE
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