Pharmacogenomic variation in the Malagasy population: implications for the antimalarial drug primaquine metabolism

Abstract

Aim: Antimalarial primaquine (PQ) eliminates liver hypnozoites of Plasmodium vivax. CYP2D6 gene variation contributes to PQ therapeutic failure. Additional gene variation may contribute to PQ efficacy. Information on pharmacogenomic variation in Madagascar, with vivax malaria and a unique population admixture, is scanty. Methods: The authors performed genome-wide genotyping of 55 Malagasy samples and analyzed data with a focus on a set of 28 pharmacogenes most relevant to PQ. Results: Mainly, the study identified 110 coding or splicing variants, including those that, based on previous studies in other populations, may be implicated in PQ response and copy number variation, specifically in chromosomal regions that contain pharmacogenes. Conclusion: With this pilot information, larger genome-wide association analyses with PQ metabolism and response are substantially more feasible.

Keywords::

• copy number variation
• genome-wide array
• Madagascar
• malaria treatment
• Plasmodium vivax
• primaquine

Supplementary data

To view the supplementary data that accompany this paper please visit the journal website at: www.futuremedicine.com/doi/suppl/10.2217/pgs-2023-0091

Author contributions

SM Williams and PA Zimmerman conceived the study and secured the funding. RK Mehlotra prepared the DNA samples for the genotyping, performed GenomeStudio analyses and wrote the manuscript. EY Cramer and J Bartlett analyzed the post-quality control genotype data. ER Chan downloaded and processed the 1000 Genomes Project data and assisted in the principal component analysis. A Gaedigk contributed to data interpretation and manuscript preparation. AC Ratsimbasoa was the principal collaborator and overall supervisor of the field studies. All authors contributed to the manuscript editing and approved the final version.

Acknowledgments

The authors thank all study participants, local health officials, field doctors and project technicians for their participation and support. The authors appreciate the help of Ioanna Konidari (director, Genotyping Core, HIHG, University of Miami) for performing Infinium Multi-Ethnic Genotyping Array analysis. RK Mehlotra is indebted to Kim Brustoski (Population and Quantitative Health Sciences, CWRU), Simone Edelheit (Genomics Core, CWRU) and Jose Gonzales (Technical Applications Scientist II, Illumina) for their invaluable help with GenomeStudio processing and quality control of the genotype data. In addition, RK Mehlotra thanks Kim Brustoski for generating Supplementary Figure 1 (Supplementary Document 1) and critically reading the manuscript and Jasmine Olvany and Quentin Watson for their comments on the manuscript. The authors’ sincere thanks are also due to Alexandra Stewart and James McCarthy for critically reading the manuscript.

Financial & competing interests disclosure

This study was supported by R01 grants from the NIH (AI097366 to PA Zimmerman and AI148469 to SM Williams and PA Zimmerman). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Institutional review board statement/informed consent statement

The study was approved by the University Hospitals of Cleveland Institutional Review Board (#09-13-01), CWRU IRB (STUDY20191615), the Division of Microbiology and Infectious Diseases/NIAID/National Institutes of Health (#13-0067) and the Madagascar Ministry of Health Ethics Committee (#099 and #52 MSANP/SG/AMM/CERBM). Written informed consent was obtained from all subjects, or subject guardians, prior to enrollment.

Data availability statement

Data from this study are available through one supplementary document, four tables, two figures and five (Supplementary Tables 2–6) in the manuscript.

Additional information

Funding

This study was supported by R01 grants from the NIH (AI097366 to PA Zimmerman and AI148469 to SM Williams and PA Zimmerman). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.