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Cyclooxygenase-2 haplotypes influence the longitudinal risk of malaria and severe malarial anemia in Kenyan children from a holoendemic transmission region

Journal of Human Genetics volume 65, pages 99–113 (2020)Cite this article

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Abstract

Cyclooxygenase-2 [(COX-2) or prostaglandin endoperoxide H2 synthase-2 (PTGS-2)] induces the production of prostaglandins as part of the host-immune response to infections. Although a number of studies have demonstrated the effects of COX-2 promoter variants on autoimmune and inflammatory diseases, their role in malaria remains undefined. As such, we investigated the relationship between four COX-2 promoter variants (COX-2 −512 C > T, −608 T > C, −765 G > C, and −1195 A > G) and susceptibility to malaria and severe malarial anemia (SMA) upon enrollment and longitudinally over a 36-month follow-up period. All-cause mortality was also explored. The investigation was carried out in children (n = 1081, age; 2–70 months) residing in a holoendemic Plasmodium falciparum transmission region of western Kenya. At enrollment, genotypes/haplotypes (controlling for anemia-promoting covariates) did not reveal any strong effects on susceptibility to either malaria or SMA. Longitudinal analyses showed decreased malaria episodes in children who inherited the −608 CC mutant allele (RR = 0.746, P = 1.811 × 10−4) and -512C/-608T/-765G/-1195G (CTGG) haplotype (RR = 0.856, P = 0.011), and increased risk in TTCA haplotype carriers (RR = 1.115, P = 0.026). Over the follow-up period, inheritance of the rare TTCG haplotype was associated with enhanced susceptibility to both malaria (RR = 1.608, P = 0.016) and SMA (RR = 5.714, P = 0.004), while carriage of the rare TTGG haplotype increased the risk of malaria (RR = 1.755, P = 0.007), SMA (RR = 8.706, P = 3.97 × 10−4), and all-cause mortality (HR = 110.000, P = 0.001). Collectively, these results show that SNP variations in the COX-2 promoter, and their inherited combinations, are associated with the longitudinal risk of malaria, SMA, and all-cause mortality among children living in a high transmission area for P. falciparum.

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Acknowledgements

We gratefully acknowledge the assistance of the University of New Mexico-Kenya team: Nicholas Otieno Ondiek, Vincent Odhiambo Otieno, Anne A Ong’ondo, Chrispine Wasonga Ochieng, Everlyne A Modi, Joan L A Ochieng, Jacob Oyoko Odeny, Joseph Oduor, Martin Ogalo, Moses Ebungure, Moses Lokorkeju, Rodney B Mongare, Stella Mariz Akinyi Oloo and Vincent Omanje. We are also grateful to all of the parents, guardians, and children who participated in the study. The content is solely the responsibility of the authors and does not represent the official views of the funding agencies. The content is solely the responsibility of the authors and the funders did not have any role in study design, data collection, data analysis, interpretation, or writing of the report. The work was supported by National Institutes of Health (NIH) Research Grants R01AI130473 and R01AI51305 (DJP), NIH Fogarty International Center Grants D43TW05884 (DJP, SBA) and D43 TW010543 (SBA, DJP), and LANL-LDRD 20150090DR (BHM, DJP).

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Authors and Affiliations

  1. University of New Mexico-Kenya Global Health Programs, Kisumu and Siaya, Kenya

    Samuel B. Anyona, Evans Raballah, Collins Ouma & Douglas J. Perkins

  2. Department of Medical Biochemistry, School of Medicine, Maseno University, Maseno, Kenya

    Samuel B. Anyona

  3. Theoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM, USA

    Nicolas W. Hengartner, Paul W. Fenimore & Benjamin H. McMahon

  4. Department of Medical Laboratory Sciences, School of Public Health Biomedical Sciences and Technology, Masinde Muliro University of Science and Technology, Kakamega, Kenya

    Evans Raballah

  5. Kenya Medical Research Institute, Centre for Global Health Research, Kisumu, Kenya

    John Michael Ong’echa

  6. Center for Global Health, University of New Mexico, Albuquerque, NM, USA

    Nick Lauve, Qiuying Cheng, Christophe G. Lambert & Douglas J. Perkins

  7. Department of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno University, Maseno, Kenya

    Collins Ouma

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Anyona, S.B., Hengartner, N.W., Raballah, E. et al. Cyclooxygenase-2 haplotypes influence the longitudinal risk of malaria and severe malarial anemia in Kenyan children from a holoendemic transmission region. J Hum Genet 65, 99–113 (2020). https://doi.org/10.1038/s10038-019-0692-3

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