Nonsynonymous amino acid changes in the α-chain of complement component 5 influence longitudinal susceptibility to Plasmodium falciparum infections and severe malarial anemia in kenyan children
Background: Severe malarial anemia (SMA; Hb < 5.0 g/dl) is a leading cause of childhood morbidity and mortality in holoendemic Plasmodium falciparum transmission regions such as western Kenya.Methods: We investigated the relationship between two novel complement component 5 (C5) missense muta...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-09-01
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| Series: | Frontiers in Genetics |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fgene.2022.977810/full |
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| author | Evans Raballah Evans Raballah Kristen Wilding Samuel B. Anyona Samuel B. Anyona Elly O. Munde Elly O. Munde Ivy Hurwitz Clinton O. Onyango Clinton O. Onyango Cyrus Ayieko Christophe G. Lambert Kristan A. Schneider Philip D. Seidenberg Collins Ouma Collins Ouma Benjamin H. McMahon Qiuying Cheng Douglas J. Perkins Douglas J. Perkins |
| author_facet | Evans Raballah Evans Raballah Kristen Wilding Samuel B. Anyona Samuel B. Anyona Elly O. Munde Elly O. Munde Ivy Hurwitz Clinton O. Onyango Clinton O. Onyango Cyrus Ayieko Christophe G. Lambert Kristan A. Schneider Philip D. Seidenberg Collins Ouma Collins Ouma Benjamin H. McMahon Qiuying Cheng Douglas J. Perkins Douglas J. Perkins |
| author_sort | Evans Raballah |
| collection | DOAJ |
| description | Background: Severe malarial anemia (SMA; Hb < 5.0 g/dl) is a leading cause of childhood morbidity and mortality in holoendemic Plasmodium falciparum transmission regions such as western Kenya.Methods: We investigated the relationship between two novel complement component 5 (C5) missense mutations [rs17216529:C>T, p(Val145Ile) and rs17610:C>T, p(Ser1310Asn)] and longitudinal outcomes of malaria in a cohort of Kenyan children (under 60 mos, n = 1,546). Molecular modeling was used to investigate the impact of the amino acid transitions on the C5 protein structure.Results: Prediction of the wild-type and mutant C5 protein structures did not reveal major changes to the overall structure. However, based on the position of the variants, subtle differences could impact on the stability of C5b. The influence of the C5 genotypes/haplotypes on the number of malaria and SMA episodes over 36 months was determined by Poisson regression modeling. Genotypic analyses revealed that inheritance of the homozygous mutant (TT) for rs17216529:C>T enhanced the risk for both malaria (incidence rate ratio, IRR = 1.144, 95%CI: 1.059–1.236, p = 0.001) and SMA (IRR = 1.627, 95%CI: 1.201–2.204, p = 0.002). In the haplotypic model, carriers of TC had increased risk of malaria (IRR = 1.068, 95%CI: 1.017–1.122, p = 0.009), while carriers of both wild-type alleles (CC) were protected against SMA (IRR = 0.679, 95%CI: 0.542–0.850, p = 0.001).Conclusion: Collectively, these findings show that the selected C5 missense mutations influence the longitudinal risk of malaria and SMA in immune-naïve children exposed to holoendemic P. falciparum transmission through a mechanism that remains to be defined. |
| first_indexed | 2024-04-12T21:48:37Z |
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| language | English |
| last_indexed | 2024-04-12T21:48:37Z |
| publishDate | 2022-09-01 |
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| spelling | doaj.art-5ae3a1aecc984592bc7e6396beae2d812022-12-22T03:15:33ZengFrontiers Media S.A.Frontiers in Genetics1664-80212022-09-011310.3389/fgene.2022.977810977810Nonsynonymous amino acid changes in the α-chain of complement component 5 influence longitudinal susceptibility to Plasmodium falciparum infections and severe malarial anemia in kenyan childrenEvans Raballah0Evans Raballah1Kristen Wilding2Samuel B. Anyona3Samuel B. Anyona4Elly O. Munde5Elly O. Munde6Ivy Hurwitz7Clinton O. Onyango8Clinton O. Onyango9Cyrus Ayieko10Christophe G. Lambert11Kristan A. Schneider12Philip D. Seidenberg13Collins Ouma14Collins Ouma15Benjamin H. McMahon16Qiuying Cheng17Douglas J. Perkins18Douglas J. Perkins19University of New Mexico-Kenya Global Health Programs, Kisumu, KenyaDepartment of Medical Laboratory Sciences, School of Public Health Biomedical Sciences and Technology, Masinde Muliro University of Science and Technology, Kakamega, KenyaTheoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM, United StatesUniversity of New Mexico-Kenya Global Health Programs, Kisumu, KenyaDepartment of Medical Biochemistry, School of Medicine, Maseno University, Maseno, KenyaUniversity of New Mexico-Kenya Global Health Programs, Kisumu, KenyaDepartment of Clinical Medicine, School of Health Sciences, Kirinyaga University, Kerugoya, KenyaUniversity of New Mexico, Center for Global Health, Department of Internal Medicine, Albuquerque, NM, United StatesUniversity of New Mexico-Kenya Global Health Programs, Kisumu, KenyaDepartment of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno University, Maseno, KenyaDepartment of Zoology, Maseno University, Maseno, KenyaUniversity of New Mexico, Center for Global Health, Department of Internal Medicine, Albuquerque, NM, United StatesDepartment of Applied Computer and Biosciences, University of Applied Sciences Mittweida, Mittweida, Germany0University of New Mexico, Department of Emergency Medicine, Albuquerque, NM, United StatesUniversity of New Mexico-Kenya Global Health Programs, Kisumu, KenyaDepartment of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno University, Maseno, KenyaTheoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National Laboratory, Los Alamos, NM, United StatesUniversity of New Mexico, Center for Global Health, Department of Internal Medicine, Albuquerque, NM, United StatesUniversity of New Mexico-Kenya Global Health Programs, Kisumu, KenyaUniversity of New Mexico, Center for Global Health, Department of Internal Medicine, Albuquerque, NM, United StatesBackground: Severe malarial anemia (SMA; Hb < 5.0 g/dl) is a leading cause of childhood morbidity and mortality in holoendemic Plasmodium falciparum transmission regions such as western Kenya.Methods: We investigated the relationship between two novel complement component 5 (C5) missense mutations [rs17216529:C>T, p(Val145Ile) and rs17610:C>T, p(Ser1310Asn)] and longitudinal outcomes of malaria in a cohort of Kenyan children (under 60 mos, n = 1,546). Molecular modeling was used to investigate the impact of the amino acid transitions on the C5 protein structure.Results: Prediction of the wild-type and mutant C5 protein structures did not reveal major changes to the overall structure. However, based on the position of the variants, subtle differences could impact on the stability of C5b. The influence of the C5 genotypes/haplotypes on the number of malaria and SMA episodes over 36 months was determined by Poisson regression modeling. Genotypic analyses revealed that inheritance of the homozygous mutant (TT) for rs17216529:C>T enhanced the risk for both malaria (incidence rate ratio, IRR = 1.144, 95%CI: 1.059–1.236, p = 0.001) and SMA (IRR = 1.627, 95%CI: 1.201–2.204, p = 0.002). In the haplotypic model, carriers of TC had increased risk of malaria (IRR = 1.068, 95%CI: 1.017–1.122, p = 0.009), while carriers of both wild-type alleles (CC) were protected against SMA (IRR = 0.679, 95%CI: 0.542–0.850, p = 0.001).Conclusion: Collectively, these findings show that the selected C5 missense mutations influence the longitudinal risk of malaria and SMA in immune-naïve children exposed to holoendemic P. falciparum transmission through a mechanism that remains to be defined.https://www.frontiersin.org/articles/10.3389/fgene.2022.977810/fullsevere malarial anaemiacomplement 5missense mutationsP. facliparummalaria |
| spellingShingle | Evans Raballah Evans Raballah Kristen Wilding Samuel B. Anyona Samuel B. Anyona Elly O. Munde Elly O. Munde Ivy Hurwitz Clinton O. Onyango Clinton O. Onyango Cyrus Ayieko Christophe G. Lambert Kristan A. Schneider Philip D. Seidenberg Collins Ouma Collins Ouma Benjamin H. McMahon Qiuying Cheng Douglas J. Perkins Douglas J. Perkins Nonsynonymous amino acid changes in the α-chain of complement component 5 influence longitudinal susceptibility to Plasmodium falciparum infections and severe malarial anemia in kenyan children Frontiers in Genetics severe malarial anaemia complement 5 missense mutations P. facliparum malaria |
| title | Nonsynonymous amino acid changes in the α-chain of complement component 5 influence longitudinal susceptibility to Plasmodium falciparum infections and severe malarial anemia in kenyan children |
| title_full | Nonsynonymous amino acid changes in the α-chain of complement component 5 influence longitudinal susceptibility to Plasmodium falciparum infections and severe malarial anemia in kenyan children |
| title_fullStr | Nonsynonymous amino acid changes in the α-chain of complement component 5 influence longitudinal susceptibility to Plasmodium falciparum infections and severe malarial anemia in kenyan children |
| title_full_unstemmed | Nonsynonymous amino acid changes in the α-chain of complement component 5 influence longitudinal susceptibility to Plasmodium falciparum infections and severe malarial anemia in kenyan children |
| title_short | Nonsynonymous amino acid changes in the α-chain of complement component 5 influence longitudinal susceptibility to Plasmodium falciparum infections and severe malarial anemia in kenyan children |
| title_sort | nonsynonymous amino acid changes in the α chain of complement component 5 influence longitudinal susceptibility to plasmodium falciparum infections and severe malarial anemia in kenyan children |
| topic | severe malarial anaemia complement 5 missense mutations P. facliparum malaria |
| url | https://www.frontiersin.org/articles/10.3389/fgene.2022.977810/full |
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