Genetic variation in CSF2 (5q31.1) is associated with longitudinal susceptibility to pediatric malaria, severe malarial anemia, and all-cause mortality in a high-burden malaria and HIV region of Kenya
Abstract Plasmodium falciparum infections remain among the leading causes of morbidity and mortality in holoendemic transmission areas. Located within region 5q31.1, the colony-stimulating factor 2 gene (CSF2) encodes granulocyte–macrophage colony-stimulating factor (GM-CSF), a hematopoietic growth...
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BMC
2022-06-01
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| Series: | Tropical Medicine and Health |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s41182-022-00432-5 |
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| author | Lily E. Kisia Qiuying Cheng Evans Raballah Elly O. Munde Benjamin H. McMahon Nick W. Hengartner John M. Ong’echa Kiprotich Chelimo Christophe G. Lambert Collins Ouma Prakasha Kempaiah Douglas J. Perkins Kristan A. Schneider Samuel B. Anyona |
| author_facet | Lily E. Kisia Qiuying Cheng Evans Raballah Elly O. Munde Benjamin H. McMahon Nick W. Hengartner John M. Ong’echa Kiprotich Chelimo Christophe G. Lambert Collins Ouma Prakasha Kempaiah Douglas J. Perkins Kristan A. Schneider Samuel B. Anyona |
| author_sort | Lily E. Kisia |
| collection | DOAJ |
| description | Abstract Plasmodium falciparum infections remain among the leading causes of morbidity and mortality in holoendemic transmission areas. Located within region 5q31.1, the colony-stimulating factor 2 gene (CSF2) encodes granulocyte–macrophage colony-stimulating factor (GM-CSF), a hematopoietic growth factor that mediates host immune responses. Since the effect of CSF2 variation on malaria pathogenesis remains unreported, we investigated the impact of two genetic variants in the 5q31.1 gene region flanking CSF2:g-7032 G > A (rs168681:G > A) and CSF2:g.64544T > C (rs246835:T > C) on the rate and timing of malaria and severe malarial anemia (SMA, Hb < 5.0 g/dL) episodes over 36 months of follow-up. Children (n = 1654, aged 2–70 months) were recruited from a holoendemic P. falciparum transmission area of western Kenya. Decreased incidence rate ratio (IRR) for malaria was conferred by inheritance of the CSF2:g.64544 TC genotype (P = 0.0277) and CSF2 AC/GC diplotype (P = 0.0015). Increased IRR for malaria was observed in carriers of the CSF2 AT/GC diplotype (P = 0.0237), while the inheritance of the CSF2 AT haplotype increased the IRR for SMA (P = 0.0166). A model estimating the longitudinal risk of malaria showed decreased hazard rates among CSF2 AC haplotype carriers (P = 0.0045). Investigation of all-cause mortality revealed that inheritance of the GA genotype at CSF2:g-7032 increased the risk of mortality (P = 0.0315). Higher risk of SMA and all-cause mortality were observed in younger children (P < 0.0001 and P = 0.0015), HIV-1(+) individuals (P < 0.0001 and P < 0.0001), and carriers of HbSS (P = 0.0342 and P = 0.0019). Results from this holoendemic P. falciparum area show that variation in gene region 5q31.1 influences susceptibility to malaria, SMA, and mortality, as does age, HIV-1 status, and inheritance of HbSS. |
| first_indexed | 2024-04-12T09:39:01Z |
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| id | doaj.art-9181a3a765424ab5950663800c7efad4 |
| institution | Directory Open Access Journal |
| issn | 1349-4147 |
| language | English |
| last_indexed | 2024-04-12T09:39:01Z |
| publishDate | 2022-06-01 |
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| series | Tropical Medicine and Health |
| spelling | doaj.art-9181a3a765424ab5950663800c7efad42022-12-22T03:38:09ZengBMCTropical Medicine and Health1349-41472022-06-0150111510.1186/s41182-022-00432-5Genetic variation in CSF2 (5q31.1) is associated with longitudinal susceptibility to pediatric malaria, severe malarial anemia, and all-cause mortality in a high-burden malaria and HIV region of KenyaLily E. Kisia0Qiuying Cheng1Evans Raballah2Elly O. Munde3Benjamin H. McMahon4Nick W. Hengartner5John M. Ong’echa6Kiprotich Chelimo7Christophe G. Lambert8Collins Ouma9Prakasha Kempaiah10Douglas J. Perkins11Kristan A. Schneider12Samuel B. Anyona13Department of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno UniversityCenter for Global Health, University of New MexicoUniversity of New Mexico-Kenya Global Health ProgramsUniversity of New Mexico-Kenya Global Health ProgramsTheoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National LaboratoryTheoretical Biology and Biophysics Group, Theoretical Division, Los Alamos National LaboratoryCentre for Global Health Research, Kenya Medical Research InstituteDepartment of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno UniversityCenter for Global Health, University of New MexicoDepartment of Biomedical Sciences and Technology, School of Public Health and Community Development, Maseno UniversityDepartment of Medicine, Loyola University Medical CenterUniversity of New Mexico-Kenya Global Health ProgramsDepartment Applied Computer and Bio-Sciences, University of Applied Sciences MittweidaUniversity of New Mexico-Kenya Global Health ProgramsAbstract Plasmodium falciparum infections remain among the leading causes of morbidity and mortality in holoendemic transmission areas. Located within region 5q31.1, the colony-stimulating factor 2 gene (CSF2) encodes granulocyte–macrophage colony-stimulating factor (GM-CSF), a hematopoietic growth factor that mediates host immune responses. Since the effect of CSF2 variation on malaria pathogenesis remains unreported, we investigated the impact of two genetic variants in the 5q31.1 gene region flanking CSF2:g-7032 G > A (rs168681:G > A) and CSF2:g.64544T > C (rs246835:T > C) on the rate and timing of malaria and severe malarial anemia (SMA, Hb < 5.0 g/dL) episodes over 36 months of follow-up. Children (n = 1654, aged 2–70 months) were recruited from a holoendemic P. falciparum transmission area of western Kenya. Decreased incidence rate ratio (IRR) for malaria was conferred by inheritance of the CSF2:g.64544 TC genotype (P = 0.0277) and CSF2 AC/GC diplotype (P = 0.0015). Increased IRR for malaria was observed in carriers of the CSF2 AT/GC diplotype (P = 0.0237), while the inheritance of the CSF2 AT haplotype increased the IRR for SMA (P = 0.0166). A model estimating the longitudinal risk of malaria showed decreased hazard rates among CSF2 AC haplotype carriers (P = 0.0045). Investigation of all-cause mortality revealed that inheritance of the GA genotype at CSF2:g-7032 increased the risk of mortality (P = 0.0315). Higher risk of SMA and all-cause mortality were observed in younger children (P < 0.0001 and P = 0.0015), HIV-1(+) individuals (P < 0.0001 and P < 0.0001), and carriers of HbSS (P = 0.0342 and P = 0.0019). Results from this holoendemic P. falciparum area show that variation in gene region 5q31.1 influences susceptibility to malaria, SMA, and mortality, as does age, HIV-1 status, and inheritance of HbSS.https://doi.org/10.1186/s41182-022-00432-5P. falciparumCSF2GM-CSFMalariaGenotypesHaplotypes |
| spellingShingle | Lily E. Kisia Qiuying Cheng Evans Raballah Elly O. Munde Benjamin H. McMahon Nick W. Hengartner John M. Ong’echa Kiprotich Chelimo Christophe G. Lambert Collins Ouma Prakasha Kempaiah Douglas J. Perkins Kristan A. Schneider Samuel B. Anyona Genetic variation in CSF2 (5q31.1) is associated with longitudinal susceptibility to pediatric malaria, severe malarial anemia, and all-cause mortality in a high-burden malaria and HIV region of Kenya Tropical Medicine and Health P. falciparum CSF2 GM-CSF Malaria Genotypes Haplotypes |
| title | Genetic variation in CSF2 (5q31.1) is associated with longitudinal susceptibility to pediatric malaria, severe malarial anemia, and all-cause mortality in a high-burden malaria and HIV region of Kenya |
| title_full | Genetic variation in CSF2 (5q31.1) is associated with longitudinal susceptibility to pediatric malaria, severe malarial anemia, and all-cause mortality in a high-burden malaria and HIV region of Kenya |
| title_fullStr | Genetic variation in CSF2 (5q31.1) is associated with longitudinal susceptibility to pediatric malaria, severe malarial anemia, and all-cause mortality in a high-burden malaria and HIV region of Kenya |
| title_full_unstemmed | Genetic variation in CSF2 (5q31.1) is associated with longitudinal susceptibility to pediatric malaria, severe malarial anemia, and all-cause mortality in a high-burden malaria and HIV region of Kenya |
| title_short | Genetic variation in CSF2 (5q31.1) is associated with longitudinal susceptibility to pediatric malaria, severe malarial anemia, and all-cause mortality in a high-burden malaria and HIV region of Kenya |
| title_sort | genetic variation in csf2 5q31 1 is associated with longitudinal susceptibility to pediatric malaria severe malarial anemia and all cause mortality in a high burden malaria and hiv region of kenya |
| topic | P. falciparum CSF2 GM-CSF Malaria Genotypes Haplotypes |
| url | https://doi.org/10.1186/s41182-022-00432-5 |
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