title: Effect of red blood cell variants on childhood malaria in Mali: a prospective cohort study.
abstract: BACKGROUND
  Red blood cell variants protect African children from severe falciparum malaria. However, their individual and interactive effects on mild disease and parasite density, and their modification by age-dependent immunity, are poorly understood. In this study, we address these knowledge gaps in a prospective cohort study of malaria risk and Plasmodium falciparum densities in Malian children.
  
  
  METHODS
  The Kenieroba Innate Defense Study for Malaria (KIDS-Malaria) was a 4-year prospective cohort study of children aged 6 months to 17 years undertaken in Mali between 2008 and 2011. Red blood cell variants were haemoglobin S (HbS), haemoglobin C (HbC), α thalassaemia, ABO blood groups, and glucose-6-phosphate dehydrogenase (G6PD) deficiency encoded by the X-linked A- allele. The primary outcome was malaria incidence, measured as the number of uncomplicated or severe malaria episodes over time. The secondary outcome was parasite density at the time of a malaria episode. We modelled incidence rate ratios with quasi-Poisson regression and we analysed parasite densities using generalised estimating equations. This study is registered with ClinicalTrials.gov, number NCT00669084.
  
  
  RESULTS
  Between May 1, 2008, and Dec 29, 2011, we enrolled 1586 children into the study. We successfully typed all five red blood cell variants for 1543 of these children, who therefore constituted the evaluable population and in whom we diagnosed 4091 malaria episodes over 2656 child-years of follow-up. In these 1543 children, red blood cell variants were common, and occurred at the following frequencies: sickle cell trait (HbAS) 220 (14%), HbC heterozygosity (HbAC) 103 (7%), α thalassaemia 438 (28%), type O blood group 621 (40%), and G6PD deficiency 72 (9%) in 767 boys and 158 (20%) in 776 girls. The overall incidence of malaria was 1.54 episodes per child-year of follow-up, ranging from 2.78 episodes per child-year at age 3 years to 0.40 episodes per child-year at age 17 years. The malaria incidence was lower in HbAS children than in HbAA children with normal haemoglobin (adjusted incidence rate ratio [aIRR] 0.66 [95% CI 0.59-0.75], p<0.0001) and lower in G6PD A-/A- homozygous girls than in G6PD A+/A+ girls (0.51 [0.29-0.90], p=0.020), but was higher in HbAC children than in HbAA children (1.15 [1.01-1.32], p=0.039). Parasite density was lower in HbAS children (median 10,550 parasites per μL [IQR 1350-26,250]) than in HbAA children (15,150 parasites per μL [4250-31,050]; p=0.0004). The HbAS-associated reductions in malaria risk and parasite density were greatest in early childhood.
  
  
  CONCLUSIONS
  The individual and interactive effects of HbAS, HbAC, and G6PD A-/A- genotypes on malaria risk and parasite density define clinical and cellular correlates of protection. Further identification of the molecular mechanisms of these protective effects might uncover new targets for intervention.
  
  
  BACKGROUND
  Intramural Research Program, National Institute of Allergy and Infectious Diseases, National Institutes of Health.
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Lopera-Mesa
authors.affiliation: Malaria Research and Training Center, University of Bamako, Bamako, Mali.
authors.forename: Saibou
authors.initials: S
authors.lastname: Doumbia
authors.affiliation: Malaria Research and Training Center, University of Bamako, Bamako, Mali.
authors.forename: Drissa
authors.initials: D
authors.lastname: Konaté
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Anderson
authors.affiliation: Malaria Research and Training Center, University of Bamako, Bamako, Mali.
authors.forename: Mory
authors.initials: M
authors.lastname: Doumbouya
authors.affiliation: Malaria Research and Training Center, University of Bamako, Bamako, Mali.
authors.forename: Abdoul S
authors.initials: AS
authors.lastname: Keita
authors.affiliation: Malaria Research and Training Center, University of Bamako, Bamako, Mali.
authors.forename: Seidina A S
authors.initials: SA
authors.lastname: Diakité
authors.affiliation: Malaria Research and Training Center, University of Bamako, Bamako, Mali.
authors.forename: Karim
authors.initials: K
authors.lastname: Traoré
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Krause
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA; Kelly Scientific Resources, Rockville, MD, USA.
authors.forename: Ababacar
authors.initials: A
authors.lastname: Diouf
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA; Kelly Scientific Resources, Rockville, MD, USA.
authors.forename: Samuel E
authors.initials: SE
authors.lastname: Moretz
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA; Kelly Scientific Resources, Rockville, MD, USA.
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Tullo
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA; Kelly Scientific Resources, Rockville, MD, USA.
authors.forename: Kazutoyo
authors.initials: K
authors.lastname: Miura
authors.affiliation: Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research Inc, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Gu
authors.affiliation: Biostatistics Research Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Fay
authors.affiliation: Division of Infectious Diseases and International Health and Duke Global Health Institute, Duke University Medical Center, Durham, NC, USA; Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Steve M
authors.initials: SM
authors.lastname: Taylor
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA.
authors.forename: Carole A
authors.initials: CA
authors.lastname: Long
authors.affiliation: Malaria Research and Training Center, University of Bamako, Bamako, Mali.
authors.forename: Mahamadou
authors.initials: M
authors.lastname: Diakité
authors.affiliation: Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA. Electronic address: rfairhurst@niaid.nih.gov.
authors.forename: Rick M
authors.initials: RM
authors.lastname: Fairhurst
mesh_terms: D000017:ABO Blood-Group System / Q000235:genetics; D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D004912:Erythrocytes / Q000469:parasitology*; D005260:Female; D005838:Genotype; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics; D006444:Hemoglobin C / Q000235:genetics; D006451:Hemoglobin, Sickle / Q000235:genetics; D006801:Humans; D007223:Infant; D008288:Malaria / Q000097:blood / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008302:Mali / Q000453:epidemiology; D011446:Prospective Studies; D012805:Sickle Cell Trait / Q000235:genetics; D017085:alpha-Thalassemia / Q000235:genetics
chemical_list: D000017:ABO Blood-Group System; D006451:Hemoglobin, Sickle; D006444:Hemoglobin C; D005954:Glucosephosphate Dehydrogenase