title: Hemoglobin variants and disease manifestations in severe falciparum malaria.
abstract: BACKGROUND
  The geographical distributions of hemoglobin S (HbS), hemoglobin C (HbC), and alpha+-thalassemia (-alpha) strongly suggest balancing selection with malaria. However, whereas several studies indicate that the HbS carrier state protects against all major forms of clinical malaria, malaria protection on clinical grounds has been more difficult to confirm for HbC and -alpha, and questions remain as to whether it applies to all forms of the disease.
  
  
  OBJECTIVE
  To assess the association between major clinical forms of severe falciparum malaria and HbS, HbC, and -alpha.
  
  
  METHODS
  Case-control study of 2591 children with severe falciparum malaria enrolled at a tertiary referral center in Ghana, West Africa, and 2048 age-, sex-, and ethnicity-matched control participants recruited by community surveys.
  
  
  METHODS
  Frequencies of HbS, HbC, and -alpha in patients and controls, including stratifications of patients for signs of disease.
  
  
  RESULTS
  Patients presented with partly overlapping signs of disease, including severe anemia (64%), cerebral malaria (22%), respiratory distress (30%), hyperparasitemia (32%), prostration (52%), acidosis (59%), and hyperlactatemia (56%). Carrier states of HbS, HbC, and -alpha were found in 1.4%, 9.4%, and 25.2% of the patients, respectively, and 14.8%, 8.7%, and 27.3% of controls. The HbS carrier state was negatively associated with all forms of the disease studied (overall odds ratio [OR], 0.08; 95% confidence interval [CI], 0.06-0.12). The HbC carrier state showed a negative association selectively with cerebral malaria (OR, 0.64; 95% CI, 0.45-0.91), and the -alpha carrier state showed a negative association selectively with severe anemia (OR, 0.82; 95% CI, 0.69-0.96).
  
  
  CONCLUSIONS
  Whereas the HbS carrier state was found to be negatively associated with all major forms of severe falciparum malaria, the negative associations of the carrier states of HbC and -alpha appeared to be limited to cerebral malaria and severe anemia, respectively.
authors.affiliation: Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: May
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Evans
authors.forename: Christian
authors.initials: C
authors.lastname: Timmann
authors.forename: Christa
authors.initials: C
authors.lastname: Ehmen
authors.forename: Wibke
authors.initials: W
authors.lastname: Busch
authors.forename: Thorsten
authors.initials: T
authors.lastname: Thye
authors.forename: Tsiri
authors.initials: T
authors.lastname: Agbenyega
authors.forename: Rolf D
authors.initials: RD
authors.lastname: Horstmann
mesh_terms: D000740:Anemia / Q000097:blood / Q000209:etiology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D018450:Disease Progression; D005260:Female; D005869:Ghana; D005914:Globins / Q000032:analysis; D006444:Hemoglobin C / Q000032:analysis; D006447:Hemoglobin H / Q000032:analysis; D006451:Hemoglobin, Sickle / Q000032:analysis; D006455:Hemoglobins, Abnormal / Q000032:analysis*; D006801:Humans; D007223:Infant; D016779:Malaria, Cerebral / Q000097:blood; D016778:Malaria, Falciparum / Q000097:blood* / Q000503:physiopathology*; D008297:Male; D017085:alpha-Thalassemia
chemical_list: D006451:Hemoglobin, Sickle; D006455:Hemoglobins, Abnormal; D005914:Globins; D006444:Hemoglobin C; D006447:Hemoglobin H