title: Quantitative trait locus analysis of parasite density reveals that HbS gene carriage protects severe malaria patients against Plasmodium falciparum hyperparasitaemia.
abstract: BACKGROUND
  Haemoglobin S (HbS) is the gene known to confer the strongest advantage against malaria morbidity and mortality. Multiple HbS effects have been described resulting in protection against parasitaemia and reduction of severe malaria risk. This study aimed to explore HbS protection against severe malaria and Plasmodium falciparum parasitaemia in Angolan children exhibiting different severe malaria syndromes.
  
  
  METHODS
  A case-control study was designed with 430 malaria cases (n = 288 severe malaria and n = 142 uncomplicated malaria) and 319 uninfected controls, attending a central paediatric hospital in Luanda. Severe malaria syndromes were cerebral malaria (n = 130), severe malaria anaemia (n = 30) and hyperparasitaemia (n = 128). Quantitative trait locus analysis was carried out to study HbS association to parasite densities.
  
  
  RESULTS
  Previously reported HbS protection against severe malaria was confirmed in case-control analysis (P = 2 × 10(-13)) and corroborated by transmission disequilibrium test (P = 4 × 10(-3)). High parasite density protection conferred by HbS was detectable within severe malaria patients (P = 0.04). Stratifying severe malaria patients according parasite densities, it was found that HbS was highly associated to hyperparasitaemia protection (P = 1.9 × 10(-9)) but did not protect non-hyperparasitaemic children against severe malaria complications, namely cerebral malaria and severe malaria anaemia. Many studies have shown that HbS protects from severe malaria and controls parasite densities but the analysis further suggests that HbS protection against severe malaria syndromes was at a large extent correlated with control of parasitaemia levels.
  
  
  CONCLUSIONS
  This study supports the hypothesis that HbS confers resistance to hyperparasitaemia in patients exhibiting severe malaria syndromes and highlights that parasitaemia should be taken into account when evaluating HbS protection in severe malaria.
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal. rsambo@gmail.com.|Hospital Pediátrico David Bernardino, Luanda, Angola. rsambo@gmail.com.|Faculdade de Medicina, Universidade Agostinho Neto, Luanda, Angola. rsambo@gmail.com.
authors.forename: Maria Rosário
authors.initials: MR
authors.lastname: do Sambo
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal. cpenha@igc.gulbenkian.pt.
authors.forename: Carlos
authors.initials: C
authors.lastname: Penha-Gonçalves
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal. mjesus344@gmail.com.|Centro Nacional de Endemias, São Tomé, São Tomé and Príncipe. mjesus344@gmail.com.
authors.forename: Maria Jesus
authors.initials: MJ
authors.lastname: Trovoada
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal. jcosta@igc.gulbenkian.pt.
authors.forename: João
authors.initials: J
authors.lastname: Costa
authors.affiliation: Faculdade de Medicina, Universidade Katyavala Bwila, Benguela, Angola. lardgen72@yahoo.es.
authors.forename: Roberto
authors.initials: R
authors.lastname: Lardoeyt
authors.affiliation: Instituto Gulbenkian de Ciência, Oeiras, Portugal. coutinho@igc.gulbenkian.pt.
authors.forename: António
authors.initials: A
authors.lastname: Coutinho
mesh_terms: D000293:Adolescent; D000740:Anemia / Q000469:parasitology / Q000473:pathology; D000810:Angola; D000818:Animals; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D060467:Disease Resistance; D005260:Female; D006451:Hemoglobin, Sickle / Q000235:genetics*; D006801:Humans; D007223:Infant; D016779:Malaria, Cerebral / Q000469:parasitology / Q000473:pathology; D016778:Malaria, Falciparum / Q000235:genetics* / Q000469:parasitology* / Q000473:pathology; D008297:Male; D018512:Parasitemia / Q000235:genetics*; D040641:Quantitative Trait Loci
chemical_list: D006451:Hemoglobin, Sickle