title: Negative Epistasis between Sickle and Foetal Haemoglobin Suggests a Reduction in Protection against Malaria.
abstract: BACKGROUND
  Haemoglobin variants, Sickle (HbS) and foetal (HbF) have been associated with malaria protection. This study explores epistatic interactions between HbS and HbF on malaria infection.
  
  
  METHODS
  The study was conducted between March 2004 and December 2013 within the sickle cell disease (SCD) programme at Muhimbili National Hospital, Tanzania. SCD status was categorized into HbAA, HbAS and HbSS using hemoglobin electrophoresis and High Performance Liquid Chromatography (HPLC). HbF levels were determined by HPLC. Malaria was diagnosed using rapid diagnostic test and/or blood film. Logistic regression and generalized estimating equations models were used to evaluate associations between SCD status, HbF and malaria.
  
  
  RESULTS
  2,049 individuals with age range 0-70 years, HbAA 311(15.2%), HbAS 241(11.8%) and HbSS 1,497(73.1%) were analysed. At enrolment, malaria prevalence was significantly higher in HbAA 13.2% compared to HbAS 1.24% and HbSS 1.34% (p<0.001). Mean HbF was lower in those with malaria compared to those without malaria in HbAA (0.43% vs 0.82%) but was the reverse in HbSS (8.10% vs 5.59%). An increase in HbF was associated with a decrease in risk of malaria OR=0.50 (95%CI: 0.28, 0.90; p=0.021) in HbAA, whereas for HbSS the risk of malaria increased OR=2.94 (1.44, 5.98; p=0.003). A similar pattern was seen during multiple visits; HbAA OR=0.52 (0.34, 0.80; p=0.003) vs HbSS OR=2.01 (1.27, 3.23; p=0.003).
  
  
  CONCLUSIONS
  Higher prevalence of malaria in HbAA compared to HbAS and HbSS confirmed the protective effect of HbS. Lower prevalence of malaria in HbAA with high HbF supports a protective effect of HbF. However, in HbSS, the higher prevalence of malaria with high levels of HbF suggests loss of malaria protection. This is the first epidemiological study to suggest a negative epistasis between HbF and HbS on malaria.
authors.affiliation: Muhimbili University of Health and Allied Sciences, Dar-es-Salaam, Tanzania; National Institute for Medical Research, Tanga, Tanzania.
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Mmbando
authors.affiliation: Muhimbili University of Health and Allied Sciences, Dar-es-Salaam, Tanzania.
authors.forename: Josephine
authors.initials: J
authors.lastname: Mgaya
authors.affiliation: Muhimbili University of Health and Allied Sciences, Dar-es-Salaam, Tanzania; London School of Hygiene & Tropical Medicine, London, United Kingdom.
authors.forename: Sharon E
authors.initials: SE
authors.lastname: Cox
authors.affiliation: Muhimbili University of Health and Allied Sciences, Dar-es-Salaam, Tanzania.
authors.forename: Siana N
authors.initials: SN
authors.lastname: Mtatiro
authors.affiliation: Muhimbili University of Health and Allied Sciences, Dar-es-Salaam, Tanzania.
authors.forename: Deogratias
authors.initials: D
authors.lastname: Soka
authors.affiliation: Muhimbili National Hospital, Dar-es-Salaam, Tanzania.
authors.forename: Stella
authors.initials: S
authors.lastname: Rwezaula
authors.affiliation: Muhimbili National Hospital, Dar-es-Salaam, Tanzania.
authors.forename: Elineema
authors.initials: E
authors.lastname: Meda
authors.affiliation: Muhimbili University of Health and Allied Sciences, Dar-es-Salaam, Tanzania.
authors.forename: Evarist
authors.initials: E
authors.lastname: Msaki
authors.affiliation: KEMRI-Wellcome Trust Programme, Nairobi, Kenya; University of Oxford, Oxford, United Kingdom.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Snow
authors.affiliation: National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Neal
authors.initials: N
authors.lastname: Jeffries
authors.affiliation: National Heart, Lung, and Blood Institute (NHLBI), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Geller
authors.affiliation: Muhimbili University of Health and Allied Sciences, Dar-es-Salaam, Tanzania; University of Oxford, Oxford, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Makani
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000755:Anemia, Sickle Cell / Q000097:blood*; D002648:Child; D002675:Child, Preschool; D004843:Epistasis, Genetic; D005260:Female; D005319:Fetal Hemoglobin / Q000378:metabolism*; D006451:Hemoglobin, Sickle / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016015:Logistic Models; D008288:Malaria / Q000097:blood / Q000175:diagnosis* / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D013636:Tanzania / Q000453:epidemiology; D055815:Young Adult
chemical_list: D006451:Hemoglobin, Sickle; D005319:Fetal Hemoglobin