title: Genetic determinants of anti-malarial acquired immunity in a large multi-centre study.
abstract: BACKGROUND
  Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels.
  
  
  METHODS
  Sera, DNA samples and clinical data were collected from 13,299 individuals from ten sites in Senegal, Mali, Burkina Faso, Sudan, Kenya, Tanzania, and Sri Lanka using standardized methods. DNA was extracted and typed for 202 Single Nucleotide Polymorphisms with known associations to malaria or antibody production, and antibody levels to four clinical grade malarial antigens [AMA1, MSP1, MSP2, and (NANP)4] plus total IgE were measured by ELISA techniques. Regression models were used to investigate the associations of clinical and genetic factors with antibody levels.
  
  
  RESULTS
  Malaria infection increased levels of antibodies to malaria antigens and, as expected, stable predictors of anti-malarial antibody levels included age, seasonality, location, and ethnicity. Correlations between antibodies to blood-stage antigens AMA1, MSP1 and MSP2 were higher between themselves than with antibodies to the (NANP)4 epitope of the pre-erythrocytic circumsporozoite protein, while there was little or no correlation with total IgE levels. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2.
  
  
  CONCLUSIONS
  Although the most significant finding with a consistent effect across sites was for sickle cell trait, its effect is likely to be via reducing a microscopically positive parasitaemia rather than directly on antibody levels. However, this study does demonstrate a framework for the feasibility of combining data from sites with heterogeneous malaria transmission levels across Africa and Asia with which to explore genetic effects on anti-malarial immunity.
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. jennifer.shelton@well.ox.ac.uk.
authors: Jennifer M G
authors: JM
authors: Shelton
authors: London School of Hygiene and Tropical Medicine, Keppel Street, London, UK. patrick.corran@lshtm.ac.uk.|National Institute for Biological Standards and Controls, South Mimms, Hertfordshire, UK. patrick.corran@lshtm.ac.uk.
authors: Patrick
authors: P
authors: Corran
authors: National Institute for Biological Standards and Controls, South Mimms, Hertfordshire, UK. Paul.Risley@nibsc.org.
authors: Paul
authors: P
authors: Risley
authors: National Institute for Biological Standards and Controls, South Mimms, Hertfordshire, UK. Nilupa.Silva@yahoo.co.uk.
authors: Nilupa
authors: N
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authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. christina.hubbart@well.ox.ac.uk.
authors: Christina
authors: C
authors: Hubbart
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. ajeffreys@well.ox.ac.uk.
authors: Anna
authors: A
authors: Jeffreys
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. kate.rowlands@well.ox.ac.uk.
authors: Kate
authors: K
authors: Rowlands
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. rachel.craik@obs-gyn.ox.ac.uk.
authors: Rachel
authors: R
authors: Craik
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. vikkic@well.ox.ac.uk.
authors: Victoria
authors: V
authors: Cornelius
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. mhensmann@gmail.com.
authors: Meike
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authors: Hensmann
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. sile20@hotmail.com.
authors: Sile
authors: S
authors: Molloy
authors: London School of Hygiene and Tropical Medicine, Keppel Street, London, UK. Nuno.Sepulveda@lshtm.ac.uk.
authors: Nuno
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authors: Sepulveda
authors: London School of Hygiene and Tropical Medicine, Keppel Street, London, UK. Taane.Clark@lshtm.ac.uk.
authors: Taane G
authors: TG
authors: Clark
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. gavin.band@well.ox.ac.uk.
authors: Gavin
authors: G
authors: Band
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. gclarke@well.ox.ac.uk.
authors: Geraldine M
authors: GM
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authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. spencer@well.ox.ac.uk.
authors: Christopher C A
authors: CC
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authors: Nuffield Department of Population Health, The Ethox Centre, University of Oxford, Richard Doll Building, Old Road Campus, Oxford, OX3 7LF, UK. angeliki@well.ox.ac.uk.
authors: Angeliki
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authors: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. Sc11@sanger.ac.uk.
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authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. Sarah.auburn@menzies.edu.au.
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authors: Infectious Diseases Epidemiology Unit, Institut Pasteur, BP 220, Dakar, Senegal. tall@pasteur.sn.
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authors: Alioune Badara
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authors: Odile
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authors: Unité de Génétique Fonctionnelle des Maladies Infectieuses, Institut Pasteur, 28 rue du Docteur Roux, 75724, Paris Cedex 15, France. anavaj.sakuntabhai@pasteur.fr.|Centre National de la Recherche Scientifique, URA3012, 28 rue du Docteur Roux, 75724, Paris Cedex 15, France. anavaj.sakuntabhai@pasteur.fr.
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authors: Djimdé
authors: Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy and Odonto-Stomatology, Malaria Research and Training Center, USTTB, BP 1805, Bamako, Mali. bmaiga@icermali.org.
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authors: Maiga
authors: Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy and Odonto-Stomatology, Malaria Research and Training Center, USTTB, BP 1805, Bamako, Mali. obtoure@gmail.com.
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authors: Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy and Odonto-Stomatology, Malaria Research and Training Center, USTTB, BP 1805, Bamako, Mali. okd@icermali.org.
authors: Ogobara K
authors: OK
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authors: Department of Epidemiology of Parasitic Diseases, Faculty of Medicine, Pharmacy and Odonto-Stomatology, Malaria Research and Training Center, USTTB, BP 1805, Bamako, Mali. adolo@icermali.org.
authors: Amagana
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authors: Marita
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authors: Troye-Blomberg
authors: Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy. valentina.mangano@uniroma1.it.
authors: Valentina D
authors: VD
authors: Mangano
authors: Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy. fverra66@gmail.com.
authors: Frederica
authors: F
authors: Verra
authors: Department of Public Health and Infectious Diseases, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185, Rome, Italy. david.modiano@uniroma1.it.
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authors: Institute of Endemic Diseases, University of Khartoum, Medical Sciences Campus, Qasser Street, Khartoum, Sudan. mibrahim@iend.org.
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authors: Institute of Endemic Diseases, University of Khartoum, Medical Sciences Campus, Qasser Street, Khartoum, Sudan. aymanhussain@gmail.com.
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authors: Institute of Endemic Diseases, University of Khartoum, Medical Sciences Campus, Qasser Street, Khartoum, Sudan. neid@iend.org.
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authors: Institute of Endemic Diseases, University of Khartoum, Medical Sciences Campus, Qasser Street, Khartoum, Sudan. abier_elzein@hotmail.com.
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authors: Institute of Endemic Diseases, University of Khartoum, Medical Sciences Campus, Qasser Street, Khartoum, Sudan. hmohammed@iend.org.
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authors: Institute of Endemic Diseases, University of Khartoum, Medical Sciences Campus, Qasser Street, Khartoum, Sudan. aelhassan@iend.org.
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authors: KEMRI-Wellcome Trust Research Programme, CGMRC, PO Box 230-80108, Kilifi, Kenya. tom.williams@imperial.ac.uk.|Department of Medicine, Imperial College, St Mary's Campus, Norfolk Place, London, W2 1PG, UK. tom.williams@imperial.ac.uk.
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authors: KEMRI-Wellcome Trust Research Programme, CGMRC, PO Box 230-80108, Kilifi, Kenya. cndila@gmail.com.
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authors: KEMRI-Wellcome Trust Research Programme, CGMRC, PO Box 230-80108, Kilifi, Kenya. amacharia@kemri-wellcome.org.
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authors: London School of Hygiene and Tropical Medicine, Keppel Street, London, UK. amanjurano@yahoo.co.uk.|Kilimanjaro Christian Medical College, Tumaini University, Moshi, Tanzania. amanjurano@yahoo.co.uk.
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authors: Manjurano
authors: London School of Hygiene and Tropical Medicine, Keppel Street, London, UK. Hugh.Reyburn@lshtm.ac.uk.|Kilimanjaro Christian Medical College, Tumaini University, Moshi, Tanzania. Hugh.Reyburn@lshtm.ac.uk.
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authors: National Institute for Medical Research, Ocean Road, Dar es Salaam, Tanzania. marthalemnge@yahoo.com.
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authors: National Institute for Medical Research, Ocean Road, Dar es Salaam, Tanzania. deusishe@yahoo.com.
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authors: Division of Biological Sciences, Ashworth Laboratories, University of Edinburgh, West Mains Rd., Edinburgh, EH9 3JT, UK. r.carter@ed.ac.uk.
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authors: Department of Parasitology, Faculty of Medicine, University of Colombo, Kynsey Road, Colombo, Sri Lanka. nadira@parasit.cmb.ac.lk.
authors: Nadira
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authors: Department of Parasitology, Faculty of Medicine, University of Colombo, Kynsey Road, Colombo, Sri Lanka. ferndeep@gmail.com.
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authors: Department of Parasitology, Faculty of Medicine, University of Colombo, Kynsey Road, Colombo, Sri Lanka. rdewasurendra@yahoo.com.
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authors: London School of Hygiene and Tropical Medicine, Keppel Street, London, UK. chris.drakeley@lshtm.ac.uk.|Kilimanjaro Christian Medical College, Tumaini University, Moshi, Tanzania. chris.drakeley@lshtm.ac.uk.
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authors: London School of Hygiene and Tropical Medicine, Keppel Street, London, UK. Eleanor.Riley@lshtm.ac.uk.|Kilimanjaro Christian Medical College, Tumaini University, Moshi, Tanzania. Eleanor.Riley@lshtm.ac.uk.
authors: Eleanor M
authors: EM
authors: Riley
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. dominic@well.ox.ac.uk.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. dominic@well.ox.ac.uk.
authors: Dominic P
authors: DP
authors: Kwiatkowski
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, UK. kirk.rockett@well.ox.ac.uk.|Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK. kirk.rockett@well.ox.ac.uk.
authors: Kirk A
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authors: Rockett
mesh_terms: D000293:Adolescent; D000328:Adult; D017954:Africa South of the Sahara / Q000453:epidemiology; D000913:Antibodies, Protozoan / Q000097:blood / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006451:Hemoglobin, Sickle / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016014:Linear Models; D008288:Malaria / Q000453:epidemiology* / Q000235:genetics* / Q000276:immunology*; D008297:Male; D013188:Sri Lanka / Q000453:epidemiology; D055815:Young Adult
chemical_list: D000913:Antibodies, Protozoan; D006451:Hemoglobin, Sickle; C028671:hemoglobin AS