1. Genetic determinants of anti-malarial acquired immunity in a large multi-centre study
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Shelton, Jennifer MG, Corran, Patrick, Risley, Paul, Silva, Nilupa, Hubbart, Christina, Jeffreys, Anna, Rowlands, Kate, Craik, Rachel, Cornelius, Victoria, Hensmann, Meike, Molloy, Sile, Sepulveda, Nuno, Clark, Taane G, Band, Gavin, Clarke, Geraldine M, Spencer, Christopher CA, Kerasidou, Angeliki, Campino, Susana, Auburn, Sarah, Tall, Adama, Ly, Alioune Badara, Mercereau-Puijalon, Odile, Sakuntabhai, Anavaj, Djimdé, Abdoulaye, Maiga, Boubacar, Touré, Ousmane, Doumbo, Ogobara K, Dolo, Amagana, Troye-Blomberg, Marita, Mangano, Valentina D, Verra, Frederica, Modiano, David, Bougouma, Edith, Sirima, Sodiomon B, Ibrahim, Muntaser, Hussain, Ayman, Eid, Nahid, Elzein, Abier, Mohammed, Hiba, Elhassan, Ahmed, Elhassan, Ibrahim, Williams, Thomas N, Ndila, Carolyne, Macharia, Alexander, Marsh, Kevin, Manjurano, Alphaxard, Reyburn, Hugh, Lemnge, Martha, Ishengoma, Deus, Carter, Richard, Karunaweera, Nadira, Fernando, Deepika, Dewasurendra, Rajika, Drakeley, Christopher J, Riley, Eleanor M, Kwiatkowski, Dominic P, Rockett, Kirk A, MalariaGEN Consortium, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], London School of Hygiene and Tropical Medicine (LSHTM), National Institute for Biological Standards and Control (NIBSC), Medicines and Healthcare Products Regulatory Agency (MHRA), Nuffield Department of Population Health [Oxford], The Wellcome Trust Sanger Institute [Cambridge], Unité d'Epidémiologie des Maladies Infectieuses, Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Immunologie Moléculaire des Parasites, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Malaria Research and Training Center [Bamako, Mali], Université de Bamako, Stockholm University, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Centre National de Recherche et de Formation sur le Paludisme [Ouagadougou, Burkina Faso] (CNRFP), University of Khartoum, KEMRI-Wellcome Trust Research Programme (KWTRP), Tumaini University Makumira, National Institute for Medical Research [Tanzania] (NIMR), University of Edinburgh, University of Colombo [Sri Lanka], MalariaGEN is supported by the Wellcome Trust (077383/Z/05/Z) and by the Foundation for the National Institutes of Health (566) as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative. The Resource Centre for Genomic Epidemiology of Malaria is supported by the Wellcome Trust (090770/Z/09/Z). Support was also provided by the Medical Research Council (G0600718). DPK receives support from the Medical Research Council (G19/9). CCAS was supported by a Wellcome Trust Career Development Fellowship (097364/Z/11/Z). The Wellcome Trust also provides core awards to The Wellcome Trust Centre for Human Genetics (075491/Z/04, 090532/Z/09/Z) and the Wellcome Trust Sanger Institute (077012/Z/05/Z). MTB and BM received funding through the EU Network of Excellence EviMalar. VDM was funded by a Biomalpar (European Community’s Sixth Framework Programme) PhD fellowship. FV was funded by the Italian Malaria Network, sponsored by Compagnia di San Paolo, Turin, Italy. TNW is supported by a Senior Research Fellowship from the Wellcome Trust (091758/Z/10/Z). This study was conducted as part of the Joint Malaria Programme, a collaboration between the National Institute for Medical Research (NIMR), Kilimanjaro Christian Medical College (KCMC), the London School of Hygiene and Tropical Medicine (LSHTM) and the Centre for Medical Parasitology, University of Copenhagen (CMP) with funding from the UK Medical Research Council (GG9901439) and the Danish International Development Agency. CJD is supported by the Wellcome Trust (091924). RD is supported by the University of Colombo Research Grants 2011 (AP/3/2011/PG/15)., European Project: 26843,BIOMALPAR, University of Oxford, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)
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Male ,Hemoglobin, Sickle ,Antibodies, Protozoan ,Sickle ,MESH: Linear Models ,MESH: Child ,Child ,HbAS ,MESH: Infant, Newborn ,Antibody ,CD36 ,Genotype ,Malaria ,Sickle cell trait ,Adolescent ,Adult ,Africa South of the Sahara ,Child, Preschool ,Female ,Humans ,Infant ,Infant, Newborn ,Linear Models ,Sri Lanka ,Young Adult ,Infectious Diseases ,Parasitology ,MESH: Infant ,MESH: Young Adult ,Protozoan ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,MESH: Malaria ,Antibodies ,parasitic diseases ,MESH: Antibodies, Protozoan ,Hemoglobin ,MESH: Africa South of the Sahara ,Preschool ,MESH: Sri Lanka ,MESH: Adolescent ,MESH: Humans ,Research ,MESH: Child, Preschool ,MESH: Adult ,Newborn ,MESH: Hemoglobin, Sickle ,MESH: Male ,antibody ,cd36 ,genotype ,hbas ,malaria ,sickle cell trait ,infectious diseases ,parasitology ,[SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie ,MESH: Female - 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. Conclusion 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. Electronic supplementary material The online version of this article (doi:10.1186/s12936-015-0833-x) contains supplementary material, which is available to authorized users.
- Published
- 2015
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