Introduction

Consortial Project 1 investigated human genetic factors involved in resistance to severe malaria in order to better understand why, in regions where people are repeatedly exposed to malaria parasites, some people die from the infection while others survive.

Objectives & Coordination

Investigating the genetic determinants of resistance to malaria

A person’s risk of developing severe malaria is influenced by many different genetic and environmental factors, but we know relatively little about their precise nature and how they interact.

This project’s primary objective was to better understand the human genetic factors involved in resistance to severe malaria. This information could provide vital clues about molecular mechanisms of protective immunity and host-parasite interactions, as well as accelerate the development of an effective vaccine.

There are many aspects to our work:

• Leading research into the ethical issues inherit in these studies, for example informed consent, and data-sharing in low- and middle-income countries
• Working with our partner studies to support the necessary clinical research infrastructure to gather standardised samples from many thousands of individuals in several malaria-endemic countries in Africa
• Generating a large and unique data resource for case-control and family-based studies of genetic resistance and susceptibility to severe malaria
• Developing methods to overcome the unique challenges confronting multi-centre genome-wide association studies (GWAS) in Africa, for example higher levels of genetic diversity, ethnic diversity, and population structure in Africa than on other continents
• Supporting capacity building for genetic and genomic research amongst scientists in malaria-endemic countries.

This project began shortly after MalariaGEN was formed in 2005, and has greatly influenced our approach to collaborative science.

Locations

Across the different partner studies, samples were collected from 11,890 children and adults with severe P. falciparum malaria and 17,441 healthy controls matched with the cases by ethnic group, providing a unique resource for case-control and family-based studies.

Sampling locations

Burkina Faso, Cameroon, The Gambia, Ghana, Kenya, Malawi, Mali, Nigeria, Papua New Guinea, Tanzania, Vietnam.

Data

The MalariaGEN human consortial projects have produced substantial data resources and collectively agreed to a managed access mechanism for releasing Human GWAS data sets.

For information on how to apply for access, see Human GWAS data.

Current

Partner studies

We worked with investigators who pursued independent partner studies in a number of malaria-endemic countries.

Publications

• The protective effect of sickle cell haemoglobin against severe malaria depends on parasite genotype
  Gavin Band, Ellen M. Leffler, Muminatou Jallow, Fatoumatta Sisay-Joof, Carolyne M. Ndila, Alexander W. Macharia, Christina Hubbart, Anna E. Jeffreys, Kate Rowlands, Thuy Nguyen, Sónia Gonçalves, Cristina V. Ariani, Jim Stalker, Richard D. Pearson, Roberto Amato, Eleanor Drury, Giorgio Sirugo, Umberto d’Alessandro, Kalifa A. Bojang, Kevin Marsh, Norbert Peshu, Joseph W. Saelens, Mahamadou Diakité, Steve M. Taylor, David J. Conway, Thomas N. Williams, Kirk A. Rockett & Dominic P. Kwiatkowski
  Malaria protection due to sickle haemoglobin depends on parasite genotype, 2021;
  10.1038/s41586-021-04288-3
• Insights into malaria susceptibility using genome-wide data on 17,000 individuals from Africa, Asia and Oceania
  MalariaGEN
  Nature Communications, 2019; 10 5732
  10.1038/s41467-019-13480-z
• Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study
  Ndila CM, Uyoga S, Macharia AW, Nyutu G, Peshu N, Ojal J, Shebe M, Awuondo KO, Mturi N, Tsofa B, Sepulveda N, Clark TG, Band G, Clarke G, Rowlands K, Hubbart C, Jeffreys A, Kariuki S, Marsh K, Mackinnon M, Maitland K, Kwiatkowski DP, Rockett KA & Williams TN.
  The Lancet Haematology, 2018; 5
  10.1016/S2352-3026(18)30107-8
• Two complement receptor one alleles have opposing associations with cerebral malaria and interact with alpha(+)thalassaemia
  Opi DH, Swann O, Macharia A, Uyoga S, Band G, Ndila CM, Harrison EM, Thera MA, Kone AK, Diallo DA, Doumbo OK, lyke KE, Plowe CV, Moulds JM, Shebbe M, Mturi N, Peshu N, Maitland K, Raza A, Kwiatkowski DP, Rockett KA, Williams TN & Rowe JA.
  eLife, 2018; 7
  10.7554/eLife.31579
• Evidence from a natural experiment that malaria parasitemia is pathogenic in retinopathy-negative cerebral malaria
  Small, Taylor et al.
  eLife, 2017; 6 e2369
  10.7554/eLife.23699
• Malaria host candidate genes validated by association with current, recent and historic measures of transmission intensity
  Sepúlveda, Manjurano et al.
  The Journal of Infectious Diseases, 2017;
  10.1093/infdis/jix250
• Resistance to malaria through structural variation of red blood cell invasion receptors
  Leffler, Band et al.
  Science, 2017;
  10.1126/science.aam6393
• Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia
  Clarke, Rockett et al.
  eLife, 2017; 6 e15085
  10.7554/eLife.15085
• Admixture into and within sub-Saharan Africa
  Busby et al
  eLife, 2016; 5:e15266
  10.7554/eLife.15266
• A novel locus of resistance to severe malaria in a region of ancient balancing selection
  Malaria Genomic Epidemiology Network
  Nature, 2015; 526(7572) 253-257
  10.1038/nature15390
• USP38, FREM3, SDC1, DDC, and LOC727982 Gene Polymorphisms and Differential Susceptibility to Severe Malaria in Tanzania
  Manjurano et al.
  Journal of Infectious Diseases, 2015; 212(7) 1129-39
  10.1093/infdis/jiv192
• African glucose-6-phosphate dehydrogenase alleles associated with protection from severe malaria in heterozygous females in Tanzania
  Manjurano et al.
  PloS Genetics, 2015; 11(2) e1004960
  10.1371/journal.pgen.1004960
• Reappraisal of known malaria resistance loci in a large multi-centre study
  Rockett et al.
  Nature Genetics, 2014; 46(11) 1197-204
  10.1038/ng.3107
• Association of candidate gene polymorphisms and TGF-beta/IL-10 levels with malaria in three regions of Cameroon: a case-control study
  Apinjoh et al.
  Malaria Journal, 2014; 13 236
  10.1186/1475-2875-13-236
• Association of cytokine and Toll-like receptor gene polymorphisms with severe malaria in three regions of Cameroon
  Apinjoh et al.
  PLoS One, 2013; 8(11) e81071
  10.1371/journal.pone.0081071
• Imputation-based meta-analysis of severe malaria in three African populations
  Band et al.
  PloS Genetics, 2013; 9(5) e1003509
  10.1371/journal.pgen.1003509
• Candidate human genetic polymorphisms and severe malaria in a Tanzanian population
  Manjurano et al.
  PLoS One, 2012; 7(10) e47463
  10.1371/journal.pone.0047463
• Candidate polymorphisms and severe malaria in a Malian population
  Toure et al.
  PLoS One, 2012; 7(9) e43987
  10.1371/journal.pone.0043987
• Variation in human genes encoding adhesion and proinflammatory molecules are associated with severe malaria in the Vietnamese
  Dunstan et al.
  Genes Immunology, 2012; 13(6) 503-8
  10.1038/gene.2012.25
• Severe and uncomplicated falciparum malaria in children from three regions and three ethnic groups in Cameroon: prospective study
  Achidi et al.
  Malaria Journal, 2012; 11 215
  10.1186/1475-2875-11-215
• Variation in human genes encoding adhesion and proinflammatory molecules are associated with severe malaria in the Vietnamese
  Dunstan SJ et al
  Variation in human genes encoding adhesion and proinflammatory molecules are associated with severe malaria in the Vietnamese, 2012; 13(6) 503-8
  10.1038/gene.2012.25
• Genome-wide and fine-resolution association analysis of malaria in West Africa
  Jallow et al.
  Nature Genetics, 2009; 41(6) 657-65
  10.1038/ng.388
• A global network for investigating the genomic epidemiology of malaria
  Malaria Genomic Epidemiology Network
  Nature, 2008; 456(7223) 732-7
  10.1038/nature07632