A global network for investigating the genomic epidemiology of malaria

Achidi, Eric A.; Agbenyega, Tsiri; Allen, SJ; Amodu, Olukemi K.; Bojang, Kalifa; Conway, David J.; Corran, Patrick H.; Deloukas, Panos; Djimdé, Abdoulaye; Dolo, Amagana; Doumbo, Ogobara K.; Drakeley, Chris; Duffy, Patrick E.; Dunstan, Sarah J.; Evans, Jennifer; Farrar, Jeremy; Fernando, Deepika; Hien, Tran Tinh; Horstmann, Rolf D.; Ibrahim, Muntaser E.; Karunaweera, Nadira D.; Kokwaro, Gilbert; Koram, Kojo; Kwiatkowski, Dominic P.; Lemnge, Martha; Makani, Julie; Marsh, Kevin; Michon, P; Modiano, David; Molyneux, Malcolm E.; Müeller, Ivo; Mutabingwa, Theonest K.; Parker, Michael; Peshu, Norbert; Plowe, C V; Puijalon, Odile; Ragoussis, Jiannis; Reeder, John C.; Reyburn, Hugh; Riley, Eleanor M.; Rogers, Jane; Sakuntabhai, Anavaj; Singhasivanon, Pratap; Sirima, Sodiomon B.; Sirugo, Giorgio; Tall, Adama; Taylor, Terrie E.; Thera, Mahamadou A.; Troye‐Blomberg, Marita; Williams, Tom N.; Wilson, Michael D.; Amenga-Etego, Lucas; Apinjoh, Tobias O.; Bougouma, Edith C.; Dewasurendra, Rajika; Diakité, Mahamadou; Enimil, Anthony; Hussein, Ayman A.; Ishengoma, Deus S.; Jallow, Muminatou; Lin, Enmoore; Ly, Alioune Badara; Mangano, Valentina; Manjurano, Alphaxard; Manning, Laurens; Ndila, Carolyne; Nyirongo, Vysaul; Oluoch, Tom; Quyen, Nguyen Thi Ngoc; Suriyaphol, Prapat; Touré, O.; Rockett, Kirk A.; Vanderwal, Aaron; Clark, Taane G.; Wrigley, Rebecca; Alcock, Daniel; Auburn, Sarah; Barnwell, David E.; Bull, Susan; Campino, Susana; Vries, Jantina de; el-Zein, A; Evans, Julie; Fitzpatrick, Kathryn; Ghansah, Anita; Green, Angie; Hart, Lee; Hilton, Eliza; Hubbart, Christina; Hughes, C; Jeffreys, Anna E.; Kivinen, Katja; MacInnis, Bronwyn; Manske, Magnus; Maslen, G.; McCreight, Marilyn; Mendy, Alieu; Moyes, Catherine L.; Nyika, Aceme; Potter, Claire; Risley, Paul; Rowlands, Kate; SanJoaquin, Miguel; Small, Kerrin S.; Somaskantharajah, Elilan; Stevens, Marryat; Teo, Yik-Ying; Watson, Renee; Carucci, Dan; Cook, Katharine C.; Doyle, Alan; Duombo, Ogobara; Gottlieb, Michael

doi:10.1038/nature07632

Cited by 154 publications

(107 citation statements)

References 35 publications

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“…Individuals with severe P. falciparum malaria and population controls were recruited in Burkina Faso, Cameroon, The Gambia, Ghana, Kenya, Malawi, Mali, Nigeria, Tanzania, Vietnam and Papua New Guinea as described elsewhere (Malaria Genomic Epidemiology Network, 2008, 2014). After data curation and quality control, this analysis included 11,871 cases of severe malaria and 16,889 population controls.…”

Section: Resultsmentioning

confidence: 99%

Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

Clarke¹,

Rockett²,

Kivinen³

et al. 2017

eLife

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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effect has proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual’s level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations.DOI: http://dx.doi.org/10.7554/eLife.15085.001

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Section: Resultsmentioning

confidence: 99%

Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

Clarke¹,

Rockett²,

Kivinen³

et al. 2017

eLife

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“…The cooperative efforts of the partnerships in the Malaria Genomic Epidemiology Network (MalariaGEN) have created a panel of highly credible SNPs ascertained in the context of 1685 parasites, contributed from 17 countries, and we utilize this community resource here [11].…”

Section: Introductionmentioning

confidence: 99%

A Genome Wide Association Study of Plasmodium falciparum Susceptibility to 22 Antimalarial Drugs in Kenya

et al. 2014

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BackgroundDrug resistance remains a chief concern for malaria control. In order to determine the genetic markers of drug resistant parasites, we tested the genome-wide associations (GWA) of sequence-based genotypes from 35 Kenyan P. falciparum parasites with the activities of 22 antimalarial drugs.Methods and Principal FindingsParasites isolated from children with acute febrile malaria were adapted to culture, and sensitivity was determined by in vitro growth in the presence of anti-malarial drugs. Parasites were genotyped using whole genome sequencing techniques. Associations between 6250 single nucleotide polymorphisms (SNPs) and resistance to individual anti-malarial agents were determined, with false discovery rate adjustment for multiple hypothesis testing. We identified expected associations in the pfcrt region with chloroquine (CQ) activity, and other novel loci associated with amodiaquine, quinazoline, and quinine activities. Signals for CQ and primaquine (PQ) overlap in and around pfcrt, and interestingly the phenotypes are inversely related for these two drugs. We catalog the variation in dhfr, dhps, mdr1, nhe, and crt, including novel SNPs, and confirm the presence of a dhfr-164L quadruple mutant in coastal Kenya. Mutations implicated in sulfadoxine-pyrimethamine resistance are at or near fixation in this sample set.Conclusions/SignificanceSequence-based GWA studies are powerful tools for phenotypic association tests. Using this approach on falciparum parasites from coastal Kenya we identified known and previously unreported genes associated with phenotypic resistance to anti-malarial drugs, and observe in high-resolution haplotype visualizations a possible signature of an inverse selective relationship between CQ and PQ.

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“…Why only a small proportion (1–3%) of Plasmodium falciparum infections progress to severe or fatal episodes [2] while others remain asymptomatic or develop an uncomplicated illness is not yet fully understood. Epidemiological data indicate that about 25% of the risk to Plasmodium infection in Africa is determined by human genetic factors [3].…”

Section: Introductionmentioning

confidence: 99%

Association of candidate gene polymorphisms and TGF-beta/IL-10 levels with malaria in three regions of Cameroon: a case–control study

Apinjoh

Anchang-Kimbi

Njua-Yafi

et al. 2014

Malar J

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BackgroundPlasmodium falciparum malaria is one of the most widespread and deadliest infectious diseases in children under five years in endemic areas. The disease has been a strong force for evolutionary selection in the human genome, and uncovering the critical host genetic factors that confer resistance to the disease would provide clues to the molecular basis of protective immunity and improve vaccine development initiatives.MethodsThe effect of single nucleotide polymorphisms (SNPs) and plasma transforming growth factor beta (TGF-β) and interleukin 10 (IL-10) levels on malaria pathology was investigated in a case–control study of 1862 individuals from two major ethnic groups in three regions with intense perennial P. falciparum transmission in Cameroon. Thirty-four malaria candidate polymorphisms, including the sickle cell trait (HbS), were assayed on the Sequenom iPLEX platform while plasma TGF-β and IL-10 levels were measured by sandwich ELISA.ResultsThe study confirms the known protective effect of HbS against severe malaria and also reveals a protective effect of SNPs in the nitrogen oxide synthase 2 (NOS2) gene against malaria infection, anaemia and uncomplicated malaria. Furthermore, ADCY9 rs10775349 (additive G) and ABO rs8176746 AC individuals were associated with protection from hyperpyrexia and hyperparasitaemia, respectively. Meanwhile, individuals with the EMR1 rs373533 GT, EMR1 rs461645 CT and RTN3 rs542998 (additive C) genotypes were more susceptible to hyperpyrexia while both females and males with the rs1050828 and rs1050829 SNPs of G6PD, respectively, were more vulnerable to anaemia. Plasma TGF-β levels were strongly correlated with heterozygosity for the ADCY9 rs2230739 and HBB rs334 SNPs while individuals with the ABO rs8176746 AC genotype had lower IL-10 levels.ConclusionTaken together, this study suggests that some rare polymorphisms in candidate genes may have important implications for the susceptibility of Cameroonians to severe malaria. Moreover using the uncomplicated malaria phenotype may permit the identification of novel pathways in the early development of the disease.

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A global network for investigating the genomic epidemiology of malaria

Abstract: Large-scale studies of genomic variation could assist efforts to eliminate malaria.

Cited by 154 publications

References 35 publications

Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

A Genome Wide Association Study of Plasmodium falciparum Susceptibility to 22 Antimalarial Drugs in Kenya

Association of candidate gene polymorphisms and TGF-beta/IL-10 levels with malaria in three regions of Cameroon: a case–control study

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