Genetic polymorphisms linked to susceptibility to malaria
© Driss et al; licensee BioMed Central Ltd. 2011
Received: 16 May 2011
Accepted: 19 September 2011
Published: 19 September 2011
The influence of host genetics on susceptibility to Plasmodium falciparum malaria has been extensively studied over the past twenty years. It is now clear that malaria parasites have imposed strong selective forces on the human genome in endemic regions. Different genes have been identified that are associated with different malaria related phenotypes. Factors that promote severity of malaria include parasitaemia, parasite induced inflammation, anaemia and sequestration of parasitized erythrocytes in brain microvasculature.
Recent advances in human genome research technologies such as genome-wide association studies (GWAS) and fine genotyping tools have enabled the discovery of several genetic polymorphisms and biomarkers that warrant further study in host-parasite interactions. This review describes and discusses human gene polymorphisms identified thus far that have been shown to be associated with susceptibility or resistance to P. falciparum malaria. Although some polymorphisms play significant roles in susceptibility to malaria, several findings are inconclusive and contradictory and must be considered with caution. The discovery of genetic markers associated with different malaria phenotypes will help elucidate the pathophysiology of malaria and enable development of interventions or cures. Diversity in human populations as well as environmental effects can influence the clinical heterogeneity of malaria, thus warranting further investigations with a goal of developing new interventions, therapies and better management against malaria.
Introduction: severity of malaria is influenced by host genetics
Genetic mutations involved in susceptibility/resistance to P.falciparum malaria
Proposed protective mechanisms
↓UM & ↓SM
Reduced cyto-adherence of infected erythrocytes
Reduced erythrocyte invasion by merozoites, lower intra-erythrocytic parasite growth, and enhanced phagocytosis of infected erythrocytes.
↓UM & ↓SM
Selective sickling of infected sickle trait erythrocytes leading to enhanced clearance by the spleen. Reduced erythrocyte invasion, early phagocytosis, and inhibited parasite growth under oxygen stress in venous micro vessels. Enhancement of innate and acquired immunity.
↓SM & ↓SMA
Reduced resetting. Increased micro-erythrocyte count in homozygotes reduces the amount of haemoglobin lost for given parasite density, thus protecting against severe anaemia.
Glucose-6-Phosphate dehydrogenase (G6PD)
↓UM & ↓SM
Increased vulnerability of the G6PD deficient erythrocyte to oxidant stress causes its protection against parasitization.
Pyruvate kinase (PKLR)
Invasion defect of erythrocytes and preferential macrophage clearance of ring-stage-infected erythrocytes.
↓SM & ↓CM
Inhibition of merozoite entry into the red cell, impairment of intracellular parasite growth and prevention of the erythrocyte lysis that occurs with parasite maturation, leading to release of merozoites into the blood stream.
Glycophorins A (GYP ABC)
Reduced P. falciparum rosetting.
Oxidative damage to uninfected cells might be more marked in HP polymorphic individuals since HP proteins bind less efficiently to Hb, increasing premature destruction of erythrocytes and stimulating cytokine release by these circulating cells.
Nitric oxide synthase 2
Increased NO production induces Th1 cytokines which activate macrophages and could thus be an anti-malarial resistance mechanism.
haem oxygenase I (HO-1)
Release of free haem in the blood stream.
Gene mutations involved in susceptibility and resistance to P. falciparum malaria
It has been shown that severity of several malaria infections (such as asymptomatic, CM and SMA) varies significantly between individuals and between populations . Several gene mutations causing inherited diseases or traits have been reported to influence malaria severity (Table 1) . Mutations in these genes have been linked to erythrocytes including haemoglobin (Hb) variants, or related to proteins such as haptoglobin and Nitric Oxide metabolism. For example, the heterozygote HbAS (sickle cell trait) which protects against severe malaria (SM) [7–10] is widespread in malaria endemic regions as a result of natural selection over generations . It has also been shown that the rate limiting enzyme haem oxygenase I (HO-1), responsible for the catabolism of free haem in the body, plays an important moderator role in malaria and is also important in the pathophysiology of haemolytic diseases, such as sickle cell disease [12–15]. Epistatic interactions between genetic disorders of haemoglobin (HbAS, thalassaemia, HbE, etc.) show evidence of heterozygote protection from malaria (Table 1)  and protection against malaria by the sickle cell trait is removed if there is co-inheritance of alpha-thalassaemia . These studies emphasize the underlying complexity of the field and therefore stress the need for newer methods of genomic analysis. Although malaria resistance gene mutations have been well studied, genes associated with red cell disease severity deserve further scrutiny.
Genome-wide linkage and association studies in malaria
Some landmark genome wide linkage (GWL) and association studies (GWAS) have been conducted in recent years in African, European, Asian European and Asian populations. Application of GWAS to populations in Africa could provide insights into pathways controlling resistance to malaria as well as genetic origins of related diseases.
A GW gene expression study conducted by Griffiths et al showed that a cluster of genes were expressed in correlation with absolute neutrophil count. The neutrophil-related gene region contained genes predicted to encode mediators of innate and adaptive immunity, including those for cytokine receptors (IL1R2, IL18R1, and IL6R), Toll-like receptors (TLR1 and TLR4), heat-shock proteins (HSPA1A and HSPA1L), the acute-phase proteins ferritin (FTL) and alkaline phoshatase (ALPL), and intracellular signaling factors (NFKBIA, JUNB, and FOSL2). The region also contained genes linked with neutrophil activation, such as those for grancalcin (GCA), a degranulation marker (CD66), and MAPK14 kinase. Many other genes, whose transcript levels were previously noted in human leukocyte models of in vitro bacterial infection, were also present (e.g., those for adrenomedullin, pre-B cell colony enhancing factor, and tumor necrosis factor-associated inducible protein) . Based on changes in expression patterns of these genes, febrile and convalescent children could be assigned to distinct groups, indicating that neutrophil response plays a role in acute malarial infection. A second gene cluster was found to be associated with parasite density such that children with malaria could be distinguished from non-malaria patients, on the basis of different expression profiles. The cluster included genes encoding for pro-inflammatory molecules, markers of cellular stress and pro-apoptotic mediators . Results also identified host gene responses (HMOX1, HSPCB, and TNFRSF6) that were related to the level of plasmodium parasitaemia. These studies identified several interesting candidate genes for further association studies to determine their roles in malarial immunity and pathogenesis.
GW linkage analyses of malaria infection severity revealed significant linkages to chromosome 10p15.3-14 and chromosome 13q . Despite previous convincing results, no evidence of linkage was obtained for the 5q31 region to parasite density. Interestingly, a weak signal of linkage was observed for this region to malarial anaemia. The authors emphasized the difficulty of accurately defining the phenotype of malaria infection that could partially explain the divergence of linkage results .
Another GW linkage screening was carried out in a longitudinal survey of parasitological and clinical data from two independent Senegalese villages, Dielmo and Ndiop, that differ in ethnicity, malaria transmission and endemicity . Analysis of several malaria-related phenotypes both during clinical disease and asymptomatic infection showed evidence of strong genetic contribution to both phenotypes studied. Asymptomatic parasite density showed linkage to chromosome 5q31, confirming previous findings . Suggestive linkage values were also obtained: episodes of clinical malaria disease were linked to chromosome 5p15 and 13q13, while the maximum parasite density during asymptomatic infection was linked to chromosome 12q21. While regions of linkage showed little overlap with genes known to be involved in SM, the four regions appeared to overlap with regions linked to asthma or atopy related traits, suggesting that common immune related pathways may be involved. These newly identified linkage regions are interesting, but will require validation by independent studies. Also, fine mapped association studies are required to identify the genes underlying these linkages . Ockenhouse et al investigated aspects of the earliest responses to malaria infection at the molecular level, and suggested an important role of innate and adaptive immune responses in different stages of infection .
Several inter-ethnic comparative studies showed that the Fulani population from West Africa is more resistant to P. falciparum malaria than are other sympatric ethnic groups . The analysis of the immune response to P. falciparum sporozoite and blood stage antigens, as well as non-malaria antigens, revealed higher immune reactivity in the Fulani and that higher resistance to malaria among them could derive from a functional deficit of T-regulatory cells . In this study, the results suggest that T-regulatory cell activity could be central in the control of malaria infection also in populations exposed to naturally high P. falciparum transmission. Furthermore, this study highlights the existence of clear-cut differences in strategic pathways of the immunoregulatory network between sympatric populations differing in their genetic background and degree of susceptibility to malaria. A higher resistance against P. falciparum malaria could have been the driving selective force of this disorder.
Jallow et al conducted a GWAS of SM in 2,500 children from The Gambia, which was replicated in an additional 3,400 children . Besides the considerable population stratification found, their result show that signals of association at known malaria resistance loci were greatly attenuated due to weak linkage disequilibrium (LD). Conversely, the GW association analysis did not identify any of the well-known erythrocyte variants that have been selected by malaria, other than HbS. They explained this partly by population genetic factors; for example, the Duffy FY*O allele has reached fixation in The Gambia, whereas other variants, such as those affecting haemoglobin C and Southeast Asian ovalocytosis, are rare or absent in this population. No associations were found at G6PD and HBA1-HBA2, the loci for glucose-6-phosphate deficiency and β+-thalassaemia, respectively, possibly due to the lack of fine mapping of the SNPs (single nucleotide polymorphisms) dataset within these regions. The group genotyped the SNP rs1050828, a G6PD coding polymorphism, that was suggested to be a marker for protection against SM . The minor allele frequency of rs1050828 in the Gambian control sample was 0.03, considerably lower than for samples from Kenya (0.18) and Malawi (0.19) . The power to detect association with rs1050828 in The Gambia was affected by this low allele frequency, and the results were consistent with a modest protective effect although not statistically significant.
The rs8176719 genotype (a splice-site insertion in the ABO gene) is consistent with previous studies, which found that individuals of different populations who are not of blood group O, have 1.2-fold increased risk of SM . Other SNP associations (on CD36, CD40LG, CR1, ICAM1, IL22, NOS2, and TNF) have been reported for malaria, but have not been conclusively replicated in large studies across different populations, and are mostly thought to be markers rather than true causal variants. The authors attribute this in part to low tagging efficiency of the Affymetrix 500 K array used and low statistical power, particularly low allele frequencies. In addition, they identified several significant association regions other than HBB (Hb-beta locus): on chromosome 2q37 (with the closest genes SPATA3, LOC257407, PSMD1 and GPR55), on chromosome 5p12 (in a region that has a number of genes encoding proteins of unknown function) and on chromosome 14q21 (in an area with few genes) . Further investigations are needed to prove that polymorphisms in these genes significantly affect malaria outcomes.
Gene polymorphisms associated with protection against P. falciparum malaria
Recently published polymorphisms that are significantly associated with susceptibility and resistance to P. falciparum malaria are summarized in additional file 1. The large majority of the polymorphisms found in these reports were mainly genes directly or indirectly involved with host immunity, including human leukocyte antigen system (HLA) genes, cytokine genes, complement regulatory genes and endothelial receptor genes. These polymorphisms do not cause host genetic pathology themselves, but are associated with malaria severity. A description of the function of their corresponding gene products is summarized in Additional file 2.
Although malaria remains a devastating disease responsible for high global mortalities, only few association studies have been reported on malaria phenotypes and polymorphisms of candidate loci. It is well established that in some cases as in haemoglobinopathies, despite the lack of a consensus on the mechanism of protection, the actual protective role has been identified and solid epidemiological evidence has been reported (Table 1). However, much information remains to be obtained for many genes related to the red cell surface, oxidative stress, cyto-adherence and immune response associated with malaria. In fact, only a few of the associations reviewed in Additional file 1 have been tested in independent studies in different populations and even when replication has been attempted, results have often been conflicting; either the initial finding could not be replicated or a polymorphism initially associated with increased risk of SM in a study was associated with protection against SM in another study. Finally, in some instances the genotypic and/or haplotypic patterns of association varied across different studies/populations (Additional file 1). These inconsistencies can be explained in several ways:
Sample size and source
It has been established that GW screening conducted on large sample sizes and in multiple populations have greater potential to be more informative. Sometimes, the lack of association can be a false negative result due to lack of statistical power. Another difficulty is that in most cases, when population based phenotype-genotype relationships are studied, it is assumed that the population is genetically isolated. The extensive genomic diversity within Africa and across different continents complicates the situation. Association signals for a genotyped variant could show different patterns in different populations, due to local variation in haplotype structure and linkage disequilibrium architecture. Furthermore, it is important to emphasize that the genetic basis of susceptibility/resistance to malaria is due to a broad range of susceptibility/protective genes, each resulting in small population effects, which may be missed at low analytical power, such as low allele frequencies. In both cases, the use of larger sample sizes would certainly be of great value.
Population substructure and/or admixture
Inconsistency of results may also be due to issues of population structure and/or admixture . This is particularly true in African populations, where genetic diversity is exceptionally high. Studies on the same population but in different areas (endemic versus non-endemic regions) have revealed differences in host response to P. falciparum. There is also the possible impact of variation in environment (climate, nutritional status) which results in variation of pathogen epidemiology and which becomes more relevant in the rapidly changing socio-economic forces impacting these populations. Furthermore, the lesson learned about genetics of haemoglobinopathies illustrates how distinct malaria resistant alleles have emerged in different populations due to selective pressure, with HbS being found much more endemic in Africa (on four distinct haplotypes) than in Asia, and the opposite for HbE, or again with the relative prevalence of HbS and HbC varying greatly between neighboring countries and even villages . Fine mapping of GW SNP studies in several different populations, and re-confirmed sequencing of regions of special interest, could provide accurate representations of the genetic background and, therefore, a more effective interpretation of association results.
Variation in sampling methodology
Another very important cause of discrepancy is the way severity of malaria is defined. Each of the reported studies classifies malaria severity on the basis of different criteria and thus a common unified and systematic international classification is absolutely needed. This must be considered when studying a large number of individuals across geographical populations. Factors like age may have an important effect on results. Studies that have both children and adults will yield very different results from those involving only adults. The setting where samples are collected may also impact results (urban vs. rural, hospital/clinic based vs. population random cluster sampling).
The establishment of a well-characterized tissue repository with accompanying databases and a robust data-sharing plan would be of great benefit for standardizing phenotype definition, genotyping technology, experimental and analytical plans across multiple sites, to improve the power of the GW studies and ensure reproducibility of the results.
A major driving force in this field of research has been the recent availability of the genome variations data and other information free on line. Databases like dbSNP and Nucleotide, Genome and Entrez and PubMed among others have helped scientists around the world, especially in Africa, to obtain uniform data on host genetics and infectious diseases. Another factor is the benefit of using high throughput technologies and automated microarrays that can screen whole genomes simultaneously. This kind of costly research will only be possible if serious, consistent and strong collaborative effort is encouraged. Infrastructure to conduct case-controlled GW and multi-centre association studies on malaria susceptibility and resistance must be established where the disease in endemic. Such important studies are very necessary and will provide new insights into the effects of genetic variation on malaria susceptibility and on molecular mechanisms for protective immune responses . However, some studies using these technologies missed some of the significant associations unequivocally determined by classical genetics  and the role of regions of the genome involved in malaria resistance, such as alpha-thalassaemia or G6PD deficiency was missed. This raises doubts about the sensitivity of the approach employed. The major limiting factor, at all stages of GW association analysis in Africa, is the need for population-specific data on genome sequence variation. In the near future, this limiting factor should be overcome by advances in genome sequencing technologies, through initiatives such as the 1000 Genomes Project.
Sensitivity of methods
Until GW studies picked up sickle cell trait as a bench mark reference protective factor, utility of these studies in understanding genes associated with malaria severity continues to be limited to identifying only broad associations within the genome. It will be beneficial to use sickle cell trait to assess the power of GWAS. There is also a need for associating gene polymorphism to expressed protein variants using sensitive immunoassay procedures that could identify clusters of biomarker proteins associated with susceptibility and severity of malaria. This approach could be used to establish panels for predicting potentially fatal malaria. Multiplex immunoassay procedures and proteomic technologies should be combined with GWAS and new diagnostics for detecting susceptibility to fatal disease . For example, recent human and murine gene knock out studies suggest that plasma levels of Interferon inducible protein 10 (IP-10; CXCL10) , soluble TNF receptor 2 (sTNF-R2)  and soluble Fas (sFas)  predict risk of malaria related mortality and may be potential biomarkers of CM severity. Additionally, angiogenic factors such as vascular endothelial growth factor (VEGF) were found to be protective against CM associated mortality and may be considered for adjunctive therapy, to improve treatment outcomes in CM patients . Other potential biomarker candidates are interleukin-10 (IL10) and the Granulocyte colony-stimulating factor (G-CSF), cytokines which are associated with susceptibility to asymptomatic malaria during pregnancy . Another recent study has suggested a prominent role for CXCL4 and CXCL10 in the pathogenesis of fatal CM . Clearly, assessment of polymorphisms associated with these significant risk factors or prognostic biomarkers could predict fatal disease outcomes and must be investigated in malaria endemic population. Recent studies have implicated several other genes in the pathogenesis of SMA, CM and placental malarial. It is very important to determine if any gene polymorphisms are associated with these candidate genes.
The Macrophage migration inhibitory factor (MIF) has also been suggested to have a protective role in pathogenesis of malaria . MIF is a multifunctional cytokine which is an important regulator of immune and inflammatory responses in a number of human diseases, such as sepsis, rheumatoid arthritis, cancer and inflammatory neurological diseases . The potential role of MIF in the pathogenesis of malaria anaemia became apparent in an experimental study using a mouse model in which high MIF levels were associated with malaria anaemia . Human studies conducted on African children reported lower levels of MIF in malaria infected children compared with healthy asymptomatic children . Another study demonstrated a decline in MIF levels during experimental malaria infection using healthy European volunteers . The role of circulating MIF, gene polymorphisms as well as potential interactions with other factors in the pathogenesis of CM and its outcome, need to be further investigated.
Role of co-infection in hosts
Several gene pathways reported here are also involved in host responses to bacterial infection. However, caution must be exercised when defining severity phenotype. For example, in high transmission areas most children will have asymptomatic carriage of parasites in their blood such that any acute illness may be ascribed to malaria. It is becoming clear that many of these children carry bacterial sepsis along with the malaria . It will, therefore, be necessary to check for bacterial infection to exclude combined effects during recruitment of volunteer participants in case control studies. Another important factor is to determine whether individual patients have multiple Plasmodium infections since each species may present different etiologies. For example, it would be very interesting to determine host factors mediating susceptibility to Plasmodium vivax malaria, which is fast becoming recognized as a major cause of SM in Southeast Asia and elsewhere [44, 45].
Gene polymorphisms associated with multiple diseases
A recent review of gene polymorphisms involved in different phenotypes of sickle cell disease  revealed that many genes or pathways mediating sickle cell disease severity are also involved in malaria severity/resistance. For example, the TNFα (-308A, rs1800629) polymorphism, which reduces SM, CM, SMA and iron deficiency anaemia, is also protective against large vessel stroke in sickle cell disease. Findings such as these, which reveal genetic similarities across related diseases, will be valuable for identifying important diagnostic biomarkers and for population comparisons.
It is clear that genetically-based alterations conferring protection against malaria have led to co-adaptation of various human populations with widespread malaria parasites. This co-adaptative process has resulted in benefits for host (protection) and parasite (reduced virulence/chronicity). A global collaborative effort or consortium must be made to collect information about involvements of biomarkers in malaria susceptibility. This collaboration should include phenotype and clinical data as well as genomics, proteomics, metabolomics and parasitomics. GW research on protective polymorphisms against malaria will lead to better understanding of the mechanisms underlying malaria severity, which can be used in developing novel therapeutic solutions.
List of abbreviations
severe malaria anaemia
Haemoglobin AS or sickle cell trait
human leukocyte antigen system
genome wide linkage
genome wide association studies
Single Nucleotide Polymorphism
Acknowledgements and Funding
Major support for the biomedical research infrastructure at Morehouse School of Medicine is provided through the Research Centers at Minority Institutions (RCMI) Program, which is sponsored by the National Centers for Research Resources (NCRR) at the National Institutes of Health. Biomedical research technology cores, shared-use facilities, and other resources at MSM have been developed with RCMI funds for use by all MSM scientific investigators. Support from the NIH/Fogarty International Center (FIC) postdoctoral training grant in Genomics and Hemoglobinopathies (NIH-FIC-1R90-G004151-01) and NIH-RCMI (RR033062) are greatly appreciated.
- Snow RW, Guerra CA, Noor AM, Myint HY, Hay SI: The global distribution of clinical episodes of Plasmodium falciparum malaria. Nature. 2005, 434: 214-217. 10.1038/nature03342.PubMed CentralPubMedGoogle Scholar
- Mackinnon MJ, Mwangi TW, Snow RW, Marsh K, Williams TN: Heritability of malaria in Africa. PLoS Med. 2005, 2: e340-10.1371/journal.pmed.0020340.PubMed CentralPubMedGoogle Scholar
- Weatherall DJ, Clegg JB: Genetic variability in response to infection: malaria and after. Genes Immun. 2002, 3: 331-337. 10.1038/sj.gene.6363878.PubMedGoogle Scholar
- Hill AV: The immunogenetics of resistance to malaria. Proc Assoc Am Physicians. 1999, 111: 272-277. 10.1046/j.1525-1381.1999.99234.x.PubMedGoogle Scholar
- Greenwood B, Marsh K, Snow R: Why do some African children develop severe malaria?. Parasitol Today. 1991, 7: 277-281. 10.1016/0169-4758(91)90096-7.PubMedGoogle Scholar
- Verra F, Mangano VD, Modiano D: Genetics of susceptibility to Plasmodium falciparum: from classical malaria resistance genes towards genome-wide association studies. Parasite Immunol. 2009, 31: 234-253. 10.1111/j.1365-3024.2009.01106.x.PubMedGoogle Scholar
- Allison AC: Protection afforded by sickle-cell trait against subtertian malareal infection. BMJ. 1954, 1: 290-294. 10.1136/bmj.1.4857.290.PubMed CentralPubMedGoogle Scholar
- Aidoo M, Terlouw DJ, Kolczak MS, McElroy PD, ter Kuile FO, Kariuki S, Nahlen BL, Lal AA, Udhayakumar V: Protective effects of the sickle cell gene against malaria morbidity and mortality. Lancet. 2002, 359: 1311-1312. 10.1016/S0140-6736(02)08273-9.PubMedGoogle Scholar
- Allen SJ, Bennett S, Riley EM, Rowe PA, Jakobsen PH, O'Donnell A, Greenwood BM: Morbidity from malaria and immune responses to defined Plasmodium falciparum antigens in children with sickle cell trait in The Gambia. Trans R Soc Trop Med Hyg. 1992, 86: 494-498. 10.1016/0035-9203(92)90083-O.PubMedGoogle Scholar
- Le Hesran JY, Personne I, Personne P, Fievet N, Dubois B, Beyeme M, Boudin C, Cot M, Deloron P: Longitudinal study of Plasmodium falciparum infection and immune responses in infants with or without the sickle cell trait. Int J Epidemiol. 1999, 28: 793-798. 10.1093/ije/28.4.793.PubMedGoogle Scholar
- Livingstone FB: Simulation of the diffusion of the beta-globin variants in the Old World. Hum Biol. 1989, 61: 297-309.PubMedGoogle Scholar
- Kuesap J, Hirayama K, Kikuchi M, Ruangweerayut R, Na-Bangchang K: Study on association between genetic polymorphisms of haem oxygenase-1, tumour necrosis factor, cadmium exposure and malaria pathogenicity and severity. Malar J. 9: 260-
- Garcia-Santos D, Chies JA: HO-1 polymorphism as a genetic determinant behind the malaria resistance afforded by haemolytic disorders. Med Hypotheses. 2010, 74: 807-813. 10.1016/j.mehy.2009.12.010.PubMedGoogle Scholar
- Pamplona A, Ferreira A, Balla J, Jeney V, Balla G, Epiphanio S, Chora A, Rodrigues CD, Gregoire IP, Cunha-Rodrigues M, Portugal S, Soares MP, Mota MM: Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria. Nat Med. 2007, 13: 703-710. 10.1038/nm1586.PubMedGoogle Scholar
- Sambo MR, Trovoada MJ, Benchimol C, Quinhentos V, Goncalves L, Velosa R, Marques MI, Sepulveda N, Clark TG, Mustafa S, Wagner O, Coutinho A, Penha-Goncalves C: Transforming growth factor beta 2 and heme oxygenase 1 genes are risk factors for the cerebral malaria syndrome in Angolan children. PLoS One. 5: e11141-
- Penman BS, Pybus OG, Weatherall DJ, Gupta S: Epistatic interactions between genetic disorders of hemoglobin can explain why the sickle-cell gene is uncommon in the Mediterranean. Proc Natl Acad Sci USA. 2009, 106: 21242-21246. 10.1073/pnas.0910840106.PubMed CentralPubMedGoogle Scholar
- Williams TN, Mwangi TW, Wambua S, Peto TE, Weatherall DJ, Gupta S, Recker M, Penman BS, Uyoga S, Macharia A, Mwacharo JK, Snow RW, Marsh K: Negative epistasis between the malaria-protective effects of alpha+-thalassemia and the sickle cell trait. Nat Genet. 2005, 37: 1253-1257. 10.1038/ng1660.PubMed CentralPubMedGoogle Scholar
- Griffiths MJ, Shafi MJ, Popper SJ, Hemingway CA, Kortok MM, Wathen A, Rockett KA, Mott R, Levin M, Newton CR, Marsh K, Relman DA, Kwiatkowski DP: Genomewide analysis of the host response to malaria in Kenyan children. J Infect Dis. 2005, 191: 1599-1611. 10.1086/429297.PubMedGoogle Scholar
- Timmann C, Evans JA, Konig IR, Kleensang A, Ruschendorf F, Lenzen J, Sievertsen J, Becker C, Enuameh Y, Kwakye KO, Opoku E, Browne EN, Ziegler A, Nurnberg P, Horstmann RD: Genome-wide linkage analysis of malaria infection intensity and mild disease. PLoS Genet. 2007, 3: e48-10.1371/journal.pgen.0030048.PubMed CentralPubMedGoogle Scholar
- Rihet P, Traore Y, Abel L, Aucan C, Traore-Leroux T, Fumoux F: Malaria in humans: Plasmodium falciparum blood infection levels are linked to chromosome 5q31-q33. Am J Hum Genet. 1998, 63: 498-505. 10.1086/301967.PubMed CentralPubMedGoogle Scholar
- Sakuntabhai A, Ndiaye R, Casademont I, Peerapittayamongkol C, Rogier C, Tortevoye P, Tall A, Paul R, Turbpaiboon C, Phimpraphi W, Trape JF, Spiegel A, Heath S, Mercereau-Puijalon O, Dieye A, Julier C: Genetic determination and linkage mapping of Plasmodium falciparum malaria related traits in Senegal. PLoS One. 2008, 3: e2000-10.1371/journal.pone.0002000.PubMed CentralPubMedGoogle Scholar
- Ockenhouse CF, Hu WC, Kester KE, Cummings JF, Stewart A, Heppner DG, Jedlicka AE, Scott AL, Wolfe ND, Vahey M, Burke DS: Common and divergent immune response signaling pathways discovered in peripheral blood mononuclear cell gene expression patterns in presymptomatic and clinically apparent malaria. Infect Immun. 2006, 74: 5561-5573. 10.1128/IAI.00408-06.PubMed CentralPubMedGoogle Scholar
- Torcia MG, Santarlasci V, Cosmi L, Clemente A, Maggi L, Mangano VD, Verra F, Bancone G, Nebie I, Sirima BS, Liotta F, Frosali F, Angeli R, Severini C, Sannella AR, Bonini P, Lucibello M, Maggi E, Garaci E, Coluzzi M, Cozzolino F, Annunziato F, Romagnani S, Modiano D: Functional deficit of T regulatory cells in Fulani, an ethnic group with low susceptibility to Plasmodium falciparum malaria. Proc Natl Acad Sci USA. 2008, 105: 646-651. 10.1073/pnas.0709969105.PubMed CentralPubMedGoogle Scholar
- Jallow M, Teo YY, Small KS, Rockett KA, Deloukas P, Clark TG, Kivinen K, Bojang KA, Conway DJ, Pinder M, Sirugo G, Sisay-Joof F, Usen S, Auburn S, Bumpstead SJ, Campino S, Coffey A, Dunham A, Fry AE, Green A, Gwilliam R, Hunt SE, Inouye M, Jeffreys AE, Mendy A, Palotie A, Potter S, Ragoussis J, Rogers J, Rowlands K, Somaskantharajah E, Whittaker P, Widden C, Donnelly P, Howie B, Marchini J, Morris A, Sanjoaquin M, Achidi EA, Agbenyega T, Allen A, Amodu O, Corran P, Djimde A, Dolo A, Doumbo OK, Drakeley C, Dunstan S, Evans J, Farrar J, Fernando D, Hien TT, Horstmann RD, Ibrahim M, Karunaweera N, Kokwaro G, Koram KA, Lemnge M, Makani J, Marsh K, Michon P, Modiano D, Molyneux ME, Mueller I, Parker M, Peshu N, Plowe CV, Puijalon O, Reeder J, Reyburn H, Riley EM, Sakuntabhai A, Singhasivanon P, Sirima S, Tall A, Taylor TE, Thera M, Troye-Blomberg M, Williams TN, Wilson M, Kwiatkowski DP, Wellcome Trust Case Control C, Malaria Genomic Epidemiology N: Genome-wide and fine-resolution association analysis of malaria in West Africa. Nat Genet. 2009, 41: 657-665. 10.1038/ng.388.PubMed CentralPubMedGoogle Scholar
- Guindo A, Fairhurst RM, Doumbo OK, Wellems TE, Diallo DA: X-linked G6PD deficiency protects hemizygous males but not heterozygous females against severe malaria. PLoS Med. 2007, 4: e66-10.1371/journal.pmed.0040066.PubMed CentralPubMedGoogle Scholar
- Fry AE, Griffiths MJ, Auburn S, Diakite M, Forton JT, Green A, Richardson A, Wilson J, Jallow M, Sisay-Joof F, Pinder M, Peshu N, Williams TN, Marsh K, Molyneux ME, Taylor TE, Rockett KA, Kwiatkowski DP: Common variation in the ABO glycosyltransferase is associated with susceptibility to severe Plasmodium falciparum malaria. Hum Mol Genet. 2008, 17: 567-576.PubMed CentralPubMedGoogle Scholar
- Marchini J, Cardon LR, Phillips MS, Donnelly P: The effects of human population structure on large genetic association studies. Nat Genet. 2004, 36: 512-517. 10.1038/ng1337.PubMedGoogle Scholar
- Sinha S, Mishra SK, Sharma S, Patibandla PK, Mallick PK, Sharma SK, Mohanty S, Pati SS, Mishra SK, Ramteke BK, Bhatt R, Joshi H, Dash AP, Ahuja RC, Awasthi S, Venkatesh V, Habib S: Polymorphisms of TNF-enhancer and gene for FcgammaRIIa correlate with the severity of falciparum malaria in the ethnically diverse Indian population. Malar J. 2008, 7: 13-10.1186/1475-2875-7-13.PubMed CentralPubMedGoogle Scholar
- Agarwal A, Guindo A, Cissoko Y, Taylor JG, Coulibaly D, Kone A, Kayentao K, Djimde A, Plowe CV, Doumbo O, Wellems TE, Diallo D: Hemoglobin C associated with protection from severe malaria in the Dogon of Mali, a West African population with a low prevalence of hemoglobin S. Blood. 2000, 96: 2358-2363.PubMedGoogle Scholar
- Kwiatkowski DP: How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet. 2005, 77: 171-192. 10.1086/432519.PubMed CentralPubMedGoogle Scholar
- Wilson NO, Huang MB, Anderson W, Bond V, Powell M, Thompson WE, Armah HB, Adjei AA, Gyasi R, Tettey Y, Stiles JK: Soluble factors from Plasmodium falciparum-infected erythrocytes induce apoptosis in human brain vascular endothelial and neuroglia cells. Mol Biochem Parasitol. 2008, 162: 172-176. 10.1016/j.molbiopara.2008.09.003.PubMed CentralPubMedGoogle Scholar
- Campanella GS, Tager AM, El Khoury JK, Thomas SY, Abrazinski TA, Manice LA, Colvin RA, Luster AD: Chemokine receptor CXCR3 and its ligands CXCL9 and CXCL10 are required for the development of murine cerebral malaria. Proc Natl Acad Sci USA. 2008, 105: 4814-4819. 10.1073/pnas.0801544105.PubMed CentralPubMedGoogle Scholar
- Lucas R, Juillard P, Decoster E, Redard M, Burger D, Donati Y, Giroud C, Monso-Hinard C, De Kesel T, Buurman WA, Moore MW, Dayer JM, Fiers W, Bluethmann H, Grau GE: Crucial role of tumor necrosis factor (TNF) receptor 2 and membrane-bound TNF in experimental cerebral malaria. Eur J Immunol. 1997, 27: 1719-1725. 10.1002/eji.1830270719.PubMedGoogle Scholar
- Potter SM, Chan-Ling T, Rosinova E, Ball HJ, Mitchell AJ, Hunt NH: A role for Fas-Fas ligand interactions during the late-stage neuropathological processes of experimental cerebral malaria. J Neuroimmunol. 2006, 173: 96-107. 10.1016/j.jneuroim.2005.12.004.PubMedGoogle Scholar
- Jain V, Armah HB, Tongren JE, Ned RM, Wilson NO, Crawford S, Joel PK, Singh MP, Nagpal AC, Dash AP, Udhayakumar V, Singh N, Stiles JK: Plasma IP-10, apoptotic and angiogenic factors associated with fatal cerebral malaria in India. Malar J. 2008, 7: 83-10.1186/1475-2875-7-83.PubMed CentralPubMedGoogle Scholar
- Wilson NO, Bythwood T, Solomon W, Jolly P, Yatich N, Jiang Y, Shuaib F, Adjei AA, Anderson W, Stiles JK: Elevated levels of IL-10 and G-CSF associated with asymptomatic malaria in pregnant women. Infect Dis Obstet Gynecol. 2010Google Scholar
- Wilson NO, Jain V, Roberts CE, Lucchi N, Joel PK, Singh MP, Nagpal AC, Dash AP, Udhayakumar V, Singh N, Stiles JK: CXCL4 and CXCL10 predict risk of fatal cerebral malaria. Dis Markers. 30: 39-49.
- Jain V, McClintock S, Nagpal AC, Dash AP, Stiles JK, Udhayakumar V, Singh N, Lucchi NW: Macrophage migration inhibitory factor is associated with mortality in cerebral malaria patients in India. BMC Res Notes. 2009, 2: 36-10.1186/1756-0500-2-36.PubMed CentralPubMedGoogle Scholar
- Lolis E: Glucocorticoid counter regulation: macrophage migration inhibitory factor as a target for drug discovery. Curr Opin Pharmacol. 2001, 1: 662-668. 10.1016/S1471-4892(01)00112-6.PubMedGoogle Scholar
- McDevitt MA, Xie J, Shanmugasundaram G, Griffith J, Liu A, McDonald C, Thuma P, Gordeuk VR, Metz CN, Mitchell R, Keefer J, David J, Leng L, Bucala R: A critical role for the host mediator macrophage migration inhibitory factor in the pathogenesis of malarial anemia. J Exp Med. 2006, 203: 1185-1196. 10.1084/jem.20052398.PubMed CentralPubMedGoogle Scholar
- Awandare GA, Hittner JB, Kremsner PG, Ochiel DO, Keller CC, Weinberg JB, Clark IA, Perkins DJ: Decreased circulating macrophage migration inhibitory factor (MIF) protein and blood mononuclear cell MIF transcripts in children with Plasmodium falciparum malaria. Clin Immunol. 2006, 119: 219-225. 10.1016/j.clim.2005.12.003.PubMedGoogle Scholar
- De Mast Q, Sweep FC, McCall M, Geurts-Moespot A, Hermsen C, Calandra T, Netea MG, Sauerwein RW, van der Ven AJ: A decrease of plasma macrophage migration inhibitory factor concentration is associated with lower numbers of circulating lymphocytes in experimental Plasmodium falciparum malaria. Parasite Immunol. 2008, 30: 133-138. 10.1111/j.1365-3024.2007.01008.x.PubMedGoogle Scholar
- Mohan A, Sharma SK, Bollineni S: Acute lung injury and acute respiratory distress syndrome in malaria. J Vector Borne Dis. 2008, 45: 179-193.PubMedGoogle Scholar
- Price RN, Douglas NM, Anstey NM: New developments in Plasmodium vivax malaria: severe disease and the rise of chloroquine resistance. Curr Opin Infect Dis. 2009, 22: 430-435. 10.1097/QCO.0b013e32832f14c1.PubMedGoogle Scholar
- Sharma VP: Hidden burden of malaria in Indian women. Malar J. 2009, 8: 281-10.1186/1475-2875-8-281.PubMed CentralPubMedGoogle Scholar
- Driss A, Asare KO, Hibbert JM, Gee BE, Adamkiewicz TV, Stiles JK: Sickle cell disease in the post genomic era: a monogenic disease with a polygenic phenotype. Genomics Insights. 2009, 2009: 23-48.PubMedGoogle Scholar
- Modiano D, Luoni G, Sirima BS, Simpore J, Verra F, Konate A, Rastrelli E, Olivieri A, Calissano C, Paganotti GM, D'Urbano L, Sanou I, Sawadogo A, Modiano G, Coluzzi M: Haemoglobin C protects against clinical Plasmodium falciparum malaria. Nature. 2001, 414: 305-308. 10.1038/35104556.PubMedGoogle Scholar
- Hutagalung R, Wilairatana P, Looareesuwan S, Brittenham GM, Aikawa M, Gordeuk VR: Influence of hemoglobin E trait on the severity of Falciparum malaria. J Infect Dis. 1999, 179: 283-286. 10.1086/314561.PubMedGoogle Scholar
- Chotivanich K, Udomsangpetch R, Pattanapanyasat K, Chierakul W, Simpson J, Looareesuwan S, White N: Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P falciparum malaria. Blood. 2002, 100: 1172-1176.PubMedGoogle Scholar
- Cholera R, Brittain NJ, Gillrie MR, Lopera-Mesa TM, Diakite SA, Arie T, Krause MA, Guindo A, Tubman A, Fujioka H, Diallo DA, Doumbo OK, Ho M, Wellems TE, Fairhurst RM: Impaired cytoadherence of Plasmodium falciparum-infected erythrocytes containing sickle hemoglobin. Proc Natl Acad Sci USA. 2008, 105: 991-996. 10.1073/pnas.0711401105.PubMed CentralPubMedGoogle Scholar
- Allen SJ, O'Donnell A, Alexander ND, Alpers MP, Peto TE, Clegg JB, Weatherall DJ: alpha+-Thalassemia protects children against disease caused by other infections as well as malaria. Proc Natl Acad Sci USA. 1997, 94: 14736-14741. 10.1073/pnas.94.26.14736.PubMed CentralPubMedGoogle Scholar
- May J, Evans JA, Timmann C, Ehmen C, Busch W, Thye T, Agbenyega T, Horstmann RD: Hemoglobin variants and disease manifestations in severe falciparum malaria. JAMA. 2007, 297: 2220-2226. 10.1001/jama.297.20.2220.PubMedGoogle Scholar
- Fowkes FJ, Allen SJ, Allen A, Alpers MP, Weatherall DJ, Day KP: Increased microerythrocyte count in homozygous alpha(+)-thalassaemia contributes to protection against severe malarial anaemia. PLoS Med. 2008, 5: e56-10.1371/journal.pmed.0050056.PubMed CentralPubMedGoogle Scholar
- Luzzi GA, Merry AH, Newbold CI, Marsh K, Pasvol G: Protection by alpha-thalassaemia against Plasmodium falciparum malaria: modified surface antigen expression rather than impaired growth or cytoadherence. Immunol Lett. 1991, 30: 233-240. 10.1016/0165-2478(91)90031-5.PubMedGoogle Scholar
- Pasvol G, Wilson RJ: The interaction of malaria parasites with red blood cells. Br Med Bull. 1982, 38: 133-140.PubMedGoogle Scholar
- Tishkoff SA, Varkonyi R, Cahinhinan N, Abbes S, Argyropoulos G, Destro-Bisol G, Drousiotou A, Dangerfield B, Lefranc G, Loiselet J, Piro A, Stoneking M, Tagarelli A, Tagarelli G, Touma EH, Williams SM, Clark AG: Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance. Science. 2001, 293: 455-462. 10.1126/science.1061573.PubMedGoogle Scholar
- Allison AC, Clyde DF: Malaria in African children with deficient erythrocyte glucose-6-phosphate dehydrogenase. Br Med J. 1961, 1: 1346-1349. 10.1136/bmj.1.5236.1346.PubMed CentralPubMedGoogle Scholar
- Bienzle U, Ayeni O, Lucas AO, Luzzatto L: Glucose-6-phosphate dehydrogenase and malaria. Greater resistance of females heterozygous for enzyme deficiency and of males with non-deficient variant. Lancet. 1972, 1: 107-110.PubMedGoogle Scholar
- Ruwende C, Khoo SC, Snow RW, Yates SN, Kwiatkowski D, Gupta S, Warn P, Allsopp CE, Gilbert SC, Peschu N, Newbold CI, Greenwood BM, Marsh K, Hill AVS: Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature. 1995, 376: 246-249. 10.1038/376246a0.PubMedGoogle Scholar
- Durand PM, Coetzer TL: Pyruvate kinase deficiency protects against malaria in humans. Haematologica. 2008, 93: 939-940. 10.3324/haematol.12450.PubMedGoogle Scholar
- Cortes A, Benet A, Cooke BM, Barnwell JW, Reeder JC: Ability of Plasmodium falciparum to invade Southeast Asian ovalocytes varies between parasite lines. Blood. 2004, 104: 2961-2966. 10.1182/blood-2004-06-2136.PubMedGoogle Scholar
- Cortes A, Mellombo M, Mgone CS, Beck HP, Reeder JC, Cooke BM: Adhesion of Plasmodium falciparum-infected red blood cells to CD36 under flow is enhanced by the cerebral malaria-protective trait South-East Asian ovalocytosis. Mol Biochem Parasitol. 2005, 142: 252-257. 10.1016/j.molbiopara.2005.03.016.PubMedGoogle Scholar
- Facer CA: Erythrocytes carrying mutations in spectrin and protein 4.1 show differing sensitivities to invasion by Plasmodium falciparum. Parasitol Res. 1995, 81: 52-57. 10.1007/BF00932417.PubMedGoogle Scholar
- Wang HY, Tang H, Shen CK, Wu CI: Rapidly evolving genes in human. I. The glycophorins and their possible role in evading malaria parasites. Mol Biol Evol. 2003, 20: 1795-1804. 10.1093/molbev/msg185.PubMedGoogle Scholar
- Blumenfield S: Reflections on effective leadership: strains and successes, strategies and styles. Soc Work Health Care. 1995, 20: 21-37. 10.1300/J010v20n04_03.PubMedGoogle Scholar
- Rowe JA, Handel IG, Thera MA, Deans AM, Lyke KE, Kone A, Diallo DA, Raza A, Kai O, Marsh K, Plowe CV, Doumbo OK, Moulds JM: Blood group O protects against severe Plasmodium falciparum malaria through the mechanism of reduced rosetting. Proc Natl Acad Sci USA. 2007, 104: 17471-17476. 10.1073/pnas.0705390104.PubMed CentralPubMedGoogle Scholar
- Barragan A, Kremsner PG, Wahlgren M, Carlson J: Blood group A antigen is a coreceptor in Plasmodium falciparum rosetting. Infect Immun. 2000, 68: 2971-2975. 10.1128/IAI.68.5.2971-2975.2000.PubMed CentralPubMedGoogle Scholar
- Pare G, Chasman DI, Kellogg M, Zee RY, Rifai N, Badola S, Miletich JP, Ridker PM: Novel association of ABO histo-blood group antigen with soluble ICAM-1: results of a genome-wide association study of 6,578 women. PLoS Genet. 2008, 4: e1000118-10.1371/journal.pgen.1000118.PubMed CentralPubMedGoogle Scholar
- Elagib AA, Kider AO, Akerstrom B, Elbashir MI: Association of the haptoglobin phenotype (1-1) with falciparum malaria in Sudan. Trans R Soc Trop Med Hyg. 1998, 92: 309-311. 10.1016/S0035-9203(98)91025-2.PubMedGoogle Scholar
- Quaye IK, Ekuban FA, Goka BQ, Adabayeri V, Kurtzhals JA, Gyan B, Ankrah NA, Hviid L, Akanmori BD: Haptoglobin 1-1 is associated with susceptibility to severe Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg. 2000, 94: 216-219. 10.1016/S0035-9203(00)90281-5.PubMedGoogle Scholar
- Cox SE, Doherty C, Atkinson SH, Nweneka CV, Fulford AJ, Ghattas H, Rockett KA, Kwiatkowski DP, Prentice AM: Haplotype association between haptoglobin (Hp2) and Hp promoter SNP (A-61C) may explain previous controversy of haptoglobin and malaria protection. PLoS One. 2007, 2: e362-10.1371/journal.pone.0000362.PubMed CentralPubMedGoogle Scholar
- Kun JF, Mordmuller B, Perkins DJ, May J, Mercereau-Puijalon O, Alpers M, Weinberg JB, Kremsner PG: Nitric oxide synthase 2(Lambarene) (G-954C), increased nitric oxide production, and protection against malaria. J Infect Dis. 2001, 184: 330-336. 10.1086/322037.PubMedGoogle Scholar
- Hobbs MR, Udhayakumar V, Levesque MC, Booth J, Roberts JM, Tkachuk AN, Pole A, Coon H, Kariuki S, Nahlen BL, Mwaikambo ED, Lal AL, Granger DL, Anstey NM, Weinberg JB: A new NOS2 promoter polymorphism associated with increased nitric oxide production and protection from severe malaria in Tanzanian and Kenyan children. Lancet. 2002, 360: 1468-1475. 10.1016/S0140-6736(02)11474-7.PubMedGoogle Scholar
- Hill AV, Allsopp CE, Kwiatkowski D, Anstey NM, Twumasi P, Rowe PA, Bennett S, Brewster D, McMichael AJ, Greenwood BM: Common west African HLA antigens are associated with protection from severe malaria. Nature. 1991, 352: 595-600. 10.1038/352595a0.PubMedGoogle Scholar
- Gilbert SC, Plebanski M, Gupta S, Morris J, Cox M, Aidoo M, Kwiatkowski D, Greenwood BM, Whittle HC, Hill AV: Association of malaria parasite population structure, HLA, and immunological antagonism. Science. 1998, 279: 1173-1177. 10.1126/science.279.5354.1173.PubMedGoogle Scholar
- Young K, Frodsham A, Doumbo OK, Gupta S, Dolo A, Hu JT, Robson KJ, Crisanti A, Hill AV, Gilbert SC: Inverse associations of human leukocyte antigen and malaria parasite types in two West African populations. Infect Immun. 2005, 73: 953-955. 10.1128/IAI.73.2.953-955.2005.PubMed CentralPubMedGoogle Scholar
- McGuire W, Knight JC, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D: Severe malarial anemia and cerebral malaria are associated with different tumor necrosis factor promoter alleles. J Infect Dis. 1999, 179: 287-290. 10.1086/314533.PubMedGoogle Scholar
- McGuire W, Hill AV, Allsopp CE, Greenwood BM, Kwiatkowski D: Variation in the TNF-alpha promoter region associated with susceptibility to cerebral malaria. Nature. 1994, 371: 508-510. 10.1038/371508a0.PubMedGoogle Scholar
- Atkinson SH, Rockett KA, Morgan G, Bejon PA, Sirugo G, O'Connell MA, Hanchard N, Kwiatkowski DP, Prentice AM: Tumor necrosis factor SNP haplotypes are associated with iron deficiency anemia in West African children. Blood. 2008, 112: 4276-4283. 10.1182/blood-2008-06-162008.PubMed CentralPubMedGoogle Scholar
- Cabantous S, Poudiougou B, Traore A, Keita M, Cisse MB, Doumbo O, Dessein AJ, Marquet S: Evidence that interferon-gamma plays a protective role during cerebral malaria. J Infect Dis. 2005, 192: 854-860. 10.1086/432484.PubMedGoogle Scholar
- Koch O, Awomoyi A, Usen S, Jallow M, Richardson A, Hull J, Pinder M, Newport M, Kwiatkowski D: IFNGR1 gene promoter polymorphisms and susceptibility to cerebral malaria. J Infect Dis. 2002, 185: 1684-1687. 10.1086/340516.PubMedGoogle Scholar
- Mangano VD, Luoni G, Rockett KA, Sirima BS, Konate A, Forton J, Clark TG, Bancone G, Sadighi Akha E, Kwiatkowski DP, Modiano D: Interferon regulatory factor-1 polymorphisms are associated with the control of Plasmodium falciparum infection. Genes Immun. 2008, 9: 122-129. 10.1038/sj.gene.6364456.PubMed CentralPubMedGoogle Scholar
- Mangano VD, Clark TG, Auburn S, Campino S, Diakite M, Fry AE, Green A, Richardson A, Jallow M, Sisay-Joof F, Pinder M, Griffiths MJ, Newton C, Peshu N, Williams TN, Marsh K, Molyneux ME, Taylor TE, Modiano D, Kwiatkowski DP, Rockett KA: Lack of association of interferon regulatory factor 1 with severe malaria in affected child-parental trio studies across three African populations. PLoS One. 2009, 4: e4206-10.1371/journal.pone.0004206.PubMed CentralPubMedGoogle Scholar
- Sabeti P, Usen S, Farhadian S, Jallow M, Doherty T, Newport M, Pinder M, Ward R, Kwiatkowski D: CD40L association with protection from severe malaria. Genes Immun. 2002, 3: 286-291. 10.1038/sj.gene.6363877.PubMedGoogle Scholar
- Walley AJ, Aucan C, Kwiatkowski D, Hill AV: Interleukin-1 gene cluster polymorphisms and susceptibility to clinical malaria in a Gambian case-control study. Eur J Hum Genet. 2004, 12: 132-138. 10.1038/sj.ejhg.5201084.PubMedGoogle Scholar
- Gyan B, Goka B, Cvetkovic JT, Perlmann H, Lefvert AK, Akanmori B, Troye-Blomberg M: Polymorphisms in interleukin-1beta and interleukin-1 receptor antagonist genes and malaria in Ghanaian children. Scand J Immunol. 2002, 56: 619-622. 10.1046/j.1365-3083.2002.01161.x.PubMedGoogle Scholar
- Ohashi J, Naka I, Doi A, Patarapotikul J, Hananantachai H, Tangpukdee N, Looareesuwan S, Tokunaga K: A functional polymorphism in the IL1B gene promoter, IL1B -31C > T, is not associated with cerebral malaria in Thailand. Malar J. 2005, 4: 38-10.1186/1475-2875-4-38.PubMed CentralPubMedGoogle Scholar
- Luoni G, Verra F, Arca B, Sirima BS, Troye-Blomberg M, Coluzzi M, Kwiatkowski D, Modiano D: Antimalarial antibody levels and IL4 polymorphism in the Fulani of West Africa. Genes Immun. 2001, 2: 411-414. 10.1038/sj.gene.6363797.PubMedGoogle Scholar
- Verra F, Luoni G, Calissano C, Troye-Blomberg M, Perlmann P, Perlmann H, Arca B, Sirima BS, Konate A, Coluzzi M, Kwiatkowski D, Modiano D: IL4-589C/T polymorphism and IgE levels in severe malaria. Acta Trop. 2004, 90: 205-209. 10.1016/j.actatropica.2003.11.014.PubMedGoogle Scholar
- Vafa M, Maiga B, Berzins K, Hayano M, Bereczky S, Dolo A, Daou M, Arama C, Kouriba B, Farnert A, Doumbo OK, Troye-Blomberg M: Associations between the IL-4 -590 T allele and Plasmodium falciparum infection prevalence in asymptomatic Fulani of Mali. Microbes Infect. 2007, 9: 1043-1048. 10.1016/j.micinf.2007.04.011.PubMedGoogle Scholar
- Tangteerawatana P, Pichyangkul S, Hayano M, Kalambaheti T, Looareesuwan S, Troye-Blomberg M, Khusmith S: Relative levels of IL4 and IFN-gamma in complicated malaria: association with IL4 polymorphism and peripheral parasitemia. Acta Trop. 2007, 101: 258-265. 10.1016/j.actatropica.2007.02.008.PubMedGoogle Scholar
- Gyan BA, Goka B, Cvetkovic JT, Kurtzhals JL, Adabayeri V, Perlmann H, Lefvert AK, Akanmori BD, Troye-Blomberg M: Allelic polymorphisms in the repeat and promoter regions of the interleukin-4 gene and malaria severity in Ghanaian children. Clin Exp Immunol. 2004, 138: 145-150. 10.1111/j.1365-2249.2004.02590.x.PubMed CentralPubMedGoogle Scholar
- Ouma C, Davenport GC, Were T, Otieno MF, Hittner JB, Vulule JM, Martinson J, Ong'echa JM, Ferrell RE, Perkins DJ: Haplotypes of IL-10 promoter variants are associated with susceptibility to severe malarial anemia and functional changes in IL-10 production. Hum Genet. 2008, 124: 515-524. 10.1007/s00439-008-0578-5.PubMed CentralPubMedGoogle Scholar
- Koch O, Rockett K, Jallow M, Pinder M, Sisay-Joof F, Kwiatkowski D: Investigation of malaria susceptibility determinants in the IFNG/IL26/IL22 genomic region. Genes Immun. 2005, 6: 312-318. 10.1038/sj.gene.6364214.PubMedGoogle Scholar
- Nasr A, Iriemenam NC, Giha HA, Balogun HA, Anders RF, Troye-Blomberg M, ElGhazali G, Berzins K: FcgammaRIIa (CD32) polymorphism and anti-malarial IgG subclass pattern among Fulani and sympatric ethnic groups living in eastern Sudan. Malar J. 2009, 8: 43-10.1186/1475-2875-8-43.PubMed CentralPubMedGoogle Scholar
- Shi YP, Nahlen BL, Kariuki S, Urdahl KB, McElroy PD, Roberts JM, Lal AA: Fcgamma receptor IIa (CD32) polymorphism is associated with protection of infants against high-density Plasmodium falciparum infection. VII. Asembo Bay Cohort Project. J Infect Dis. 2001, 184: 107-111. 10.1086/320999.PubMedGoogle Scholar
- Nasr A, Iriemenam NC, Troye-Blomberg M, Giha HA, Balogun HA, Osman OF, Montgomery SM, ElGhazali G, Berzins K: Fc gamma receptor IIa (CD32) polymorphism and antibody responses to asexual blood-stage antigens of Plasmodium falciparum malaria in Sudanese patients. Scand J Immunol. 2007, 66: 87-96. 10.1111/j.1365-3083.2007.01947.x.PubMedGoogle Scholar
- Cooke GS, Aucan C, Walley AJ, Segal S, Greenwood BM, Kwiatkowski DP, Hill AV: Association of Fcgamma receptor IIa (CD32) polymorphism with severe malaria in West Africa. Am J Trop Med Hyg. 2003, 69: 565-568.PubMedGoogle Scholar
- Omi K, Ohashi J, Patarapotikul J, Hananantachai H, Naka I, Looareesuwan S, Tokunaga K: Absence of association between the Fc gamma receptor IIIA-176F/V polymorphism and the severity of malaria in Thai. Jpn J Infect Dis. 2002, 55: 167-169.PubMedGoogle Scholar
- Clatworthy MR, Willcocks L, Urban B, Langhorne J, Williams TN, Peshu N, Watkins NA, Floto RA, Smith KG: Systemic lupus erythematosus-associated defects in the inhibitory receptor FcgammaRIIb reduce susceptibility to malaria. Proc Natl Acad Sci USA. 2007, 104: 7169-7174. 10.1073/pnas.0608889104.PubMed CentralPubMedGoogle Scholar
- Mockenhaupt FP, Hamann L, von Gaertner C, Bedu-Addo G, von Kleinsorgen C, Schumann RR, Bienzle U: Common polymorphisms of toll-like receptors 4 and 9 are associated with the clinical manifestation of malaria during pregnancy. J Infect Dis. 2006, 194: 184-188. 10.1086/505152.PubMedGoogle Scholar
- Leoratti FM, Farias L, Alves FP, Suarez-Mutis MC, Coura JR, Kalil J, Camargo EP, Moraes SL, Ramasawmy R: Variants in the toll-like receptor signaling pathway and clinical outcomes of malaria. J Infect Dis. 2008, 198: 772-780. 10.1086/590440.PubMedGoogle Scholar
- Hamann L, Kumpf O, Schuring RP, Alpsoy E, Bedu-Addo G, Bienzle U, Oskam L, Mockenhaupt FP, Schumann RR: Low frequency of the TIRAP S180L polymorphism in Africa, and its potential role in malaria, sepsis, and leprosy. BMC Med Genet. 2009, 10: 65-PubMed CentralPubMedGoogle Scholar
- Uhlemann AC, Szlezak NA, Vonthein R, Tomiuk J, Emmer SA, Lell B, Kremsner PG, Kun JF: DNA phasing by TA dinucleotide microsatellite length determines in vitro and in vivo expression of the gp91phox subunit of NADPH oxidase and mediates protection against severe malaria. J Infect Dis. 2004, 189: 2227-2234. 10.1086/421242.PubMedGoogle Scholar
- Luty AJ, Kun JF, Kremsner PG: Mannose-binding lectin plasma levels and gene polymorphisms in Plasmodium falciparum malaria. J Infect Dis. 1998, 178: 1221-1224. 10.1086/515690.PubMedGoogle Scholar
- Garred P, Nielsen MA, Kurtzhals JA, Malhotra R, Madsen HO, Goka BQ, Akanmori BD, Sim RB, Hviid L: Mannose-binding lectin is a disease modifier in clinical malaria and may function as opsonin for Plasmodium falciparum-infected erythrocytes. Infect Immun. 2003, 71: 5245-5253. 10.1128/IAI.71.9.5245-5253.2003.PubMed CentralPubMedGoogle Scholar
- Holmberg V, Schuster F, Dietz E, Sagarriga Visconti JC, Anemana SD, Bienzle U, Mockenhaupt FP: Mannose-binding lectin variant associated with severe malaria in young African children. Microbes Infect. 2008, 10: 342-348. 10.1016/j.micinf.2007.12.008.PubMedGoogle Scholar
- Rowe JA, Moulds JM, Newbold CI, Miller LH: P. falciparum rosetting mediated by a parasite-variant erythrocyte membrane protein and complement-receptor 1. Nature. 1997, 388: 292-295. 10.1038/40888.PubMedGoogle Scholar
- Cockburn IA, Mackinnon MJ, O'Donnell A, Allen SJ, Moulds JM, Baisor M, Bockarie M, Reeder JC, Rowe JA: A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria. Proc Natl Acad Sci USA. 2004, 101: 272-277. 10.1073/pnas.0305306101.PubMed CentralPubMedGoogle Scholar
- Sinha S, Qidwai T, Kanchan K, Anand P, Jha GN, Pati SS, Mohanty S, Mishra SK, Tyagi PK, Sharma SK, Venkatesh V, Habib S: Variations in host genes encoding adhesion molecules and susceptibility to falciparum malaria in India. Malar J. 2008, 7: 250-10.1186/1475-2875-7-250.PubMed CentralPubMedGoogle Scholar
- Amodu OK, Gbadegesin RA, Ralph SA, Adeyemo AA, Brenchley PE, Ayoola OO, Orimadegun AE, Akinsola AK, Olumese PE, Omotade OO: Plasmodium falciparum malaria in south-west Nigerian children: is the polymorphism of ICAM-1 and E-selectin genes contributing to the clinical severity of malaria?. Acta Trop. 2005, 95: 248-255. 10.1016/j.actatropica.2005.05.011.PubMedGoogle Scholar
- Fry AE, Auburn S, Diakite M, Green A, Richardson A, Wilson J, Jallow M, Sisay-Joof F, Pinder M, Griffiths MJ, Peshu N, Williams TN, Marsh K, Molyneux ME, Taylor TE, Rockett KA, Kwiatkowski DP: Variation in the ICAM1 gene is not associated with severe malaria phenotypes. Genes Immun. 2008, 9: 462-469. 10.1038/gene.2008.38.PubMed CentralPubMedGoogle Scholar
- Ndiaye R, Sakuntabhai A, Casademont I, Rogier C, Tall A, Trape JF, Spiegel A, Dieye A, Julier C: Genetic study of ICAM1 in clinical malaria in Senegal. Tissue Antigens. 2005, 65: 474-480. 10.1111/j.1399-0039.2005.00388.x.PubMedGoogle Scholar
- Kun JF, Lehman LG, Lell B, Schmidt-Ott R, Kremsner PG: Low-dose treatment with sulfadoxine-pyrimethamine combinations selects for drug-resistant Plasmodium falciparum strains. Antimicrob Agents Chemother. 1999, 43: 2205-2208.PubMed CentralPubMedGoogle Scholar
- Fernandez-Reyes D, Craig AG, Kyes SA, Peshu N, Snow RW, Berendt AR, Marsh K, Newbold CI: A high frequency African coding polymorphism in the N-terminal domain of ICAM-1 predisposing to cerebral malaria in Kenya. Hum Mol Genet. 1997, 6: 1357-1360. 10.1093/hmg/6.8.1357.PubMedGoogle Scholar
- Kikuchi M, Looareesuwan S, Ubalee R, Tasanor O, Suzuki F, Wattanagoon Y, Na-Bangchang K, Kimura A, Aikawa M, Hirayama K: Association of adhesion molecule PECAM-1/CD31 polymorphism with susceptibility to cerebral malaria in Thais. Parasitol Int. 2001, 50: 235-239. 10.1016/S1383-5769(01)00082-4.PubMedGoogle Scholar
- Casals-Pascual C, Allen S, Allen A, Kai O, Lowe B, Pain A, Roberts DJ: Short report: codon 125 polymorphism of CD31 and susceptibility to malaria. Am J Trop Med Hyg. 2001, 65: 736-737.PubMedGoogle Scholar
- Omi K, Ohashi J, Patarapotikul J, Hananantachai H, Naka I, Looareesuwan S, Tokunaga K: CD36 polymorphism is associated with protection from cerebral malaria. Am J Hum Genet. 2003, 72: 364-374. 10.1086/346091.PubMed CentralPubMedGoogle Scholar
- Aitman TJ, Cooper LD, Norsworthy PJ, Wahid FN, Gray JK, Curtis BR, McKeigue PM, Kwiatkowski D, Greenwood BM, Snow RW, Hill AV, Scott J: Malaria susceptibility and CD36 mutation. Nature. 2000, 405: 1015-1016. 10.1038/35016636.PubMedGoogle Scholar
- Pain A, Urban BC, Kai O, Casals-Pascual C, Shafi J, Marsh K, Roberts DJ: A non-sense mutation in Cd36 gene is associated with protection from severe malaria. Lancet. 2001, 357: 1502-1503. 10.1016/S0140-6736(00)04662-6.PubMedGoogle Scholar
- Sikora M, Ferrer-Admetlla A, Laayouni H, Menendez C, Mayor A, Bardaji A, Sigauque B, Mandomando I, Alonso PL, Bertranpetit J, Casals F: A variant in the gene FUT9 is associated with susceptibility to placental malaria infection. Hum Mol Genet. 2009, 18: 3136-3144. 10.1093/hmg/ddp240.PubMedGoogle Scholar
- Kwiatkowski D, Hill AV, Sambou I, Twumasi P, Castracane J, Manogue KR, Cerami A, Brewster DR, Greenwood BM: TNF concentration in fatal cerebral, non-fatal cerebral, and uncomplicated Plasmodium falciparum malaria. Lancet. 1990, 336: 1201-1204. 10.1016/0140-6736(90)92827-5.PubMedGoogle Scholar
- Grau GE, Taylor TE, Molyneux ME, Wirima JJ, Vassalli P, Hommel M, Lambert PH: Tumor necrosis factor and disease severity in children with falciparum malaria. N Engl J Med. 1989, 320: 1586-1591. 10.1056/NEJM198906153202404.PubMedGoogle Scholar
- Charoenvit Y, Majam VF, Corradin G, Sacci JB, Wang R, Doolan DL, Jones TR, Abot E, Patarroyo ME, Guzman F, Hoffman SL: CD4(+) T-cell- and gamma interferon-dependent protection against murine malaria by immunization with linear synthetic peptides from a Plasmodium yoelii 17-kilodalton hepatocyte erythrocyte protein. Infect Immun. 1999, 67: 5604-5614.PubMed CentralPubMedGoogle Scholar
- Luty AJ, Lell B, Schmidt-Ott R, Lehman LG, Luckner D, Greve B, Matousek P, Herbich K, Schmid D, Migot-Nabias F, Deloron P, Nussenzweig RS, Kremsner PG: Interferon-gamma responses are associated with resistance to reinfection with Plasmodium falciparum in young African children. J Infect Dis. 1999, 179: 980-988. 10.1086/314689.PubMedGoogle Scholar
- Bach EA, Aguet M, Schreiber RD: The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol. 1997, 15: 563-591. 10.1146/annurev.immunol.15.1.563.PubMedGoogle Scholar
- Lohoff M, Mak TW: Roles of interferon-regulatory factors in T-helper-cell differentiation. Nat Rev Immunol. 2005, 5: 125-135. 10.1038/nri1552.PubMedGoogle Scholar
- Sabeti PC, Reich DE, Higgins JM, Levine HZ, Richter DJ, Schaffner SF, Gabriel SB, Platko JV, Patterson NJ, McDonald GJ, Ackerman HC, Campbell SJ, Altshuler D, Cooper R, Kwiatkowski D, Ward R, Lander ES: Detecting recent positive selection in the human genome from haplotype structure. Nature. 2002, 419: 832-837. 10.1038/nature01140.PubMedGoogle Scholar
- Dunn E, Sims JE, Nicklin MJ, O'Neill LA: Annotating genes with potential roles in the immune system: six new members of the IL-1 family. Trends Immunol. 2001, 22: 533-536. 10.1016/S1471-4906(01)02034-8.PubMedGoogle Scholar
- Marsh DG, Neely JD, Breazeale DR, Ghosh B, Freidhoff LR, Ehrlich-Kautzky E, Schou C, Krishnaswamy G, Beaty TH: Linkage analysis of IL4 and other chromosome 5q31.1 markers and total serum immunoglobulin E concentrations. Science. 1994, 264: 1152-1156. 10.1126/science.8178175.PubMedGoogle Scholar
- Pestka S, Krause CD, Sarkar D, Walter MR, Shi Y, Fisher PB: Interleukin-10 and related cytokines and receptors. Annu Rev Immunol. 2004, 22: 929-979. 10.1146/annurev.immunol.22.012703.104622.PubMedGoogle Scholar
- Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R: IL-22 increases the innate immunity of tissues. Immunity. 2004, 21: 241-254. 10.1016/j.immuni.2004.07.007.PubMedGoogle Scholar
- Bolland S, Ravetch JV: Spontaneous autoimmune disease in Fc(gamma)RIIB-deficient mice results from strain-specific epistasis. Immunity. 2000, 13: 277-285. 10.1016/S1074-7613(00)00027-3.PubMedGoogle Scholar
- Akira S, Takeda K: Functions of toll-like receptors: lessons from KO mice. C R Biol. 2004, 327: 581-589. 10.1016/j.crvi.2004.04.002.PubMedGoogle Scholar
- Bekeredjian-Ding I, Jego G: Toll-like receptors--sentries in the B-cell response. Immunology. 2009, 128: 311-323. 10.1111/j.1365-2567.2009.03173.x.PubMed CentralPubMedGoogle Scholar
- Coban C, Ishii KJ, Kawai T, Hemmi H, Sato S, Uematsu S, Yamamoto M, Takeuchi O, Itagaki S, Kumar N, Horii T, Akira S: Toll-like receptor 9 mediates innate immune activation by the malaria pigment hemozoin. J Exp Med. 2005, 201: 19-25. 10.1084/jem.20041836.PubMed CentralPubMedGoogle Scholar
- Treutiger CJ, Heddini A, Fernandez V, Muller WA, Wahlgren M: PECAM-1/CD31, an endothelial receptor for binding Plasmodium falciparum-infected erythrocytes. Nat Med. 1997, 3: 1405-1408. 10.1038/nm1297-1405.PubMedGoogle Scholar
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