Identification of a haplotype block in the 5q31 cytokine gene cluster associated with the susceptibility to severe malaria
TL;DR: A haplotype block in which a primary polymorphism associated with severe malaria is likely to be encoded was identified in Thai malaria patients.
Abstract: It has been previously demonstrated that a single nucleotide polymorphism (SNP) in the IL13 promoter region, IL13 -1055T>C (rs1800925), was associated with susceptibility to severe malaria in Thais. In the present study, fine association mapping for a cytokine gene cluster including IL4, IL5, and IL13 on chromosome 5q31 was conducted using the same malaria subjects to refine the region containing a primary variant or a haplotype susceptible to severe malaria. A total of 82 SNPs spanning 522 kb of the 5q31 region were analysed in 368 patients with Plasmodium falciparum malaria (203 mild malaria and 165 severe malaria patients). Only rs1881457 located in the promoter region of IL13, which is in linkage disequilibrium with rs1800925 (r2 = 0.73), showed a significant association with severe malaria after adjusting for multiple testing (P = 0.046 by permutation test). This SNP was in a haplotype block spanning 97 kb (from rs2069812 to rs2240032). The detected haplotype block contained the RAD50 gene and the promoter of IL13, but not the other genes. A haplotype block in which a primary polymorphism associated with severe malaria is likely to be encoded was identified in Thai malaria patients.
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TL;DR: The genetic alterations associated with erythrocytes or mediators of the immune system, which might influence malaria outcome are reviewed and polymorphisms in genes related to molecules involved in mechanisms of cytoadherence are discussed.
Abstract: Populations exposed to Plasmodium infection develop genetic mechanisms of protection against severe disease. The clinical manifestation of malaria results primarily from the lysis of infected erythrocytes and subsequent immune and inflammatory responses. Herein, we review the genetic alterations associated with erythrocytes or mediators of the immune system, which might influence malaria outcome. Moreover, polymorphisms in genes related to molecules involved in mechanisms of cytoadherence and their influence on malaria pathology are also discussed. The results of some studies have suggested that the combinatorial effects of a set of genetic factors in the erythrocyte-immunology pathway might be relevant to host resistance or susceptibility against Plasmodium infection. However, these results must be interpreted with caution because of the differences observed in the functionality and frequency of polymorphisms within different populations. With the recent advances in molecular biology techniques, more robust studies with reliable data have been reported, and the results of these studies have identified individual genetic factors for consideration in preventing severe disease and the individual response to treatment.
62 citations
Cites background from "Identification of a haplotype block..."
...Concerning IL-13, an SNP −1055T>C (rs1800925) has showed a significant association with protection from severe malaria in Thailand [135]....
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...A fine association mapping in the IL-13 gene using the same malaria subjects revealed that only rs1881457 located in the promoter region, which is in linkage disequilibrium with rs1800925, showed a significant association with severe malaria [123]....
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...Two different genes (IL1A and IL1B) encode IL-1, which are located in chromosomal region 2q14, an area that also contains genes for IL-1 receptor types 1 and 2 (ILR1 and IL1R2), the IL-1 receptor antagonist (IL1RN), and other homologous genes that have not been well characterized [149]....
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...IL-12 cytokine is a dimer composed of a 35-kD subunit encoded by the IL12A gene (chromosome 3p12-q13....
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...Furthermore, two SNPs (rs848, rs1881457) in IL-13 gene were found to be significantly different between those who have experienced one or more malaria attacks within past 10 years and those who did not in Sri Lanka [136]....
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TL;DR: Previously known genetic associations with protection from severe malaria (HbS, G6PD) are confirmed and mutations in ADCY9, IL1A and CD40L are identified as being associated with altered risk of severe respiratory distress and acidosis, both of which are characterised by high serum lactate levels.
Abstract: Human genetic background strongly influences susceptibility to malaria infection and progression to severe disease and death. Classical genetic studies identified haemoglobinopathies and erythrocyte-associated polymorphisms, as protective against severe disease. High throughput genotyping by mass spectrometry allows multiple single nucleotide polymorphisms (SNPs) to be examined simultaneously. We compared the prevalence of 65 human SNP's, previously associated with altered risk of malaria, between Tanzanian children with and without severe malaria. Five hundred children, aged 1-10 years, with severe malaria were recruited from those admitted to hospital in Muheza, Tanzania and compared with matched controls. Genotyping was performed by Sequenom MassArray, and conventional PCR was used to detect deletions in the alpha-thalassaemia gene. SNPs in two X-linked genes were associated with altered risk of severe malaria in females but not in males: heterozygosity for one or other of two SNPs in the G6PD gene was associated with protection from all forms of severe disease whilst two SNPs in the gene encoding CD40L were associated with respiratory distress. A SNP in the adenyl cyclase 9 (ADCY9) gene was associated with protection from acidosis whilst a polymorphism in the IL-1α gene (IL1A) was associated with an increased risk of acidosis. SNPs in the genes encoding IL-13 and reticulon-3 (RTN3) were associated with increased risk of cerebral malaria. This study confirms previously known genetic associations with protection from severe malaria (HbS, G6PD). It identifies two X-linked genes associated with altered risk of severe malaria in females, identifies mutations in ADCY9, IL1A and CD40L as being associated with altered risk of severe respiratory distress and acidosis, both of which are characterised by high serum lactate levels, and also identifies novel genetic associations with severe malaria (TRIM5) and cerebral malaria(IL-13 and RTN3). Further studies are required to test the generality of these associations and to understand their functional consequences.
48 citations
Cites result from "Identification of a haplotype block..."
...Our data support other studies implicating IL-13 polymorphisms with risk of severe malaria in Thai adults [55,56] and associations between 5q31–q33 haplotypes (which span the IL13 locus) and antimalarial antibody responses [57]; the recurrent link between IL-13 and risk of severe malaria would seem to warrant further investigation....
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TL;DR: This study suggests that NRG-1 attenuates ECM-associated brain inflammation and injuries and may represent a novel supportive therapy for the management of CM.
Abstract: Cerebral Malaria (CM) is a diffuse encephalopathy caused by Plasmodium falciparum infection. Despite availability of antimalarial drugs, CM-associated mortality remains high at approximately 30% and a subset of survivors develop neurological and cognitive disabilities. While antimalarials are effective at clearing Plasmodium parasites they do little to protect against CM pathophysiology and parasite-induced brain inflammation that leads to seizures, coma and long-term neurological sequelae in CM patients. Thus, there is urgent need to explore therapeutics that can reduce or prevent CM pathogenesis and associated brain inflammation to improve survival. Neuregulin-1 (NRG-1) is a neurotrophic growth factor shown to protect against brain injury associated with acute ischemic stroke (AIS) and neurotoxin exposure. However, this drug has not been tested against CM-associated brain injury. Since CM-associated brain injuries and AIS share similar pathophysiological features, we hypothesized that NRG-1 will reduce or prevent neuroinflammation and brain damage as well as improve survival in mice with late-stage experimental cerebral malaria (ECM). We tested the effects of NRG-1 on ECM-associated brain inflammation and mortality in P. berghei ANKA (PbA)-infected mice and compared to artemether (ARM) treatment; an antimalarial currently used in various combination therapies against malaria. Treatment with ARM (25 mg/kg/day) effectively cleared parasites and reduced mortality in PbA-infected mice by 82%. Remarkably, NRG-1 therapy (1.25 ng/kg/day) significantly improved survival against ECM by 73% despite increase in parasite burden within NRG-1-treated mice. Additionally, NRG-1 therapy reduced systemic and brain pro-inflammatory factors TNFalpha, IL-6, IL-1alpha and CXCL10 and enhanced anti-inflammatory factors, IL-5 and IL-13 while decreasing leukocyte accumulation in brain microvessels. This study suggests that NRG-1 attenuates ECM-associated brain inflammation and injuries and may represent a novel supportive therapy for the management of CM.
31 citations
Cites background from "Identification of a haplotype block..."
...In contrast, Th2 cytokines IL-5 and IL-13 associated with reduced severity of disease and increased protection against CM [76-79] were significantly elevated in serum after treatment with NRG-1compared to saline-treated mice, P <0....
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...Genetic studies in African and south-east Asian populations have linked IL-13 to protection against cerebral malaria and show that polymorphisms that alter IL-13 production may increase risk of severe malaria [76-78]....
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TL;DR: Evidence is suggestive of an age–acquired immunity in this study population in spite of low malaria transmission levels, suggesting that these host genetic mutations might have an individual or collective effect on inducing or/and maintaining high anti-malarial antibody levels.
Abstract: Background
The incidence of malaria in Sri Lanka has significantly declined in recent years. Similar trends were seen in Kataragama, a known malaria endemic location within the southern province of the country, over the past five years. This is a descriptive study of anti-malarial antibody levels and selected host genetic mutations in residents of Kataragama, under low malaria transmission conditions.
24 citations
TL;DR: A new genome-wide significant malaria locu on chromosome 17p12 and a new suggestive locus on chromosome 19p13 are reported, which are believed to be significant as loci controlling mild malaria or asymptomatic parasitaemia.
Abstract: Genome-wide studies have mapped several loci controlling Plasmodium falciparum mild malaria and parasitaemia, only two of them being significant at the genome level. The objective of the present study was to identify malaria resistance loci in individuals living in Burkina Faso. A genome scan that involved 314 individuals belonging to 63 families was performed. Markers located within chromosomes 6p21.3 and 17p12 were genotyped in 247 additional individuals belonging to 55 families. The linkage and the association of markers with parasitaemia and mild malaria were assessed by using the maximum-likelihood binomial method extended to quantitative trait linkage and the quantitative trait disequilibrium test, respectively. Multipoint linkage analysis showed a significant linkage of mild malaria to chromosome 6p21.3 (LOD score 3.73, P = 1.7 10−5), a suggestive linkage of mild malaria to chromosome 19p13.12 (LOD score 2.50, P = 3.5 10−4), and a suggestive linkage of asymptomatic parasitaemia to chromosomes 6p21.3 (LOD score 2.36, P = 4.9 10−4) and 17p12 (LOD score 2.87, P = 1.4 10−4). Genome-wide family-based association analysis revealed a significant association between three chromosome 5q31 markers and asymptomatic parasitaemia, whereas there was no association with mild malaria. When taking into account 247 additional individuals, a significant linkage of asymptomatic parasitaemia to chromosome 17p12 (LOD score 3.6, P = 2 10−5) was detected. A new genome-wide significant malaria locus on chromosome 17p12 and a new suggestive locus on chromosome 19p13.12 are reported. Moreover, there was evidence that confirmed the influence of chromosomes 5q31 and 6p21.3 as loci controlling mild malaria or asymptomatic parasitaemia.
21 citations
Cites result from "Identification of a haplotype block..."
...The influence of chromosome 5q31, which has been reported [6-8,12,25,26], is further supported by our linkage and association results at the genome wide significance level in the initial population....
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TL;DR: While regions of linkage show little overlap with genes known to be involved in severe malaria, the four regions appear to overlap with regions linked to asthma or atopy related traits, suggesting that common immune related pathways may be involved.
Abstract: Plasmodium falciparum malaria episodes may vary considerably in their severity and clinical manifestations. There is good evidence that host genetic factors contribute to this variability. To date, most genetic studies aiming at the identification of these genes have used a case/control study design for severe malaria, exploring specific candidate genes. Here, we performed a family-based genetic study of falciparum malaria related phenotypes in two independent longitudinal survey cohorts, as a first step towards the identification of genes and mechanisms involved in the outcome of infection. We studied two Senegalese villages, Dielmo and Ndiop that differ in ethnicity, malaria transmission and endemicity. We performed genome-scan linkage analysis of several malaria-related phenotypes both during clinical attacks and asymptomatic infection. We show evidence for a strong genetic contribution to both the number of clinical falciparum malaria attacks and the asymptomatic parasite density. The asymptomatic parasite density showed linkage to chromosome 5q31 (LOD = 2.26, empirical p = 0.0014, Dielmo), confirming previous findings in other studies. Suggestive linkage values were also obtained at three additional chromosome regions: the number of clinical malaria attacks on chromosome 5p15 (LOD = 2.57, empirical p = 0.001, Dielmo) and 13q13 (LOD = 2.37, empirical p = 0.0014 Dielmo), and the maximum parasite density during asymptomatic infection on chromosome 12q21 (LOD = 3.1, empirical p<10−4, Ndiop). While regions of linkage show little overlap with genes known to be involved in severe malaria, the four regions appear to overlap with regions linked to asthma or atopy related traits, suggesting that common immune related pathways may be involved.
58 citations
"Identification of a haplotype block..." refers background in this paper
...Background Over the course of the last decade a number of studies have provided evidence for a linkage between the blood infection level of Plasmodium falciparum and the human chromosome 5q31 region in African populations [1-4]....
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TL;DR: Several genes in the immune response gene cluster at 5q23.3–q31.1 influence outcomes of L. chagasi infection in this region of Brazil.
Abstract: Visceral leishmaniasis (VL) caused by Leishmania chagasi is endemic to northeast Brazil A positive delayed-type hypersensitivity skin test response (DTH+) is a marker for acquired resistance to disease, clusters in families and may be genetically controlled Twenty-three single nucleotide polymorphisms (SNPs) were genotyped in the cytokine 5q233-q311 region IRF1-IL5-IL13-IL4-IL9-LECT2-TGFBI in 102 families (323 DTH+; 190 DTH-; 123 VL individuals) from a VL endemic region in northeast Brazil Data from 20 SNPs were analyzed for association with DTH+/- status and VL using family-based, stepwise conditional logistic regression analysis Independent associations were observed between the DTH+ phenotype and markers in separate linkage disequilibrium blocks in LECT2 (OR 225; P=0005; 95% CI=128-397) and TGFBI (OR 194; P=0003; 95% CI=124-303) VL child/parent trios gave no evidence of association, but the DTH- phenotype was associated with SNP rs2070874 at IL4 (OR 314; P=0006; 95% CI=138-714), and SNP rs30740 between LECT2 and TGFBI (OR 300; P=0042; 95% CI=104-865) These results indicate several genes in the immune response gene cluster at 5q233-q311 influence outcomes of L chagasi infection in this region of Brazil
56 citations
"Identification of a haplotype block..." refers background in this paper
...In addition to malaria, the 5q31 region shows a linkage to the response against other infectious diseases such as schistosomiasis [5] and leishmaniasis [6]....
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TL;DR: IL-13 −1055T may show resistance to severe malaria through the alteration of IL-13 production as well as other single-nucleotide polymorphisms in the promoters of IL, IL, and IL-4 genes on the 5q31–33.
Abstract: We examined a possible association of single-nucleotide polymorphisms (SNPs) in the promoters of IL-3, IL-4, and IL-13 genes on the 5q31-33, IL-3 -16T>C, IL-4 -590T>C, and IL-13 -1055C>T, with severity of malaria in 361 adult malaria patients in Thailand. The IL-13 -1055T allele showed a significant association with protection from severe malaria (OR 0.51, 95% CI 0.32-0.80; P=0.0032 by the chi(2) test), while allele frequencies of IL-3 -16T>C and IL-4 -590T>C were not statistically different between mild and severe malaria patients. An IL-13 -1055C>T has been reported to alter the regulation of IL-13 production. Thus, IL-13 -1055T may show resistance to severe malaria through the alteration of IL-13 production.
43 citations
"Identification of a haplotype block..." refers background in this paper
...In previous study, rs1800925 was found to be associated with severe malaria [7]....
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...Of which, a SNP in the IL13 promoter region, IL13 -1055T>C (rs1800925), was found to be associated with susceptibility to severe malaria in Thais [7]....
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TL;DR: Interestingly, although single polymorphisms of IL4RA are not associated with any phenotype analyzed, the interaction betweenIL4RA I50V/Q551R was strongly associated with the asthma phenotype, suggesting IL13 and IL4 RA could be relevant markers for allergy to olive pollen and asthma development.
Abstract: Background: Previous results demonstrated that sensitization to specific olive pollen allergens could be related with a different clinical pattern (asthma and/or rhinitis), and that
34 citations
TL;DR: Patients with systemic mastocytosis are at risk to develop disease progression or a nonMC‐lineage haematopoietic neoplasm and one factor may be cytokine regulation of MC progenitors.
Abstract: Background: Mastocytosis is a heterogenous disease involving mast cells (MC) and their progenitors. Cutaneous and systemic variants of the disease have been reported. In contrast to cutaneous mastocytosis (CM), patients with systemic mastocytosis (SM) are at risk to develop disease progression or a nonMC-lineage haematopoietic neoplasm. Little is known, however, about factors predisposing for the development of SM. One factor may be cytokine regulation of MC progenitors.
Methods: We examined the role of the interleukin-13 (IL-13) promoter gene polymorphism -1112C/T, known to be associated with increased transcription, in mastocytosis using allele-specific polymerase chain reaction method. Serum tryptase and IL-13 levels were determined by immunoassay, and expression of the IL-13 receptor in neoplastic MC by reverse transcription-polymerase chain reaction and flow cytometry.
Results: The frequency of the -1112T allele of the IL-13 promoter was significantly higher in patients with SM compared with CM (P < 0.008) and in mastocytosis patients compared with healthy controls (P < 0.0001). Correspondingly, the polymorphism was found to correlate with an elevated serum tryptase level (P = 0.004) and with adult-onset of the disease (P < 0.0015), both of which are almost invariably associated with SM. Serum IL-13 levels were also higher in SM patients compared with CM (P = 0.011), and higher in CT- than in CC carriers (P < 0.05). Finally, we were able to show that neoplastic human MC display IL-13 receptors and grow better in IL-13-containing medium.
Conclusions: The -1112C/T IL-13 gene polymorphism and the resulting ‘hypertranscription’ may predispose for the development of SM.
33 citations
"Identification of a haplotype block..." refers background in this paper
...Among IL13 polymorphisms, rs1800925 in the IL13 promoter has been reported to be associated with various diseases [21-24]....
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