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Journal ArticleDOI

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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Citations
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Journal ArticleDOI
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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Journal ArticleDOI
29 Oct 2012-PLOS ONE
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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Journal ArticleDOI
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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Journal ArticleDOI
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

Journal ArticleDOI
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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References
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Journal ArticleDOI
TL;DR: The next version of the assay, DigiTag2, is described, which works with simple protocols and uses unmodified genotyping probes and is suitable for genotypesing an intermediate number of SNPs with a high conversion rate, high accuracy, and low cost.

75 citations


"Identification of a haplotype block..." refers methods in this paper

  • ...A total of 82 SNPs within a 522 kb region on human chromosome 5q31 were genotyped by using the DigiTag2 assay [8] or TaqMan assay (Table 1)....

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Journal ArticleDOI
TL;DR: It is suggested that MRN promotes DNA cleavage and/or mutagenic repair of lesions initiated by activation-induced deaminase, acting in the shared pathway of immunoglobulin gene diversification.
Abstract: Targeted diversification of immunoglobulin variable regions is induced by activation-induced deaminase and may occur by either somatic hypermutation or gene conversion. MRE11-RAD50-NBS1 (MRN) is a ubiquitous and conserved nuclease complex critical for DNA break repair and is essential in class-switch recombination. Here we show that ectopic expression of NBS1, the regulatory subunit of MRN, accelerated hypermutation in the human B cell line Ramos and accelerated gene conversion in the chicken B cell line DT40. In both cases, accelerated diversification depended on MRN complex formation. These data suggest that MRN promotes DNA cleavage and/or mutagenic repair of lesions initiated by activation-induced deaminase, acting in the shared pathway of immunoglobulin gene diversification.

73 citations


"Identification of a haplotype block..." refers background in this paper

  • ..., Ig class-switch recombination, somatic hypermutation, and gene conversion) [14,15]....

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Journal ArticleDOI
TL;DR: The results provide the foundation for additional studies required to fully dissect the associations within this cytokine-rich genomic region, as polymorphisms in closely linked candidate genes, such as IRF1, IL5 or IL4, may be driving these results through linkage disequilibrium.
Abstract: A multitiered genetic association study of 25 215 single-nucleotide polymorphisms (SNPs) in three case-control sample sets (1446 patients and 1432 controls) identified three IL13-linked SNPs (rs1800925, rs20541 and rs848) associated with psoriasis. Although the susceptibility effects at these SNPs were modest (joint allelic odds ratios (ORs): 0.76 to 0.78; P(comb): 1.3E-03 to 2.50E-04), the association patterns were consistent across the sample sets, with the minor alleles being protective. Haplotype analyses identified one common, susceptible haplotype CCG (joint allelic OR=1.27; P(comb)=1.88E-04) and a less common, protective haplotype TTT (joint allelic OR=0.74; P(comb)=7.05E-04). In combination with the other known genetic risk factors, HLA-C, IL12B and IL23R, the variants reported here generate an 11-fold psoriasis-risk differential. Residing in the 5q31 cytokine gene cluster, IL13 encodes an important T-cell-derived cytokine that regulates cell-mediated immunity. These results provide the foundation for additional studies required to fully dissect the associations within this cytokine-rich genomic region, as polymorphisms in closely linked candidate genes, such as IRF1, IL5 or IL4, may be driving these results through linkage disequilibrium.

69 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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Journal ArticleDOI
01 Aug 2009-Allergy
TL;DR: This work has shown that suppression of IL13 and IL4 in mice with atopy and asthma is associated with poorer lung function and some studies suggest association with chronic obstructive pulmonary disease.
Abstract: Background: Genetic variants of the two adjacent genes, IL13 and IL4 have frequently been reported as being associated with susceptibility to atopy and asthma, both in adults and children, and some studies also suggest association with lung function and chronic obstructive pulmonary disease. Methods: In this study, we examined for the first time the effect of these variants in 2918 adults in a longitudinal birth cohort, the British National Survey of Health and Development, where there are extensive life style, developmental and environmental data. We examine two IL13 single nucleotide polymorphisms (SNPs) IL13 rs20541 (R110Q) and rs1800925 (−1024C>T) and one IL4 SNP, rs2070874 (−33C>T) with likely function. Results: We show that IL13 rs20541 and rs1800925 are each significantly associated with self-reported asthma and allergy, and that this association is not confounded by any of the known developmental and environmental risk factors for asthma and atopy, including in particular place of birth. IL13 rs20541 does however act as a confounder for the IL13 rs1800925 associations, meaning that there is no statistical support for rs1800925 having an independent effect. There is nevertheless evidence for interaction between smoking and rs1800925, with allergy as outcome. None of the SNPs showed association with measures of lung function, nor any interaction with the effect of smoking on lung function. Conclusion: In a longitudinal population cohort we have established a role for polymorphism of IL13 in determining susceptibility to both atopy and asthma.

66 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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Journal ArticleDOI
TL;DR: The results confirm the importance of chromosome 5q31–q33 in the genetic control of PFBI levels and detect allelic association in the presence of linkage between blood infection levels and D5S487.
Abstract: Linkage and association between Plasmodium falciparum blood infection levels and chromosome 5q31–q33

62 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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