Haplotype of non-synonymous mutations within IL-23R is associated with susceptibility to severe malaria anemia in a P. falciparum holoendemic transmission area of Kenya

Munde, Elly O.; Raballah, Evans; Okeyo, Winnie A.; Ong’echa, John Michael; Perkins, Douglas J; Ouma, Collins

doi:10.1186/s12879-017-2404-y

Cited by 12 publications

(8 citation statements)

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“…falciparum cases from India [ 22 ] and with the risk of cerebral malaria in Africa [ 23 ]. IL-23R haplotypes have also been associated with increased susceptibility to severe malarial anaemia in Kenya [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Novel genetic polymorphisms associated with severe malaria and under selective pressure in North-eastern Tanzania

et al. 2018

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Significant selection pressure has been exerted on the genomes of human populations exposed to Plasmodium falciparum infection, resulting in the acquisition of mechanisms of resistance against severe malarial disease. Many host genetic factors, including sickle cell trait, have been associated with reduced risk of developing severe malaria, but do not account for all of the observed phenotypic variation. Identification of novel inherited risk factors relies upon high-resolution genome-wide association studies (GWAS). We present findings of a GWAS of severe malaria performed in a Tanzanian population (n = 914, 15.2 million SNPs). Beyond the expected association with the sickle cell HbS variant, we identify protective associations within two interleukin receptors (IL-23R and IL-12RBR2) and the kelch-like protein KLHL3 (all P<10−6), as well as near significant effects for Major Histocompatibility Complex (MHC) haplotypes. Complementary analyses, based on detecting extended haplotype homozygosity, identified SYNJ2BP, GCLC and MHC as potential loci under recent positive selection. Through whole genome sequencing of an independent Tanzanian cohort (parent-child trios n = 247), we confirm the allele frequencies of common polymorphisms underlying associations and selection, as well as the presence of multiple structural variants that could be in linkage with these SNPs. Imputation of structural variants in a region encompassing the glycophorin genes on chromosome 4, led to the characterisation of more than 50 rare variants, and individually no strong evidence of associations with severe malaria in our primary dataset (P>0.3). Our approach demonstrates the potential of a joint genotyping-sequencing strategy to identify as-yet unknown susceptibility loci in an African population with well-characterised malaria phenotypes. The regions encompassing these loci are potential targets for the design of much needed interventions for preventing or treating malarial disease.

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Section: Discussionmentioning

confidence: 99%

Novel genetic polymorphisms associated with severe malaria and under selective pressure in North-eastern Tanzania

et al. 2018

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“…However, the above study did not consider different haemoglobin beta sub-unit (HBB) genotypes more so sickle cell gene mutation (6GAG > 6GTG). Moreover, as shown by several studies in western Kenya, it is plausible that SMA in children is as a result of imbalance in the production of both pro-inflammatory and anti-inflammatory mediators, polymorphisms in immune regulatory genes and exacerbations in the presence of co-infections with HIV-1 and pathogenic bacteria [10][11][12]. Whether malaria is severe or non-severe, it is important to note that the overlapping interactions between haemoglobinopathy especially in the haemoglobin beta sub-unit gene (HBB) and malaria, remains a complex biological conundrum that is not well understood [13].…”

Section: Introductionmentioning

confidence: 99%

Haematological abnormalities in children with sickle cell disease and non-severe malaria infection in western Kenya

et al. 2021

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Background In Plasmodium falciparum infection, clinical conditions such as anaemia, thrombocytopenia and leukocytosis are common. Mutation in haemoglobin sub-unit beta gene (HBB) may be a genetic factor responsible for these haematological changes during infection. However, the contributions of the carriage of different HBB genotypes on these changes remain largely unknown. Methodology In this cross-sectional study, we evaluated haematological abnormalities in P. falciparum-infected children (n = 217, aged 1–192 months) with different haemoglobin sub-unit beta (HBB) genotypes (HbAA, HbAS and HbSS). Children with acute febrile conditions were recruited at Jaramogi Oginga Odinga Teaching and Referral Hospital at the outpatient clinic. Haematological parameters were determined using Beckman Coulter counter ACTdiff2™ while HBB genotyping was done using TaqMan® SNP genotyping assay. Chi-square (χ2) was used to determine differences between proportions. Differences in haematological parameters were compared across groups using Kruskal Wallis test and between groups using Mann Whitney U test. Partial correlation test was used to determine correlation between haematological parameters and sickle cell genotypes while controlling for age and sex. Results Haemoglobin (Hb), [median (IQR); 7.3 (1.3), P = 0.001], haematocrit (HCT), [median (IQR); 26.4 (4.4), P = 0.009], red blood cells (RBC), [median (IQR); 3.2 (1.7), P = 0.048] were markedly reduced in HbSS, however, red cell distribution with (RDW) [median (IQR); 14.9 (3.3), P = 0.030] was increased in malaria infected children with HbSS. Severe anaemia was highest in HbSS (23.1%) followed by HbAA (8.6%) and HbAS (7.1%). There were no differences in platelet count (P = 0.399) hence no severe thrombocytopeania across the genotypes. Leukocytosis was highest in HbSS (69.2%), 42% in HbAS and 31% in HbAA. The RBC, HCT and Hb had negative correlation with RDW in HbSS in malarial-infected children (r = − 0.725, P = 0.008), (r = − 0.718, P = 0.009) and (r = − 0.792, P = 0.002), respectively. Conclusion Our study reveals that anaemia is the most common abnormality in malaria-infected children with carriage of HbSS. The RBC, HCT and Hb concentration decrease with increase in RDW levels in infected children with carriage of HbSS compared to other HBB genotypes. Therefore, carriage of HbSS genotype is correlated with severity of haematological abnormalities.

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“…Phagocytosis of parasitic products, such as P. falciparum -derived haemozoin ( Pf Hz), alters inflammatory mediator production and promotes suppression of erythropoiesis [11,12]. Our previous genetic investigations in Kenyan children demonstrate that polymorphic variability in host immune response genes can impart functional changes in inflammatory mediator production that influence susceptibility to SMA [[13], [14], [15], [16], [17], [18]]. We recently used an unbiased approach to further identify genes and gene pathways involved in the pathogenesis of SMA by performing high-throughput genotyping and whole transcriptome in a subset of Kenyan children with discrete mild and severe malaria phenotypes.…”

Section: Introductionmentioning

confidence: 99%

Molecular basis of reduced LAIR1 expression in childhood severe malarial anaemia: Implications for leukocyte inhibitory signalling

et al. 2019

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Background Leukocyte-associated immunoglobulin like receptor-1 (LAIR1) is a transmembrane inhibitory receptor that influences susceptibility to a myriad of inflammatory diseases. Our recent investigations of severe malarial anaemia (SMA) pathogenesis in Kenyan children discovered that novel LAIR1 genetic variants which were associated with decreased LAIR1 transcripts enhanced the longitudinal risk of SMA and all-cause mortality. Methods To characterize the molecular mechanism(s) responsible for altered LAIR1 signalling in severe malaria, we determined LAIR1 transcripts and protein, sLAIR1, sLAIR2, and complement component 1q (C1q) in children with malarial anaemia, followed by a series of in vitro experiments investigating the LAIR1 signalling cascade. Findings Kenyan children with SMA had elevated circulating levels of soluble LAIR1 (sLAIR1) relative to non-SMA (1.69-fold P < .0001). The LAIR1 antagonist, sLAIR2, was also elevated in the circulation of children with SMA (1.59 fold-change, P < .0001). There was a positive correlation between sLAIR1 and sLAIR2 (ρ = 0.741, P < .0001). Conversely, circulating levels of complement component 1q (C1q), a LAIR1 natural ligand, were lower in SMA (−1.21-fold P = .048). These in vivo findings suggest that reduced membrane-bound LAIR1 expression in SMA is associated with elevated production of sLAIR1, sLAIR2 (antagonist), and limited C1q (agonist) availability. Since reduced LAIR1 transcripts in SMA were associated with increased acquisition of haemozoin ( Pf Hz) by monocytes ( P = .028), we explored the relationship between acquisition of intraleukocytic Pf Hz, LAIR1 expression, and subsequent impacts on leukocyte signalling in cultured PBMCs from malaria-naïve donors stimulated with physiological concentrations of Pf Hz (10 μg/mL). Phagocytosis of Pf Hz reduced LAIR1 transcript and protein expression in a time-dependent manner ( P < .050), and inhibited LAIR1 signalling through decreased phosphorylation of LAIR1 ( P < .0001) and SH2-domain containing phosphatase-1 (SHP-1) ( P < .001). This process was associated with NF-κB activation ( P < .0001) and enhanced production of IL-6, IL-1β, and TNF-α (all P < .0001). Interpretation Collectively, these findings demonstrate that SMA is characterized by reduced LAIR1 transmembrane expression, reduced C1q, and enhanced production of sLAIR1 and s...

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Haplotype of non-synonymous mutations within IL-23R is associated with susceptibility to severe malaria anemia in a P. falciparum holoendemic transmission area of Kenya

Cited by 12 publications

References 60 publications

Novel genetic polymorphisms associated with severe malaria and under selective pressure in North-eastern Tanzania

Novel genetic polymorphisms associated with severe malaria and under selective pressure in North-eastern Tanzania

Haematological abnormalities in children with sickle cell disease and non-severe malaria infection in western Kenya

Molecular basis of reduced LAIR1 expression in childhood severe malarial anaemia: Implications for leukocyte inhibitory signalling

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