Association between polymorphisms of IL4, IL13, IL10, STAT6 and IFNG genes, cytokines and immunoglobulin E levels with high burden of Schistosoma mansoni in children from schistosomiasis endemic areas of Cameroon

Mewamba, Estelle Mezajou; Noyes, Harry; Tiofack, Arnol Auvaker Zébazé; Kamga, Rolin Mitterran Ndefo; Kamdem, Cyrille Nguemnang; Mengoue, Loic Edmond Tekeu; Ofon, Elvis; Ngassam, Romuald Isaka Kamwa; Nyangiri, Oscar A.; Bucheton, Bruno; Njiokou, Flobert; Womeni, Macaire Hilaire; Matovu, Enock; MacLeod, Annette; Simo, Gustave

doi:10.1016/j.meegid.2023.105416

Cited by 3 publications

(4 citation statements)

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“…This is in keeping with the mixed results from studies of the associations of these SNPs with infection intensity [ 26 , 27 , 29 ]. Further evidence of IL10 association is from a Cameroonian family-based study [ 60 ] where the rs1800871C was associated with low worm burdens while rs1800872A was associated with high worm burdens. IL6 and IL10 cytokines have contrasting immune effects, IL6 is primarily proinflammatory, and it is possible that to control the effect of inflammation the host produces the anti-inflammatory IL10.…”

Section: Discussionmentioning

confidence: 99%

Variants of IL6, IL10, FCN2, RNASE3, IL12B and IL17B loci are associated with Schistosoma mansoni worm burden in the Albert Nile region of Uganda

Nyangiri,

Mulindwa,

Namulondo

et al. 2023

PLoS Negl Trop Dis

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Background Individuals genetically susceptible to high schistosomiasis worm burden may contribute disproportionately to transmission and could be prioritized for control. Identifying genes involved may guide development of therapy. Methodology/Principal findings A cohort of 606 children aged 10–15 years were recruited in the Albert Nile region of Uganda and assessed for Schistosoma mansoni worm burden using the Up-Converting Particle Lateral Flow (UCP-LF) test detecting circulating anodic antigen (CAA), point-of-care Circulating Cathodic Antigen (POC-CCA) and Kato-Katz tests. Whole genome genotyping was conducted on 326 children comprising the top and bottom 25% of worm burden. Linear models were fitted to identify variants associated with worm burden in preselected candidate genes. Expression quantitative trait locus (eQTL) analysis was conducted for candidate genes with UCP-LF worm burden included as a covariate. Single Nucleotide Polymorphism loci associated with UCP-LF CAA included IL6 rs2066992 (OR = 0.43, p = 0.0006) and rs7793163 (OR = 2.0, p = 0.0007); IL21 SNP kgp513476 (OR 1.79, p = 0.0025) and IL17B SNP kgp708159 (OR = 0.35, p = 0.0028). A haplotype in the IL10 locus was associated with lower worm burden (OR = 0.53, p = 0.015) and overlapped SNPs rs1800896, rs1800871 and rs1800872. Significant haplotypes (p<0.05, overlapping significant SNP) associated with worm burden were observed in IL6 and the Th17 pathway IL12B and IL17B genes. There were significant eQTL in the IL6, IL5, IL21, IL25 and IFNG regions. Conclusions Variants associated with S. mansoni worm burden were in IL6, FCN2, RNASE3, IL10, IL12B and IL17B gene loci. However only eQTL associations remained significant after Bonferroni correction. In summary, immune balance, pathogen recognition and Th17 pathways may play a role in modulating Schistosoma worm burden. Individuals carrying risk variants may be targeted first in allocation of control efforts to reduce the burden of schistosomiasis in the community.

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Section: Discussionmentioning

confidence: 99%

Variants of IL6, IL10, FCN2, RNASE3, IL12B and IL17B loci are associated with Schistosoma mansoni worm burden in the Albert Nile region of Uganda

Nyangiri,

Mulindwa,

Namulondo

et al. 2023

PLoS Negl Trop Dis

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“…Another SNV rs2069739A>G, an intron variant of IL13, has also been linked with plasma levels of IL-13. Carriers of the allele A of SNV rs2069739 are associated with an increased risk of having low plasma concentrations of IL-13 ( 30 , 60 ).…”

Section: Discussionmentioning

confidence: 99%

“…Particularly, the SNV rs1800925 located in the promoter region (−1112 C>T, with numbering relative to the IL13 open reading frame ATG), and SNV rs20541, a non-synonymous variant situated in the fourth exon of the gene, have been studied ( 25 ). Additionally, studies have been conducted in schistosomiasis ( 26 – 30 ). However, research on genetic variations of IL13 in protozoan infectious diseases remains limited.…”

Section: Introductionmentioning

confidence: 99%

A fine mapping of single nucleotide variants and haplotype analysis of IL13 gene in patients with Leishmania guyanensis-cutaneous leishmaniasis and plasma cytokines IL-4, IL-5, and IL-13

Junior,

Souza,

Silva

et al. 2023

Front. Immunol.

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IntroductionLeishmaniasis continues to pose a substantial health burden in 97 countries worldwide. The progression and outcome of Leishmania infection are influenced by various factors, including the cytokine milieu, the skin microbiota at the infection site, the specific Leishmania species involved, the genetic background of the host, and the parasite load. In endemic regions to leishmaniasis, only a fraction of individuals infected actually develops the disease. Overexpression of IL-13 in naturally resistant C57BL/6 mice renders them susceptible to L. major infection. Haplotypes constructed from several single nucleotide variant (SNV) along a chromosome fragment may provide insight into any SNV near the fragment that may be genuinely associated with a phenotype in genetic association studies.MethodsWe investigated nine SNVs (SNV1rs1881457A>C, SNV2rs1295687C>G, SNV3rs2069744C>T, SNV4rs2069747C>T, SNV5rs20541A>G, SNV6rs1295685A>G, SNV7rs848A>C, SNV8rs2069750G >C, and SNV9rs847T>C) spanning the entire IL13 gene in patients with L. guyanensis cutaneous leishmaniasis (Lg-CL). ResultsOur analysis did not reveal any significant association between the SNVs and susceptibility/protection against Lg-CL development. However, haplotype analysis, excluding SNV4rs2069747 and SNV8rs2069750 due to low minor allele frequency, revealed that carriers of the haplotype CCCTAAC had a 93% reduced likelihood developing Lg-CL. Similarly, the haplotypes ACCCGCT (ORadj=0.02 [95% CI 0.00–0.07]; p-value, 6.0×10−19) and AGCTAAC (ORadj=0.00[95% CI 0.00–0.00]; p-value 2.7×10−12) appeared to provide protection against the development of Lg-CL. Conversely, carriers of haplotype ACCTGCC have 190% increased likelihood of developing Lg-CL (ORadj=2.9 [95%CI 1.68–5.2]; p-value, 2.5×10−6). Similarly, haplotype ACCCAAT (ORadj=2.7 [95%CI 1.5–4.7]; p-value, 3.2×10−5) and haplotype AGCCGCC are associated with susceptibility to the development of Lg-CL (ORadj=1.7[95%CI 1.04–2.8]; p-value, 0.01). In our investigation, we also found a correlation between the genotypes of rs2069744, rs20541, rs1295685, rs847, and rs848 and plasma IL-5 levels among Lg-Cl patients. Furthermore, rs20541 showed a correlation with plasma IL-13 levels among Lg-Cl patients, while rs2069744 and rs848 showed a correlation with plasma IL-4 levels among the same group. ConclusionsOverall, our study identifies three haplotypes of IL13 associated with resistance to disease development and three haplotypes linked to susceptibility. These findings suggest the possibility of a variant outside the gene region that may contribute, in conjunction with other genes, to differences in susceptibility and partially to the pathology.

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“…In various infectious diseases, rs1800871C and/or rs1800872C is reportedly associated with the onset of chronic infections: a decreased susceptibility to tuberculosis ( Yu et al, 2019 ; Chen and Ma, 2020 ), increased susceptibility to leprosy ( Cardona-Castro et al, 2012 ; Dos Santos et al, 2021 ), decreased susceptibility to herpes zoster ( Haanpää et al, 2002 ), and increased susceptibility to HBV infection ( Ye et al, 2020 ). These alleles are also associated with the course, progression, response to therapy and outcome: a better outcome of leprosy ( Alvarado-Arnez et al, 2015 ), low infection intensity of Schistosoma mansoni in schistosomiasis ( Mewamba et al, 2023 ), reduced risk of cardiomyopathy in Chagas disease ( Grijalva et al, 2022 ), reduced risk of anemia in newborns in Plasmodium falciparum malaria infection ( Lokossou et al, 2013 ), increased risk of Epstein–Barr virus (EBV)-associated hemophagocytic lymphocytosis ( Tang et al, 2021 ), reduced risk of breast cancer after EBV infection ( He et al, 2012 ), increased risk of AIDS-related non-Hodgkin lymphoma ( Wong et al, 2010 ), increased risk of progressive liver disease in chronic hepatitis B ( Miyazoe et al, 2002 ), reduced chance of seroclearance after antiviral treatment of chronic hepatitis B ( Rybicka et al, 2020 ), poor reduced disease severity of chronic hepatitis C ( Świątek-Kościelna et al, 2017 ), and reduced risk of hepatocellular carcinoma in chronic hepatitis C ( Aroucha et al, 2016 ; Sghaier et al, 2017a ). For acute infections, s1800871C and/or rs1800872C is reportedly associated with a decreased risk of dengue infection ( Eloisa Monroy-Muñoz et al, 2023 ) and dengue hemorrhagic fever ( Alagarasu et al, 2015 ), decreased risk of asthma after bronchiolitis in infancy ( Korppi et al, 2017 ), and reduced severity (requiring admission to intensive care unit) of sepsis ( Montoya-Ruiz et al, 2016 ).…”

Section: Discussionmentioning

confidence: 99%

Association of IL6 and IL10 gene promotor polymorphisms with susceptibility to acute necrotizing encephalopathy

et al. 2023

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ObjectiveAcute necrotizing encephalopathy (ANE) is a severe complication of infectious diseases affecting the brain and systemic organs. The main pathogenesis is cytokine storm, in which interleukin-6 (IL-6) and interleukin-10 (IL-10) are candidates for key cytokines. To further elucidate their roles in the etiology and pathogenesis of ANE, we studied polymorphisms in the promotor regions of the IL6 and IL10 genes by genetic and functional analyses.MethodsWe first conducted a case–control association study of four IL6 and three IL10 polymorphisms. We genotyped 31 Japanese ANE cases and compared the results with those of approximately 200 Japanese controls. For the two polymorphisms showing a possible association, we next studied whether the polymorphisms alter the production of IL-6 or IL-10 by lymphoblasts upon phorbol 12-myristate 13-acetate (PMA) stimulation.ResultsThe frequencies of IL6 rs1800796G allele and IL10 rs1800871/rs1800872 CC/CC diplotype were significantly higher in ANE cases than in controls. The IL10 CC/CC diplotype was associated with low IL-10 production, whereas the IL6 GG genotype was not associated with IL-6 production.ConclusionIL10 rs1800871/rs1800872 CC/CC diplotype may predispose Japanese children to ANE by altering IL-10 production in the early phase of infection. Etio-pathogenetic significance of IL6 rs1800796G remains to be elucidated.

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Association between polymorphisms of IL4, IL13, IL10, STAT6 and IFNG genes, cytokines and immunoglobulin E levels with high burden of Schistosoma mansoni in children from schistosomiasis endemic areas of Cameroon

Cited by 3 publications

References 77 publications

Variants of IL6, IL10, FCN2, RNASE3, IL12B and IL17B loci are associated with Schistosoma mansoni worm burden in the Albert Nile region of Uganda

Variants of IL6, IL10, FCN2, RNASE3, IL12B and IL17B loci are associated with Schistosoma mansoni worm burden in the Albert Nile region of Uganda

A fine mapping of single nucleotide variants and haplotype analysis of IL13 gene in patients with Leishmania guyanensis-cutaneous leishmaniasis and plasma cytokines IL-4, IL-5, and IL-13

Association of IL6 and IL10 gene promotor polymorphisms with susceptibility to acute necrotizing encephalopathy

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