Type I Interferon Receptor Variants in Gene Regulatory Regions are Associated with Susceptibility to Cerebral Malaria in Malawi

Catherine Manix Feintuch Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York;

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Archana Tare Department of Genetics, Albert Einstein College of Medicine, Bronx, New York;

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Lucas R. Cusumano Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York;

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Jacqueline Benayoun Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York;

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Seungjin Ryu Department of Genetics, Albert Einstein College of Medicine, Bronx, New York;

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Alick Sixpence Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi;

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Karl Seydel Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi;
Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan;

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Miriam Laufer Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore, Maryland

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Terrie Taylor Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi;
Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan;

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Yousin Suh Department of Genetics, Albert Einstein College of Medicine, Bronx, New York;

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Johanna P. Daily Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York;

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Cerebral malaria (CM) remains an important cause of morbidity and mortality. Risk for developing CM partially depends on host genetic factors, including variants encoded in the type I interferon (IFN) receptor 1 (IFNAR1). Type I IFNs bind to IFNAR1 resulting in increased expression of IFN responsive genes, which modulate innate and adaptive immune responses. To comprehensively study IFNAR1 genetic variant associations in Malawians with CM or uncomplicated malaria, we used a tag single nucleotide polymorphism approach, based on the HapMap Yoruba in Ibadan, Nigeria, population database. We identified three novel (rs914142, rs12626750, and rs1041867) and one previously published (Chr21:34696785 [C > G]) IFNAR1 variants to be associated with CM. Some of these variants are in gene regulatory regions. Chr21:34696785 (C > G) is in a region encoding histone modifications and transcription factor–binding sites, which suggests gene regulatory activity. Rs12626750 is predicted to bind embryonic lethal abnormal vision system-like RNA-binding protein 1, a RNA-binding protein which can increase the type I IFN response. Furthermore, we examined these variants in an expression quantitative trait loci database and found that a protective variant, rs914142, is associated with lower expression of IFNAR1, whereas the CM-associated variant rs12626750 was associated with increased IFNAR1 expression, suggesting that activation of the type I IFN pathway may contribute to pathogenesis of CM. Future functional studies of IFNAR1 variants are now needed to clarify the role of this pathway in severe malarial diseases.

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Author Notes

Address correspondence to Johanna P. Daily, Albert Einstein College of Medicine, 1301 Morris Park Ave., Bronx, NY 10461. E-mail: jdaily@einstein.yu.edu

Financial support: This work was supported by the National Institute of Allergy and Infectious Diseases: NIH 3U19 AI089683-03S1 and NIH-RO1 (PI) R01AI077623.

Authors’ addresses: Catherine Manix Feintuch, Archana Tare, Yousin Suh, and Johanna P. Daily, Albert Einstein College of Medicine, Bronx, NY, E-mails: cmanix@gmail.com, archana.tare@phd.einstein.yu.edu, yousin.suh@einstein.yu.edu, and jdaily@einstein.yu.edu. Lucas R. Cusumano, University of California, Los Angeles, Los Angeles, CA, E-mail: lcusumano@mednet.ucla.edu. Jacqueline Benayoun, Downstate Medical Center, Brooklyn, NY, E-mail: jacqueline.benayoun@mail.yu.edu. Seungjin Ryu, Yale University, New Haven, CT, E-mail: seungjin.ryu@phd.einstein.yu.edu. Alick Sixpence, Malawi Medical College, Blantyre, Malawi, E-mail: asixpence@mac.medcol.mw. Karl Seydel and Terrie Taylor, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, E-mails: seydel@msu.edu and ttmalawi@gmail.org. Miriam Laufer, University of Maryland School of Medicine, Baltimore, MD, E-mail: mlaufer@som.umaryland.edu.

These authors contributed equally to this work.

  • 1.

    World Health Organization, 2017. World Malaria Report 2017, Geneva, Switzerland: World Health Organization.

    • PubMed
    • Export Citation
  • 2.

    World Health Organization, 2015. Guidelines for the Treatment of Malaria. 3rd edition. Geneva, Switzerland: World Health Organization.

    • PubMed
    • Export Citation
  • 3.

    Kwiatkowski DP, 2005. How malaria has affected the human genome and what human genetics can teach us about malaria. Am J Hum Genet 77: 171192.

  • 4.

    Aucan C, Walley AJ, Hennig BJ, Fitness J, Frodsham A, Zhang L, Kwiatkowski D, Hill AV, 2003. Interferon-alpha receptor-1 (IFNAR1) variants are associated with protection against cerebral malaria in the Gambia. Genes Immun 4: 275282.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Khor CC et al. 2007. Positive replication and linkage disequilibrium mapping of the chromosome 21q22.1 malaria susceptibility locus. Genes Immun 8: 570576.

  • 6.

    Ball EA, Sambo MR, Martins M, Trovoada MJ, Benchimol C, Costa J, Antunes Goncalves L, Coutinho A, Penha-Goncalves C, 2013. IFNAR1 controls progression to cerebral malaria in children and CD8+ T cell brain pathology in Plasmodium berghei-infected mice. J Immunol 190: 51185127.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Stryker GA, Nickell SP, 1995. Trypanosoma cruzi: exposure of murine cells to live parasites in vitro leads to enhanced surface class I MHC expression which is type I interferon-dependent. Exp Parasitol 81: 564573.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Stetson DB, Medzhitov R, 2006. Type I interferons in host defense. Immunity 25: 373381.

  • 9.

    Berry MP et al. 2010. An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis. Nature 466: 973977.

  • 10.

    Stifter SA, Feng CG, 2015. Interfering with immunity: detrimental role of type I IFNs during infection. J Immunol 194: 24552465.

  • 11.

    Pichyangkul S et al. 2004. Malaria blood stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a toll-like receptor 9-dependent pathway. J Immunol 172: 49264933.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Sharma S et al. 2011. Innate immune recognition of an AT-rich stem-loop DNA motif in the Plasmodium falciparum genome. Immunity 35: 194207.

  • 13.

    Krupka M, Seydel K, Feintuch CM, Yee K, Kim R, Lin CY, Calder RB, Petersen C, Taylor T, Daily J, 2012. Mild Plasmodium falciparum malaria following an episode of severe malaria is associated with induction of the interferon pathway in Malawian children. Infect Immun 80: 11501155.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 14.

    Vigario AM et al. 2007. Recombinant human IFN-alpha inhibits cerebral malaria and reduces parasite burden in mice. J Immunol 178: 64166425.

  • 15.

    Morrell CN, Srivastava K, Swaim A, Lee MT, Chen J, Nagineni C, Hooks JJ, Detrick B, 2011. Beta interferon suppresses the development of experimental cerebral malaria. Infect Immun 79: 17501758.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Palomo J et al. 2013. Type I interferons contribute to experimental cerebral malaria development in response to sporozoite or blood-stage Plasmodium berghei ANKA. Eur J Immunol 43: 26832695.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Haque A et al. 2011. Type I interferons suppress CD4+ T-cell-dependent parasite control during blood-stage Plasmodium infection. Eur J Immunol 41: 26882698.

  • 18.

    Spaulding E, Fooksman D, Moore JM, Saidi A, Feintuch CM, Reizis B, Chorro L, Daily J, Lauvau G, 2016. STING-licensed macrophages prime type I IFN production by plasmacytoid dendritic cells in the bone marrow during severe Plasmodium yoelii malaria. PLoS Pathog 12: e1005975.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Zander RA, Guthmiller JJ, Graham AC, Pope RL, Burke BE, Carr DJ, Butler NS, 2016. Type I interferons induce T regulatory 1 responses and restrict humoral immunity during experimental malaria. PLoS Pathog 12: e1005945.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Mooney JP, Wassmer SC, Hafalla JC, 2017. Type I interferon in malaria: a balancing act. Trends Parasitol 33: 257260.

  • 21.

    Barrera V et al. 2015. Severity of retinopathy parallels the degree of parasite sequestration in the eyes and brains of Malawian children with fatal cerebral malaria. J Infect Dis 211: 19771986.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    World Health Organization, 2015. Guidelines for the Treatment of Malaria, 3rd edition. Geneva, Switzerland: WHO.

    • PubMed
    • Export Citation
  • 23.

    Taylor TE, Fu WJ, Carr RA, Whitten RO, Mueller JS, Fosiko NG, Lewallen S, Liomba NG, Molyneux ME, 2004. Differentiating the pathologies of cerebral malaria by postmortem parasite counts. Nat Med 10: 143145.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Mathanga DP, Walker ED, Wilson ML, Ali D, Taylor TE, Laufer MK, 2012. Malaria control in Malawi: current status and directions for the future. Acta Trop 121: 212217.

  • 25.

    International HapMap Consortium, 2003. The international HapMap project. Nature 426: 789796.

  • 26.

    Barrett JC, Fry B, Maller J, Daly MJ, 2005. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21: 263265.

  • 27.

    The 1000 Genomes Project Consortium; Auton A, Brooks LD, Durbin RM, Garrison EP, Kang HM, Korbel JO, Marchini JL, McCarthy S, McVean GA, Abecasis GR, 2015. A global reference for human genetic variation. Nature 526: 6874.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Exome Variant Server, 2011. NHLBI Exome Sequencing Project (ESP). Available at: http://evs.gs.washington.edu/EVS/. Accessed December 15, 2011.

    • PubMed
    • Export Citation
  • 29.

    Namipashaki A, Razaghi-Moghadam Z, Ansari-Pour N, 2015. The essentiality of reporting Hardy-Weinberg equilibrium calculations in population-based genetic association studies. Cell J 17: 187192.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Purcell S et al. 2007. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 81: 559575.

  • 31.

    Benjamini Y, Hochberg Y, 1995. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J R Stat Soc B 57: 289300.

  • 32.

    Ward LD, Kellis M, 2012. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res 40: D930D934.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM, Haussler D, 2002. The human genome browser at UCSC. Genome Res 12: 9961006.

  • 34.

    Boyle AP et al. 2012. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res 22: 17901797.

  • 35.

    Aponte JJ, Menendez C, Schellenberg D, Kahigwa E, Mshinda H, Vountasou P, Tanner M, Alonso PL, 2007. Age interactions in the development of naturally acquired immunity to Plasmodium falciparum and its clinical presentation. PLoS Med 4: e242.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Westra HJ et al. 2013. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 45: 12381243.

  • 37.

    Rowell J, Koitabashi N, Kass DA, Barth AS, 2014. Dynamic gene expression patterns in animal models of early and late heart failure reveal biphasic-bidirectional transcriptional activation of signaling pathways. Physiol Genomics 46: 779787.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    O’Reilly D, Quinn CM, El-Shanawany T, Gordon S, Greaves DR, 2003. Multiple Ets factors and interferon regulatory factor-4 modulate CD68 expression in a cell type-specific manner. J Biol Chem 278: 2190921919.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Hikami K et al. 2011. Association of a functional polymorphism in the 3′-untranslated region of SPI1 with systemic lupus erythematosus. Arthritis Rheum 63: 755763.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Kubosaki A et al. 2010. The combination of gene perturbation assay and ChIP-chip reveals functional direct target genes for IRF8 in THP-1 cells. Mol Immunol 47: 22952302.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 41.

    Pruitt KD et al. 2014. RefSeq: an update on mammalian reference sequences. Nucleic Acids Res 42: D756D763.

  • 42.

    Herdy B et al. 2015. The RNA-binding protein HuR/ELAVL1 regulates IFN-β mRNA abundance and the type I IFN response. Eur J Immunol 45: 15001511.

  • 43.

    Takeuchi O, 2015. HuR keeps interferon-β mRNA stable. Eur J Immunol 45: 12961299.

  • 44.

    de Weerd NA, Samarajiwa SA, Hertzog PJ, 2007. Type I interferon receptors: biochemistry and biological functions. J Biol Chem 282: 2005320057.

  • 45.

    Idro R, Jenkins NE, Newton CR, 2005. Pathogenesis, clinical features, and neurological outcome of cerebral malaria. Lancet Neurol 4: 827840.

  • 46.

    Tishkoff SA et al. 2009. The genetic structure and history of Africans and African Americans. Science 324: 10351044.

  • 47.

    Xing J, Witherspoon DJ, Watkins WS, Zhang Y, Tolpinrud W, Jorde LB, 2008. HapMap tagSNP transferability in multiple populations: general guidelines. Genomics 92: 4151.

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