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Positive replication and linkage disequilibrium mapping of the chromosome 21q22.1 malaria susceptibility locus

Genes & Immunity volume 8, pages 570–576 (2007)Cite this article

Abstract

Four cytokine receptor genes are located on Chr21q22.11, encoding the α and β subunits of the interferon-α receptor (IFNAR1 and IFNAR2), the β subunit of the interleukin 10 receptor (IL10RB) and the second subunit of the interferon-γ receptor (IFNGR2). We previously reported that two variants in IFNAR1 were associated with susceptibility to malaria in Gambians. We now present an extensive fine-scale mapping of the associated region utilizing 45 additional genetic markers obtained from public databases and by sequencing a 44 kb region in and around the IFNAR1 gene in 24 Gambian children (12 cases/12 controls). Within the IFNAR1 gene, a newly studied C → G single-nucleotide polymorphism (IFNAR1 272354c-g) at position −576 relative to the transcription start was found to be more strongly associated with susceptibility to severe malaria. Association was observed in three populations: in Gambian (P=0.002), Kenyan (P=0.022) and Vietnamese (P=0.005) case–control studies. When all three studies were combined, using the Mantel–Haenszel test, the presence of IFNAR1 −576G was associated with a substantially elevated risk of severe malaria (N=2444, OR=1.38, 95% CI: 1.17–1.64; P=1.7 × 10−4). This study builds on previous work to further highlight the importance of the type-I interferon pathway in malaria susceptibility and illustrates the utility of typing SNPs within regions of high linkage disequilibrium in multiple populations to confirm initial positive associations.

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Acknowledgements

We thank the patients from the Gambian, Kenyan and Vietnamese malaria study populations, as well as the many investigators involved in the original case-control studies in these populations for their contributions. We acknowledge Angela Frodsham and Branwen Hennig for information on IFNAR2 F8S and IL10RB markers +1165 and +1797. This work was funded by the Wellcome Trust, UK and the Agency for Science, Technology and Research (A-STAR), Singapore. CCK is a scholar of A-STAR and is a member of the MBBS–PhD programme, Faculty of Medicine, National University of Singapore. AS, JAB, KM, NP, KM and TNW are supported by the Wellcome Trust and the Kenya Medical Research Institute. AVSH is a Wellcome Trust Principal Research Fellow. This study was published with permission from the Director of KEMRI.

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Author notes

  1. A Walley

    Present address: 10Current address: Section of Genomic Medicine, Imperial College London, Hammersmith Hospital, London, UK.,

Authors and Affiliations

  1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

    C C Khor, F O Vannberg, S J Chapman, A Walley, C Aucan, H Loke, D Kwiatkowski & A V S Hill

  2. Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand

    N J White

  3. Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK

    T Peto

  4. Department of Diagnostic Imaging, National University Hospital, Singapore

    L K Khor

  5. MRC Laboratories, Banjul, The Gambia

    D Kwiatkowski

  6. Center for Tropical Diseases, Cho Quan Hospital, Ho Chi Minh City, Vietnam

    N Day

  7. Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, UK

    N Day

  8. KEMRI/Wellcome Trust Programme, Centre for Geographic Medicine Research, Kilifi District Hospital, Kilifi, Kenya

    A Scott, J A Berkley, K Marsh, N Peshu, K Maitland & T N Williams

  9. Department of Paediatrics, John Radcliffe Hospital, University of Oxford, Oxford, UK

    T N Williams

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Correspondence to C C Khor.

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The authors declare no competing financial interests.

Supplementary Information accompanies the paper on Genes and Immunity website (http://www.nature.com/gene)

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Khor, C., Vannberg, F., Chapman, S. et al. Positive replication and linkage disequilibrium mapping of the chromosome 21q22.1 malaria susceptibility locus. Genes Immun 8, 570–576 (2007). https://doi.org/10.1038/sj.gene.6364417

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  • DOI: https://doi.org/10.1038/sj.gene.6364417

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