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

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

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references 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. AUTHOR INFORMATION Author notes * A Walley Present address: 10Current address: Section of Genomic

Medicine, Imperial College London, Hammersmith Hospital, London, UK., AUTHORS AND AFFILIATIONS * 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 * Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand N J White * Nuffield Department of

Clinical Medicine, University of Oxford, Oxford, UK T Peto * Department of Diagnostic Imaging, National University Hospital, Singapore L K Khor * MRC Laboratories, Banjul, The Gambia D

Kwiatkowski * Center for Tropical Diseases, Cho Quan Hospital, Ho Chi Minh City, Vietnam N Day * Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Oxford, UK N Day

* 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 *

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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 Download citation * Received: 23 May 2007 * Revised: 05 July 2007 * Accepted: 05 July 2007 * Published: 16 August 2007 * Issue Date: October 2007 *

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currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative KEYWORDS * association * _IFNAR1_ * severe malaria