title: 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 alpha and beta subunits of the interferon-alpha receptor (IFNAR1 and IFNAR2), the beta subunit of the interleukin 10 receptor (IL10RB) and the second subunit of the interferon-gamma 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 x 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.
authors: Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. khor_chiea_chuen@sics.a-star.edu.sg
authors: C C
authors: CC
authors: Khor
authors: F O
authors: FO
authors: Vannberg
authors: S J
authors: SJ
authors: Chapman
authors: A
authors: A
authors: Walley
authors: C
authors: C
authors: Aucan
authors: H
authors: H
authors: Loke
authors: N J
authors: NJ
authors: White
authors: T
authors: T
authors: Peto
authors: L K
authors: LK
authors: Khor
authors: D
authors: D
authors: Kwiatkowski
authors: N
authors: N
authors: Day
authors: A
authors: A
authors: Scott
authors: J A
authors: JA
authors: Berkley
authors: K
authors: K
authors: Marsh
authors: N
authors: N
authors: Peshu
authors: K
authors: K
authors: Maitland
authors: T N
authors: TN
authors: Williams
authors: A V S
authors: AV
authors: Hill
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D002648:Child; D002874:Chromosome Mapping; D002891:Chromosomes, Human, Pair 21 / Q000235:genetics*; D005714:Gambia; D005787:Gene Frequency; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D053710:Interleukin-10 Receptor beta Subunit / Q000235:genetics; D007630:Kenya; D015810:Linkage Disequilibrium; D008288:Malaria / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D053633:Receptor, Interferon alpha-beta / Q000235:genetics; D017471:Receptors, Interferon / Q000235:genetics; D014744:Vietnam; D000096743:Interferon gamma Receptor
chemical_list: D005819:Genetic Markers; D053710:Interleukin-10 Receptor beta Subunit; D053633:Receptor, Interferon alpha-beta; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C507964:IFNAR1 protein, human; C508033:IFNAR2 protein, human; C081846:IL10RB protein, human
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