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.

Original publication

DOI

10.1038/sj.gene.6364417

Type

Journal article

Journal

Genes and immunity

Publication Date

10/2007

Volume

8

Pages

570 - 576

Addresses

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. khor_chiea_chuen@sics.a-star.edu.sg

Keywords

Chromosomes, Human, Pair 21, Humans, Malaria, Genetic Predisposition to Disease, Receptors, Interferon, Genetic Markers, Case-Control Studies, Chromosome Mapping, Gene Frequency, Genotype, Haplotypes, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Alleles, Adult, Child, Kenya, Gambia, Vietnam, Receptor, Interferon alpha-beta, Interleukin-10 Receptor beta Subunit