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

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.