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 a and b subunits of the interferon-a receptor (IFNAR1 and IFNAR2), the b subunit of the interleukin 10 receptor (IL10RB) and the second subunit of the interferon-g 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 À576 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 ¼ 0.002), Kenyan (P ¼ 0.022) and Vietnamese (P ¼ 0.005) case-control studies. When all three studies were combined, using the Mantel-Haenszel test, the presence of IFNAR1 À576G was associated with a substantially elevated risk of severe malaria (N ¼ 2444, OR ¼ 1.38, 95% CI: 1.17-1.64; P ¼ 1.7 Â 10 À4 ). 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.

IFNAR1 Controls Progression to Cerebral Malaria in Children and CD8+ T Cell Brain Pathology in Plasmodium berghei–Infected Mice

“…In Gambian children, two SNPs, which were identified in the IFNAR1 gene in intron 3 and exon 4, were associated with severe malaria and CM (13). However, the study of Gambian, Kenyan, and Vietnamese populations (14) highlighted positive associations in the 59 region of the IFNAR1 locus. This was also found as a region of strong association in our study, suggesting that the 59 region of the IFNAR1 gene known to control transcriptional activity (35) represents a malaria-susceptibility factor throughout diverse populations.…”

“…The IFNAR1 gene has been associated with severe forms of malaria (13,14). In this study, we used a cohort of Angolan children to identify IFNAR1 genetic variants that specifically modify the risk for progressing from uncomplicated forms of malaria to CM syndrome.…”

“…12). Initial studies by Hill and coworkers (13,14) began exploring the necessary role of type I IFN (type I IFN) in CM progression and found that genetic variants in IFNAR1 led to protection from CM development. Because IFNAR1 is the key signaling receptor mediating type I IFN activity (15) and is expressed on virtually every cell surface (16,17), the impact that type I IFN has on the immune response is vast.…”

Mild Plasmodium falciparum Malaria following an Episode of Severe Malaria Is Associated with Induction of the Interferon Pathway in Malawian Children

“…Genetic studies of malaria-infected patients have found an association between mutations within IFN-␣ receptor (IFN-␣R) and severe disease susceptibility, suggesting that the type I IFN pathway may play a role in severe disease (3,17). IFN-␣ has been identified in a subset of malaria-infected patient sera (25,29).…”

Interferon-γ (IFNG) microsatellite repeat and single nucleotide polymorphism haplotypes of IFN-α receptor (IFNAR1) associated with enhanced malaria susceptibility in Indian populations

“…A promoter polymorphism each of IFNA2 and IFNA8 has recently been shown to be associated with reduced IFNa production and increased susceptibility to severe malarial anaemia and mortality in Kenyan populations (Kempaiah et al, 2012). Association of IFNAR1 variants with protection against severe and cerebral malaria in African and South East Asian populations has also been reported (Aucan et al, 2003;Ball et al, 2013;Khor et al, 2007).…”