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

Genes Immun. 2007 Oct;8(7):570-6. doi: 10.1038/sj.gene.6364417. Epub 2007 Aug 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Genetic Markers
  • IFNAR1 protein, human
  • IFNAR2 protein, human
  • IL10RB protein, human
  • Interleukin-10 Receptor beta Subunit
  • Receptors, Interferon
  • interferon gamma receptor
  • Receptor, Interferon alpha-beta