Variation in the ICAM1 gene is not associated with severe malaria phenotypes - PubMed (original) (raw)

doi: 10.1038/gene.2008.38. Epub 2008 Jun 5.

S Auburn, M Diakite, A Green, A Richardson, J Wilson, M Jallow, F Sisay-Joof, M Pinder, M J Griffiths, N Peshu, T N Williams, K Marsh, M E Molyneux, T E Taylor, K A Rockett, D P Kwiatkowski

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Variation in the ICAM1 gene is not associated with severe malaria phenotypes

A E Fry et al. Genes Immun. 2008 Jul.

Abstract

Evidence from autopsy and in vitro binding studies suggests that adhesion of erythrocytes infected with Plasmodium falciparum to the human host intercellular adhesion molecule (ICAM)-1 receptor is important in the pathogenesis of severe malaria. Previous association studies between polymorphisms in the ICAM1 gene and susceptibility to severe malarial phenotypes have been inconclusive and often contradictory. We performed genetic association studies with 15 single nucleotide polymorphisms (SNPs) around the ICAM1 locus. All SNPs were screened in a family study of 1071 trios from The Gambia, Malawi and Kenya. Two key non-synonymous SNPs with previously reported associations, rs5491 (K56M or 'ICAM-1(Kilifi)') and rs5498 (K469E), were tested in an additional 708 Gambian trios and a case-control study of 4058 individuals. None of the polymorphisms were associated with severe malaria phenotypes. Pooled results across our studies for ICAM-1(Kilifi) were, in severe malaria, odds ratio (OR) 1.02, 95% confidence interval (CI) 0.96-1.09, P=0.54, and cerebral malaria OR 1.07, CI 0.97-1.17, P=0.17. We assess the available epidemiological, population genetic and functional evidence that links ICAM-1(Kilifi) to severe malaria susceptibility.

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Figures

Figure 1

Figure 1

Linkage disequilibrium at the ICAM1 locus in 612 Gambian family trios. An exonic model of the ICAM1 gene (along with the nearby ICAM4 and ICAM5 genes), demonstrating the relative positions of our genotyped SNPs. All SNPs were within 5kb of the ICAM1 gene. LD (D′) calculated using the HAPLOVIEW application. A region of relatively high D′ can be seen across the 5′ of the gene, a section coding for the PfEMP1 binding N-terminal of ICAM-1. This haplotype block (7 SNPs from rs5490 to rs5496) was used in our haplotype association analysis.

Figure 2

Figure 2

ICAM-1 amino acid alignments. The first 60 residues of the mature ICAM-1 protein in Man, Common Chimpanzee, Pygmy Chimpanzee, Gorilla, Orangutan, Rhesus Monkey and Mouse (Genbank identifiers AF340038, AF340033, AF340042, AF340036, AF340041, AF340040 and NM_010493). The location of the K to M non-synonymous SNP rs5491 or ICAM-1Kilifi variant is indicated with an asterisk (position 29 of the mature protein).

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