Abstract
BackgroundHost adhesion molecules play a significant role in the pathogenesis of Plasmodium falciparum malaria and changes in their structure or levels in individuals can influence the outcome of infection. The aim of this study was to investigate the association of SNPs of three adhesion molecule genes, ICAM1, PECAM1 and CD36, with severity of falciparum malaria in a malaria-endemic and a non-endemic region of India.MethodsThe frequency distribution of seven selected SNPs of ICAM1, PECAM1 and CD36 was determined in 552 individuals drawn from 24 populations across India. SNP-disease association was analysed in a case-control study format. Genotyping of the population panel was performed by Sequenom mass spectroscopy and patient/control samples were genotyped by SNaPshot method. Haplotypes and linkage disequilibrium (LD) plots were generated using PHASE and Haploview, respectively. Odds-ratio (OR) for risk assessment was estimated using EpiInfo™ version 3.4.ResultsAssociation of the ICAM1 rs5498 (exon 6) G allele and the CD36 exon 1a A allele with increased risk of severe malaria was observed (severe versus control, OR = 1.91 and 2.66, P = 0.02 and 0.0012, respectively). The CD36 rs1334512 (-53) T allele as well as the TT genotype associated with protection from severe disease (severe versus control, TT versus GG, OR = 0.37, P = 0.004). Interestingly, a SNP of the PECAM1 gene (rs668, exon 3, C/G) with low minor allele frequency in populations of the endemic region compared to the non-endemic region exhibited differential association with disease in these regions; the G allele was a risk factor for malaria in the endemic region, but exhibited significant association with protection from disease in the non-endemic region.ConclusionThe data highlights the significance of variations in the ICAM1, PECAM1 and CD36 genes in the manifestation of falciparum malaria in India. The PECAM1 exon 3 SNP exhibits altered association with disease in the endemic and non-endemic region.
Highlights
Host adhesion molecules play a significant role in the pathogenesis of Plasmodium falciparum malaria and changes in their structure or levels in individuals can influence the outcome of infection
Single nucleotide polymorphisms (SNPs) were selected according to their reported functional relevance in disease, including falciparum malaria, in other world populations as well as their frequency in the Indian Genome Variation Consortium (IGVC) 'discovery panel' that was used for an initial screen for discovery of novel SNPs and validation of reported polymorphisms [19]
Very low frequencies of the SNP were observed in populations of both the P. falciparum malaria endemic (MAF = 0.04) and non-endemic region (MAF = 0.02) and the SNP was excluded from the disease association analysis
Summary
Host adhesion molecules play a significant role in the pathogenesis of Plasmodium falciparum malaria and changes in their structure or levels in individuals can influence the outcome of infection. The precise role of some of these molecules in mediating cytoadherence in vivo remains unresolved due to the observation of minimal to no adhesion to these receptors when using patient isolates or under flow conditions [35]. Molecules such as ICAM-1 and VCAM-1 are inducible (e.g. by TNF) and their expression levels are elevated during acute malaria infection [6]. Alterations in levels or structure of these molecules would affect an individual's response to P. falciparum infection and consequent disease manifestation
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