Polymorphisms in host genes encoding NOSII, C-reactive protein, and adhesion molecules thrombospondin and E-selectin are risk factors for Plasmodium falciparum malaria in India

Abstract

Cytoadherence of Plasmodium falciparum-infected red blood cells (RBCs) in host microvasculature and complex regulation of the immune response are important contributors to the clinical outcome of disease. We tested the association of 23 single nucleotide polymorphisms (SNPs) and a microsatellite repeat in adhesion molecule genes THBS1 and ESEL, and immune regulatory molecule genes NOSII, CRP, and MBL2 with falciparum malaria in populations residing in a malaria-endemic and a non-endemic region of India. The THBS1 haplotype CCCCA (rs1478604, rs7170682, rs2664141, rs12912082, rs3743125) was a risk factor in the endemic region (relative risk = 3.78) and an ESEL SNP (rs5368, His468Tyr) associated with cerebral malaria (CM) [CM vs. non-cerebral malaria (NCM), odds ratio (OR) = 2.23, p = 0.03]. In the non-endemic region, an ESEL 3′UTR SNP (rs5359) associated with enhanced risk of disease (OR = 3.62, p = 1 × 10^-4) and the CT genotype of the CRP promoter SNP (C/T/A) strongly associated with protection (severe vs. control, OR = 0.29, p = 6 × 10^-5). Long repeat alleles of the NOSII promoter microsatellite (CCTTT)n exhibited strong association with protection and the NOSII ATG haplotype (rs3729508, rs2297520, rs9282801) was strongly protective against severe malaria in both regions (endemic, severe vs. control, OR = 0.05, p = 0.0001; non-endemic, severe vs. control, OR = 0.3, p = 1 × 10^-5). Our results suggest differential contribution of variants of the investigated genes in determining the outcome of malaria in Indian populations.