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

Abstract

Pro-inflammatory cytokines IFNγ and IFNα function through their cellular receptors IFNγR1 and IFNαR1, respectively to mediate immune processes during malaria infection. A total of 21 SNPs, 2 ins/del polymorphisms and a microsatellite repeat, selected on the basis of their reported association with infectious diseases including malaria in world populations, were analysed for association with Plasmodium falciparum malaria susceptibility in a case-control study with adult patients and ethnically-matched controls drawn from a disease meso- to hyperendemic and a nonendemic region of India. Among the five IFNG SNPs tested, an intron 3 and a 3′UTR SNP associated with disease in the endemic region. In addition, large (CA)_n repeats of IFNG intron 1 associated with protection from severe malaria in the endemic region (severe vs. control, odds ratio = 0.21, 95% CI = 0.08–0.52, P = 1.3 × 10^-4). The TA11CAG haplotype (rs2069705 T/C, rs2430561 A/T, rs3138557 (CA)_n, rs2069718 T/C, rs2069727 A/G, rs2069728 G/A) carrying a short CA₁₁ repeat also exhibited very strong association with severe malaria, particularly in the endemic region (severe vs. control, OR = 14.56, 95% CI = 3.39–85.81, P = 3 × 10^-5). One SNP each from the IFNA8 and IFNA17 of IFNA gene cluster had a protective effect in the non-endemic region but not in the endemic region. A promoter and an intron 2 SNP of IFNAR1 were risk factors for disease and the IFNAR1 haplotype GCCAGG (rs2843710 C/G, rs2850015 C/T, +6993 C/T, rs2243594 A/G, rs1012335 G/C, rs2257167 G/C) carrying both the risk alleles strikingly associated with disease manifestation in the endemic region (severe vs. control, OR = 27.14, 95% CI = 3.12–1254, P = 2 × 10^-5; non-severe vs. control, OR = 61.87, 95% CI = 10.08–2521, P = 1 × 10^-8). The data indicates dissimilar contribution of cytokine and cytokine receptor variants to disease in populations residing in areas of differential malaria endemicity.