IL-4 Haplotype -590T, -34T and Intron-3 VNTR R2 Is Associated with Reduced Malaria Risk among Ancestral Indian Tribal Populations

Abstract

BackgroundInterleukin 4 (IL-4) is an anti-inflammatory cytokine, which regulates balance between TH1 and TH2 immune response, immunoglobulin class switching and humoral immunity. Polymorphisms in this gene have been reported to affect the risk of infectious and autoimmune diseases.MethodsWe have analyzed three regulatory IL-4 polymorphisms; -590C>T, -34C>T and 70 bp intron-3 VNTR, in 4216 individuals; including: (1) 430 ethnically matched case-control groups (173 severe malaria, 101 mild malaria and 156 asymptomatic); (2) 3452 individuals from 76 linguistically and geographically distinct endogamous populations of India, and (3) 334 individuals with different ancestry from outside India (84 Brazilian, 104 Syrian, and 146 Vietnamese).ResultsThe -590T, -34T and intron-3 VNTR R2 alleles were found to be associated with reduced malaria risk (P<0.001 for -590C>T and -34C>T, and P = 0.003 for VNTR). These three alleles were in strong LD (r2>0.75) and the TTR2 (-590T, -34T and intron-3 VNTR R2) haplotype appeared to be a susceptibility factor for malaria (P = 0.009, OR = 0.552, 95% CI = 0.356 –0.854). Allele and genotype frequencies differ significantly between caste, nomadic, tribe and ancestral tribal populations (ATP). The distribution of protective haplotype TTR2 was found to be significant (χ2 3 = 182.95, p-value <0.001), which is highest in ATP (40.5%); intermediate in tribes (33%); and lowest in caste (17.8%) and nomadic (21.6%).ConclusionsOur study suggests that the IL-4 polymorphisms regulate host susceptibility to malaria and disease progression. TTR2 haplotype, which gives protection against malaria, is high among ATPs. Since they inhabited in isolation and mainly practice hunter-gatherer lifestyles and exposed to various parasites, IL-4 TTR2 haplotype might be under positive selection.

Association of IL-4 and IL-10 maternal haplotypes with immune responses to P. falciparum in mothers and newborns

“…Our finding of a lower prevalence of placental malaria infection in mothers with either the IL-4 −590 or IL-4 +33 CT and TT genotypes, or still the IL4-TT haplotype, is in accordance with recent results indicating reduced malaria risk in IL4-TT carriers from Indian tribal populations [51]. On the contrary, the IL-4 −590 *T allele was related to high prevalence of P. falciparum infection in asymptomatic Fulani of Mali, but not in a sympatric group of Dogon [19].…”

Specific alleles at immune genes, rather than genome‐wide heterozygosity, are related to immunity and survival in the critically endangered Attwater's prairie‐chicken

“…Particular IL4 haplotypes have been associated with reduced risk of malaria and other diseases in human populations (Jha et al . ). Lastly, we examined diversity at β‐defensin 11, which codes for catatonic peptides that disrupt cell walls of bacteria (Ganz ).…”

Differential positive selection of malaria resistance genes in three indigenous populations of Peninsular Malaysia

“…The Che Wong population carries this allele, which is similar to those reported in populations from malaria-endemic regions (61 % in Ghanian, 73 % in Nigerians, 51 % in African Americans) but significantly different from those of European descent (~20 %, Table S22). The IL4 promoter variant rs2243250 (−590C > T) and rs2070874 have been reported to be associated with anti-malarial antibody levels (Jha et al 2012). The extended haplotype identified by haploPS at a frequency of 15 % and below among Che Wong carried all three T alleles at rs40401, rs2243250 and rs2070874 (Fig.…”