October 25, 2012

IL-4 genetic combo protects Indian hunter-gatherers from Malaria

Or, more precisely, protects many of those who have it in diverse populations but it is most concentrated among hunter-gatherers of the so-called Ancestral Tribal Populations (ATP).

Aditya Nath Jha et al., IL-4 Haplotype -590T, -34T and Intron-3 VNTR R2 Is Associated with Reduced Malaria Risk among Ancestral Indian Tribal Populations. PLoS ONE 2012. Open access ··> LINK [doi:10.1371/journal.pone.0048136]



Interleukin 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.

We 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).

The -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 (χ23 = 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%).

Our 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.

The protection is not absolute but it holds very strong statistical significance for the R2-R3 heterozygous combo, as shown in fig. 1:

Figure 1. Distribution of IL-4 intron-3 VNTR polymorphism.
A and B: genotype and allelic distribution between malaria case control groups, respectively; C and D: genotype and allelic distribution among caste, nomadic, tribe and ancestral tribe, respectively.

Combo that is most common (near-optimal distribution) among the ATPs. The correlation holds for the four linguistic families with variations being more a matter of individual ATP tribes: from 35% among the AoNaga (TB, Nagaland) to 67% among the Baiga (IE, Madhya Pradesh) or 63% among the Onge (Jarawa-Onge, Andaman Is.)
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