IL-4 haplotype -590T, -34T and intron-3 VNTR R2 is associated with reduced malaria risk among ancestral indian tribal populations

PLoS One. 2012;7(10):e48136. doi: 10.1371/journal.pone.0048136. Epub 2012 Oct 24.

Abstract

Background: Interleukin 4 (IL-4) is an anti-inflammatory cytokine, which regulates balance between T(H)1 and T(H)2 immune response, immunoglobulin class switching and humoral immunity. Polymorphisms in this gene have been reported to affect the risk of infectious and autoimmune diseases.

Methods: 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).

Results: 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%).

Conclusions: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Base Sequence
  • Brazil
  • Female
  • Gene Frequency
  • Genetic Predisposition to Disease / ethnology
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Haplotypes*
  • Humans
  • India
  • Interleukin-4 / genetics*
  • Introns / genetics*
  • Malaria, Falciparum / ethnology
  • Malaria, Falciparum / genetics*
  • Male
  • Middle Aged
  • Minisatellite Repeats / genetics*
  • Molecular Sequence Data
  • Risk Factors
  • Sequence Homology, Amino Acid
  • Syria
  • Vietnam
  • Young Adult

Substances

  • Interleukin-4

Grant support

This work was supported by the Council of Scientific and Industrial Research, New Delhi(www.csir.res.in) [Senior research fellowship to ANJ, Bhatanagar Fellowship OLP0011 to LS] and UK-India Education and Research Initiative (www.ukieri.org) RG-4772 to KT. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.