Interferon regulatory factor-1 polymorphisms are associated with the control of Plasmodium falciparum infection

Abstract

We describe the haplotypic structure of the interferon regulatory factor-1 (IRF-1) locus in two West African ethnic groups, Fulani and Mossi, that differ in their susceptibility and immune response to Plasmodium falciparum malaria. Both populations showed significant associations between IRF-1 polymorphisms and carriage of P. falciparum infection, with different patterns of association that may reflect their different haplotypic architecture. Genetic variation at this locus does not therefore account for the Fulani-specific resistance to malaria while it could contribute to parasite clearance's ability in populations living in endemic areas. We then conducted a case-control study of three haplotype-tagging single nucleotide polymorphisms (htSNPs) in 370 hospitalised malaria patients (160 severe and 210 uncomplicated) and 410 healthy population controls, all from the Mossi ethnic group. All three htSNPs showed correlation with blood infection levels in malaria patients, and the rs10065633 polymorphism was associated with severe disease (P=0.02). These findings provide the first evidence of the involvement in malaria susceptibility of a specific locus within the 5q31 region, previously shown to be linked with P. falciparum infection levels.

Figure 1. Linkage disequilibrium patterns and haplotype block structure of the IRF1 locus in Mossi and Fulani of Burkina Faso

(a,b) LD patterns in the Mossi and Fulani samples respectively. Typed SNPs are represented on the horizontal axis and ordered by chromosome position as in Table 1. The linkage disequilibrium (r²) between each pair of markers is represented by differently coloured diamonds. (c,d) Haplotype blocks in the Mossi and Fulani samples respectively.

Figure 2. Association of IRF-1 SNPs with disease severity in Burkina Faso subjects

Comparison of Odds Ratios and p values for Yate's-corrected Chi-Squared test at three IRF-1 loci in: Severe Malaria Cases and Healthy Population Controls (black square); Severe Malaria Cases and Mild Malaria Cases (dark gray square); Mild Malaria Cases and Healthy Population Controls (light gray square); Severe Malaria Cases and children with no severe malaria (Mild Malaria Cases plus Healthy Population Controls; white square). Asterisk (*) indicates a significant association after correction for multiple testing (p<0.033).

Figure 3. Association of IRF-1 SNPs with Plasmodium falciparum blood infection levels in malaria patients from Burkina Faso

Means of parasite density (log transformed values) ± SE for three SNPs in the IRF-1 gene in carriers and non carriers of the susceptible allele. The geometric means of the parasite counts are shown in brackets. P value calculated by linear regression analysis adjusting for disease status and age. Asterisk (*) indicates a significant association after correction for multiple testing (p<0.033).