Investigating the genetic basis of the Fulani’s lower susceptibility to malaria: the role of autoimmunity loci.

Despite equivalent exposure to infection and comparable use of protective measures, the Fulani of West Africa have been shown to mount stronger immune responses to Plasmodium falciparum antigens and to be less susceptible to infection and mild disease than sympatric populations. The Fulani also show a higher response to other pathogens, and both their Th1 and Th2 responses are enhanced, suggesting that their resistance to malaria could result from a generally stronger immune activation. Key genes related to T regulatory cell function are indeed down-regulated in the Fulani. This disorder of immune homeostasis could be driven by genetic factors positively selected by P. falciparum and may underlie the higher susceptibility of the Fulani to diseases with autoimmune pathogenesis reported in the literature. The general aim of our investigation is to explore the genetic basis of the lower susceptibility to malaria observed in the Fulani, and in particular to evaluate the role of autoimmunity loci. We conducted a large-scale epidemiological study in rural villages of Burkina Faso inhabited by Fulani, Mossi and Rimaibe communities. The field study lasted 2 years (2007-8) and consisted in a combination of cross sectional and longitudinal surveys. At each survey we collected relevant parasitological and clinical data. Serological data (IgG levels against P. falciparum and self antigens) were generated by ELISA on plasma samples from the first survey. We genotyped 363 Single Nucleotide Polymorphisms (SNPs) on 2186 samples using the Sequenom System. Principal component analysis revealed that Mossi and Rimaibe (Non-Fulani) are not genetically distinct among themselves, whereas the Fulani are a clearly distinct group. We therefore compared allele frequencies and calculated Fst between Fulani and Non-Fulani. We observed that the proportion of autoimmunity SNPs with Fst>0.05 (indicating moderate/high differentiation and corresponding to at least a two-fold difference in allele frequency) is 20% versus 10% shown by other loci. Genetic association analysis of susceptibility to infection showed, both in Fulani and Non-Fulani, signals of association among genes: i) involved in resistance to severe malaria (ABO, DDC, G6PD, GNAS, IFNG-IL22, MECP2, TNF); ii) lying in the 5q31 region of the genome, which has been previously linked to P. falciparum infection levels (IRF1); iii) related to T regulatory cell function and/or involved in autoimmunity (BLK, CD25, CR1, FCGR2A, IL1A-IL1B, IL1R1L-IL18RAP, IL21, ORMDL3, TGFB1, TGFBR3). These results support the hypothesis that malaria has exerted a selective pressure on the immune system and has affected its evolution, and suggest that common gene regulatory networks could underlie susceptibility to malaria and to immunological disorders such as autoimmune diseases.