HLA-G 3' UTR-2 haplotype is associated with Human African trypanosomiasis susceptibility

Trypanosoma brucei gambiense (Tbg) is responsible for the chronic form of Human African trypanosomiasis (HAT), classically lasting for years. Clinical evolution of HAT cases seems to be complex and reports on asymptomatic carriers and spontaneous cure have been published recently, strengthening the likely existence of the phenomenon of human trypanotolerance. Host's genetic factors could be involved in both the control of infection levels and the mortality rates, as clearly shown in experimental models, but also in human. Although genes directly involved in immune response are important candidates, genes implicated in the regulation of immunity, such as HLA-G, could also play a critical role. A candidate gene association study was previously conducted in the Democratic Republic of Congo using a family-based sample including 106 families (n=353). All individuals, from the Yansi ethnic group, were born in the area and had been exposed to the risk of infection since birth. We sequenced the HLA-G 3' untranslated region (UTR) and performed a family based association analysis of the 14 polymorphisms identified (14-bp insertion/deletion plus 13 SNPs). Three polymorphisms, 14-bp insertion/deletion and SNPs located at the +3003 and +3196 positions were associated to HAT (FBAT p=0.008, p=0.015 and p=0.022, respectively). HLA-G 3'UTR haplotypes were significantly associated with HAT (HBAT, global p=0.0026). UTR-2 haplotype (including 14-pb insertion and G allele at position +3196) was over-transmitted to the affected offspring (HBAT p=0.003) at the expense of UTR-4 haplotype, which was under-transmitted (HBAT p=0.013). These results are the first to report an association between polymorphisms in HLA-G and variable risks to develop HAT and suggest the involvement of the HLA-G molecule on HAT susceptibility.