No evidence for association with APOL1 kidney disease risk alleles and Human African Trypanosomiasis in two Ugandan populations

Background: Human African trypanosomiasis (HAT) manifests as an acute form caused by Trypanosoma brucei rhodesiense (Tbr) and a chronic form caused by Trypanosoma brucei gambiense (Tbg). Previous studies have suggested a host genetic role in infection outcomes, particularly for APOL1. We have undertaken a candidate gene association studies (CGAS) in a Ugandan Tbr and a Tbg HAT endemic area, to determine whether polymorphisms in IL10, IL8, IL4, HLAG, TNFA, TNX4LB, IL6, IFNG, MIF, APOL1, HLAA, IL1B, IL4R, IL12B, IL12R, HP, HPR, and CFH have a role in HAT. Methodology and results: We included 238 and 202 participants from the Busoga Tbr and Northwest Uganda Tbg endemic areas respectively. Single Nucleotide Polymorphism (SNP) genotype data were analysed in the CGAS. The study was powered to find odds ratios > 2 but association testing of the SNPs with HAT yielded no positive associations i.e. none significant after correction for multiple testing. However there was strong evidence for no association with Tbr HAT and APOL1 G2 of the size previously reported in the Kabermaido district. Conclusions/significance: A recent study in the Soroti and Kaberamaido focus in Central Uganda found that the APOL1 G2 allele was strongly associated with protection against Tbr HAT (odds ratio = 0.2). However, in our study no effect of G2 on Tbr HAT was found, despite being well powered to find a similar sized effect. It is possible that the G2 allele is protective from Tbr in the Soroti/Kabermaido focus but not in the Iganga district of Busoga, which differ in ethnicity and infection history. Mechanisms underlying HAT infection outcome and virulence are complex and might differ between populations, and likely involve several host, parasite or even environmental factors. Author Summary Human African Trypanosomiasis (HAT) occurs in two distinct disease forms; the acute form and the chronic form which are caused by microscopically indistinguishable hemo-parasites, Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense respectively. Uganda is the only country where both forms of the disease are found, though in geographically distinct areas. Recent studies have shown that host genetic factors play a role in HAT resistance and/or susceptibility, particularly by genes involved in the immune response. In this study, we identified single nucleotide polymorphisms in selected genes involved in immune responses and carried out a case-control candidate gene association study in Ugandan participants from the two endemic areas. We were unable to detect any polymorphisms that were robustly associated with either Tbr or Tbg HAT. However, our findings differ from recent studies carried out in the Tbr HAT another endemic area of Uganda that showed the APOL1 (Apolipoprotein 1) G2 allele to be protective against the disease which merits further investigation. Larger studies such as genome wide association studies (GWAS) by the TrypanoGEN network that has >3000 cases and controls covering seven countries (Cameroon, Cote d’Ivoire, DRC, Malawi, Uganda, Zambia) using the H3Africa customized chip reflective of African genetic diversity will present novel association targets.