APOL1 renal risk variants have contrasting resistance and susceptibility associations with African trypanosomiasis

Abstract

Reduced susceptibility to infectious disease can increase the frequency of otherwise deleterious alleles. In populations of African ancestry, two apolipoprotein-L1 (APOL1) variants with a recessive kidney disease risk, named G1 and G2, occur at high frequency. APOL1 is a trypanolytic protein that confers innate resistance to most African trypanosomes, but not Trypanosoma brucei rhodesiense or T.b. gambiense, which cause human African trypanosomiasis. In this case-control study, we test the prevailing hypothesis that these APOL1 variants reduce trypanosomiasis susceptibility, resulting in their positive selection in sub-Saharan Africa. We demonstrate a five-fold dominant protective association for G2 against T.b. rhodesiense infection. Furthermore, we report unpredicted strong opposing associations with T.b. gambiense disease outcome. G2 associates with faster progression of T.b. gambiense trypanosomiasis, while G1 associates with asymptomatic carriage and undetectable parasitemia. These results implicate both forms of human African trypanosomiasis in the selection and persistence of otherwise detrimental APOL1 kidney disease variants.

Keywords: Human African trypanosomiasis; Trypanosoma brucei; Trypanosoma brucei gambiense; Trypanosoma brucei rhodesiense; chronic kidney disease; evolutionary biology; genomics; human; infectious disease; microbiology; sleeping sickness.

Figure 1.. Schematic of G1 and G2 polymorphisms in human apolipoprotein L1.

Human apolipoprotein-L1 (APOL1) is a 398-amino acid protein consisting of a cleavable N-terminal signal peptide, a pore-forming domain, a membrane-addressing domain, and a serum resistance-associated (SRA)-interacting domain. The polymorphisms that characterize the G1 and G2 renal risk variants are located in the SRA-interacting domain, the target site for binding of the SRA protein expressed by the human-infective T.b.rhodesiense parasite, which results in loss of APOL1 lytic function. The location of the critical binding region (residues 370–392) for this interaction is indicated by a helical graphic. G1 consists of two missense SNPs rs73885319 (p.Ser342Gly) and rs60910145 (p.Ile384Met) while the G2 polymorphism, rs71785313 (p.Asn388_Tyr389del), is found on an alternative APOL1 haplotype, and represents an in-frame two amino acid deletion. DOI: http://dx.doi.org/10.7554/eLife.25461.003

Figure 2.. The geographical distribution of human African trypanosomiasis and APOL1 G1 and G2 allele frequencies across sub-Saharan Africa.

(A) The risk model for chronic kidney disease, T.b. rhodesiense infection, and T.b. gambiense disease outcome are summarized for the ancestral G0 APOL1 variant and heterozygous and homozygous carriers of the G1 and G2 variants. The direction of the risk association is indicated by arrow orientation and box colour: orange (increased risk), blue (reduced risk) and grey (no association). (B) WHO defines 36 countries as endemic for HAT, caused by T.b. gambiense in West Africa (blue) and T.b. rhodesiense in East Africa (green). Uganda is the only country endemic for both subspecies, although their distribution does not currently overlap (red). (C) Spatial frequency map of the APOL1 G1 variant. (D) Spatial frequency map of the APOL1 G2 variant. Spatial frequency maps were generated from merged published genotype data available for 40 populations (5287 individuals) in 21 countries (Figure 2—source data 1). Colour gradients illustrating predicted allele frequencies across Africa were extrapolated from available data using the Kriging algorithm in Surfer software version 8. The approximate locations of data points are indicated by filled black circles, a filled red triangle (Guinea study), or an inverted filled red triangle (Uganda study) next to the relative allele frequency, in percentage. DOI: http://dx.doi.org/10.7554/eLife.25461.016

Author response image 1.

DOI: http://dx.doi.org/10.7554/eLife.25461.020