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

Reduced susceptibility to infectious disease can increase the frequency of otherwise deleterious alleles. In populations of African ancestry, two <i>apolipoprotein-L1 (APOL1</i>) 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 <i>Trypanosoma brucei rhodesiense</i> or <i>T.b. gambiense,</i> which cause human African trypanosomiasis. In this case-control study, we test the prevailing hypothesis that these <i>APOL1</i> variants reduce trypanosomiasis susceptibility, resulting in their positive selection in sub-Saharan Africa. We demonstrate a five-fold dominant protective association for G2 against <i>T.b. rhodesiense</i> infection. Furthermore, we report unpredicted strong opposing associations with <i>T.b. gambiense</i> disease outcome. G2 associates with faster progression of <i>T.b. gambiense</i> 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 <i>APOL1</i> kidney disease variants.