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

Anneli Cooper,Oumou Camara,Mamadou Camara,Harry Noyes,Hamidou Ilboudo,V Pius Alibu,Paul Capewell,William Weir,Jacqueline Milet,Vincent Jamonneau,Sophie Ravel,Annette Macleod,Enock Matovu,John Enyaru,Bruno Bucheton

doi:10.7554/elife.25461

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.

Highlights

Infectious disease is a major driving force of natural selection on human populations
Human African trypanosomiasis (HAT) is caused by two tsetse flytransmitted African trypanosomes, Trypanosoma brucei rhodesiense and T.b. gambiense, which are responsible for the acute East African form and more chronic West Africa form of the disease, respectively (Kennedy, 2013)
We report that the association of APOL1 chronic kidney disease variants with HAT susceptibility are markedly different for the two subspecies

Summary

Introduction

Infectious disease is a major driving force of natural selection on human populations. Laboratory studies have shown that blood from individuals who carry the G1 and G2 variants is better at killing the East African parasites It is not clear if these gene versions help people living in the rural communities, where African sleeping sickness is common, to fight off the disease. HAT is caused by two tsetse flytransmitted African trypanosomes, Trypanosoma brucei rhodesiense and T.b. gambiense, which are responsible for the acute East African form and more chronic West Africa form of the disease, respectively (Kennedy, 2013) Both parasites have been responsible for widespread fatal epidemics in sub-Saharan Africa throughout recorded human history (Steverding, 2008) suggesting the potential to exert potent selection pressure on the human genome. We consider the implications of these strikingly different susceptibilities in the context of human co-evolution with African trypanosomes and the distribution, selection and persistence of these kidney disease risk variants in sub-Saharan Africa

Results

Discussion

Ethics statement

Funding Funder Wellcome