Sirugo, G. | Search bioRxiv

bioRxiv2021

The protective effect of sickle cell haemoglobin against severe malaria depends on parasite genotype

Host genetic factors can confer resistance against malaria, raising the question of whether this has led to evolutionary adaptation of parasite populations. In this study we investigated the correlation between host and parasite genetic variation in 4,171 Gambian and Kenya children ascertained with severe malaria due to Plasmodium falciparum. We identified a strong association between sickle haemoglobin (HbS) in the host and variation in three regions of the parasite genome, including nonsynonymous variants in the acyl-CoA synthetase family member PfACS8 on chromosome 2, in a second region of chromosome 2, and in a region containing structural variation on chromosome 11. The HbS-associated parasite alleles are in strong linkage disequilibrium and have frequencies which covary with the frequency of HbS across populations, in particular being much more common in Africa than other parts of the world. The estimated protective effect of HbS against severe malaria, as determined by comparison of cases with population controls, varies greatly according to the parasite genotype at these three loci. These findings open up a new avenue of enquiry into the biological and epidemiological significance of the HbS-associated polymorphisms in the parasite genome, and the evolutionary forces that have led to their high frequency and strong linkage disequilibrium in African P. falciparum populations.

genetics↗

bioRxiv2019

Interaction between host genes and M. tuberculosis lineage can affect tuberculosis severity: evidence for co-evolution

Genetic studies of both the human host and Mycobacterium tuberculosis (MTB) demonstrate independent association with tuberculosis (TB) risk. However, neither explains a large portion of disease risk or severity. Based on studies in other infectious diseases and animal models of TB, we hypothesized that the genomes of the two interact to modulate risk of developing active TB or increasing the severity of disease, when present. We examined this hypothesis in our TB household contact study in Kampala, Uganda, in which there were 3 MTB lineages of which L4-Ugandan (L4.6) is the most recent. TB severity, measured using the Bandim TBscore, was modeled as a function of host SNP genotype, MTB lineage, and their interaction, within two independent cohorts of TB cases, N=113 and 122. No association was found between lineage and severity, but association between multiple polymorphisms in IL12B and TBscore was replicated in two independent cohorts (most significant rs3212227, combined p=0.0006), supporting previous associations of IL12B with TB susceptibility. We also observed significant interaction between a single nucleotide polymorphism (SNP) in SLC11A1 and the L4-Ugandan lineage in both cohorts (rs17235409, meta p=0.0002). Interestingly, the presence of the L4-Uganda lineage in the presence of the ancestral human allele associated with more severe disease. These findings demonstrate that IL12B is associated with severity of TB in addition to susceptibility, and that the association between TB severity and human genetics can be due to an interaction between genes in the two species, providing evidence of host-pathogen coevolution in TB.\n\nAUTHOR SUMMARYSusceptibility to tuberculosis (TB) is affected by genetic variation in both the human host and the causative bacterium, Mycobacterium tuberculosis. However, prior studies of the genetics of each species have not explained a large part of TB risk. The possibility exists that risk can be better estimated from patterns of variation in two species as a unit, such that some combinations provide increased risk, or in the presence of TB, increased disease severity. We hypothesized that alleles in the two species that have co-existed for long periods are more likely to reduce disease severity so as to promote prolonged co-occurrence. We tested this by studying TB severity in two patient cohorts from Uganda for which paired MTB-human DNA were available. We examined severity, as measured by the Bandim TBscore, and assessed whether there was an interaction between MTB lineage and SNPs in the host with this metric. Our results indicate that the most recent TB lineage (L4.6/Uganda) when found together with an ancestral allele in SLC11A1 resulted in more severe disease. This finding is consistent with the conclusion that MTB and human have coevolved to modulate TB severity.

evolutionary biology↗