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Kidney Disease Is Parasite-Slaying Protein's Downside

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Science  16 Jul 2010:
Vol. 329, Issue 5989, pp. 263
DOI: 10.1126/science.329.5989.263

Kidney disease could be the price of resistance to a virulent parasite. Researchers describe two Jekyll-and-Hyde genetic variations online in Science this week ( that can lead to kidney shutdown but may also fend off a microorganism that causes sleeping sickness in thousands of people in Africa.

“This is perhaps the best example, except for sickle cell anemia, of a common disease being caused by genetic variants that also play a role in resistance to infectious disease,” says human geneticist Sarah Tishkoff of the University of Pennsylvania. Similar findings may soon follow, researchers predict. The study “offers a lot of encouragement that we are going to find more cases where there are genetic bases for human adaptations,” says evolutionary biologist Gregory Wray of Duke University in Durham, North Carolina.

For a long time, the prime example of how natural selection can favor “harmful” mutations if they also confer pathogen protection has been sickle cell disease. A mutation in the gene for hemoglobin produces deformed red blood cells and can lead to an early death in severe cases. But it also enhances resistance to the most serious variety of malaria. The sickle cell mutation is so prevalent where this type of malaria is rife—particularly sub-Saharan Africa—that researchers have concluded that, despite its lethal downside, the mutated gene evolved to higher frequencies in these areas because of its malaria-stopping benefits.

Africa's parasites may also explain the new kidney disease–promoting gene variants. Martin Pollak, a nephrologist and human geneticist at Harvard Medical School in Boston, and colleagues were searching for genetic risk factors for two renal conditions—focal segmental glomerulosclerosis and hypertension-attributed end-stage kidney disease—that are four to five times more common among African Americans than among people of European ancestry. Previous studies had homed in on a stretch of chromosome 22 but couldn't pinpoint the culprits.

Pollak and colleagues expanded the search to nearby DNA, including the APOL1 gene, which codes for the blood protein apolipoprotein L-1 (ApoL1). The researchers used data from the 1000 Genomes Project—which is sequencing DNA of people from around the world—and scoured this chromosome region for mutations that were much more common in Africans than in Europeans. Then by statistically analyzing the gene variants in African Americans who had either of the kidney diseases, the team identified two alterations in the APOL1 gene that correlated with illness. The G1 variant, for example, turned up in 52% of glomerulosclerosis patients, versus 18% of controls. And the G2 variant was about 50% more common in patients with either kidney disease than it was in healthy people.

Good gene, bad gene.

The same gene variants that promote destruction of the kidney's filtration units (above) also combat Trypanosoma brucei rhodesiense parasites (left).


The power of these gene alterations surprised the team, Pollak says. The researchers calculated that if both of a person's APOL1 genes have one of the illness-causing mutations (no gene carries both), the risk of developing hypertension-attributed end-stage kidney disease shoots up more than seven times.

Given this impact, it is surprising how common G1 and G2 are in Africa. Among the Yoruba people of Nigeria, G2's frequency was 8%, and G1's was a whopping 38%. What's more, when the researchers applied a statistical technique that can discern the effects of natural selection, they found that G1's prevalence in Africa had surged within the past 10,000 years. “The variants must have positive effects in order to balance out kidney disease,” Pollak says.

He and his colleagues hypothesized that the G1 and G2 versions of ApoL1 better protect against Trypanosoma brucei, a microscopic parasite spread in Africa by tsetse flies. The standard version of ApoL1 slays one subspecies of the parasite, T. brucei brucei, but not another subspecies, T. brucei rhodesiense, which makes a protein called SRA that neutralizes the blood defender.

But G1 and G2 reconfigure ApoL1, restoring its potency. Blood plasma from people who carried G1 or G2 killed the rhodesiense version of the parasite, as did lab-made copies of the altered proteins. “The effect was really dramatic,” Pollak says.

Parasitologist Jayne Raper of New York University says the new study illustrates the ongoing “molecular arms race between host and pathogen.” However, the study isn't conclusive, the authors and outside experts agree. The Yoruba people hail from West Africa, whereas the altered ApoL1 proteins were effective against the subspecies of T. brucei that lives in East Africa. The G1 and G2 variants didn't kill T. brucei gambiense, which causes sleeping sickness in West Africa. “That discrepancy needs to be resolved,” Wray says.

Pollak and his colleagues plan to determine if the variants are common elsewhere in Africa, including East Africa. They also suggest that synthetic versions of the more effective ApoL1 proteins, or even plasma from people who carry G1 or G2, could provide a new treatment for African sleeping sickness. The work doesn't yet offer such clear direction for helping people who get kidney disease because of the mutations. But discovering that APOL1 has a role in renal illness is valuable, Pollak says: “Now we know the biological pathways we should be trying to understand.”

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