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Study Suggests African American Kidney Disease Risk Variants May Protect against Sleeping Sickness Parasites

By Andrea Anderson

NEW YORK (GenomeWeb News) – A pair of haplotypes that apparently protect against parasites causing African sleeping sickness also increase the risk of kidney disease in African Americans, according to a study appearing in the early, online version of Science today.

By focusing in a genomic locus linked to kidney disease through past genome-wide association studies, an international team detected new kidney disease associated variants that turn up in many African American individuals but not individuals of European descent. The variants fall in a gene called APOL1, which codes for a protein involved in human defense against some sleeping sickness-causing trypanosome parasites. The team's findings suggest these changes make the protein more effective against at least one parasite sub-species.

Trypanosome parasites transmitted by the tsetse fly in sub-Saharan Africa can cause a nervous system disease called trypanosomiasis or African sleeping sickness. In severe cases, this infection can lead to brain damage or even death. APOL1 codes for a protein that is released into the blood and helps thwart sleeping sickness by destroying some parasites.

"We show that two specific variants in the APOL1 gene are highly associated with kidney disease in African Americans," senior author Martin Pollak, a researcher affiliated with the Beth Israel Deaconess Medical Center and the Broad Institute, told GenomeWeb Daily News. "These variants confer activity that kills certain forms of trypanosomes — the trypanosomes that are responsible for sleeping sickness. What we think is that these variants have both beneficial and detrimental effects."

Both focal segmental glomerulosclerosis (FSGS) kidney disease and end-stage kidney disease associated with high blood pressure are more common in African Americans than in other American populations, the researchers explained, with kidney disease occurring in African Americans at roughly four times the rate seen in European Americans.

Past GWAS turned up kidney disease susceptibility variants in and around a gene called MYH9 in a locus on chromosome 22, Pollak explained. But he and his team suspected that they would have to look at the genetic region more broadly to track down causal alleles in kidney disease.

To explore this in more detail, the researchers used data from the 1000 Genomes Project to look for variants in the chromosome 22 region that were more common in African Americans and used association analyses involving 205 African Americans with FSGS kidney disease and 180 unaffected control individuals.

"We thought that since these were probably reasonably common variants, that if we looked at the 1000 Genomes Project for variants that had very different frequencies between Europeans and Africans, these variants would be in that data set," Pollak said.

In the process, the researchers found two kidney disease-associated signals of selection in APOL1, a gene in the same locus as MYH9 that codes for apolipoprotein L-1, or ApoL1. The first signal involved two non-synonymous SNPs in the last exon of APOL1, while the second reflected a nearby six base pair deletion in the gene. Both were in linkage disequilibrium with previously detected MYH9 variants.

The team then verified the link between APOL1 variants and kidney disease by testing 1,030 African Americans with high blood pressure related to end stage kidney disease and 1,025 healthy African Americans from the same part of the country.

Their results suggest that while individuals carrying just one APOL1 risk allele had only a slightly higher risk of kidney disease, those with two alleles appear to be at much higher risk.

But despite such links, the risk variants seem to be fairly common in African Americans — with an estimated 30 percent carrying at least one risk allele and roughly 10 percent carrying two risk alleles.

And when the researchers sifted through 180 Yoruba HapMap samples assessed through the 1000 Genomes Project, they found allele frequencies of 38 percent for one of the newly identified APOL1 haplotypes and eight percent for the other.

"We found it very surprising that such a harmful gene could reach such high frequency in African Americans, and we assumed that it must be doing something beneficial in Africa in order for it to ever reach such high frequency," co-lead author David Friedman, a Beth Israel Deaconess Medical Center researcher, told GWDN.

Indeed, the team's subsequent experiments indicated that human serum containing either variant or typical versions of ApoL1 could destroy Trypanosoma brucei brucei parasites. But only the serum from individuals with kidney disease-associated changes to ApoL1 was more effective against the T. b. rhodesiense sub-species, mainly found in East and Southeast Africa.

"We speculate that evolution of a critical survival factor in Africa may have contributed to the high rates of renal disease in African Americans," the researchers wrote.

The mechanism by which the APOL1 variants contribute to kidney disease risk is still unclear, though the team intends to do additional studies using human genetic data and cell culture experiments to try to tease apart how APOL1 could affect kidney function.

The researchers also plan to explore possible clinical implications of their findings and hope to do studies aimed at determining whether the prevalence of the APOL1 variants differs within Africa.

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