Kidney Disease Research Updates Winter 2010

Kidney Disease Research Updates
Winter 2011
Gene Variants That Prevent African Sleeping Sickness Increase Kidney Disease Risk

A gene that evolved to protect against trypanosomes—microscopic parasites endemic to sub-Saharan Africa that cause African sleeping sickness—increases kidney disease risk, according to a recent genetic analysis. Precisely how the genetic changes increase risk is unclear, but the finding may help explain why kidney disease disproportionately affects African Americans. The analysis was supported in part by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and reported in the August 13 issue of Science.

Analyzing DNA from African Americans, scientists found two variants of the gene APOL1 that strongly associated with kidney disease. APOL1 directs the production of ApoL1 protein, which is toxic to the trypanosome subspecies T.b. brucei. T.b. brucei and other trypanosomes are bloodborne pathogens, most often transmitted by the bite of the tsetse fly.

Scanning data from the 1000 Genomes Project, which catalogs human genetic variation around the world, the researchers found that one of the two variants, called G1, was present in 38 percent of DNA samples collected from the Yoruba people in West Africa. The second variant, G2, was present in 8 percent. Both variants were absent in European, Japanese, and Chinese samples. Additional analysis determined these variants evolved relatively recently over the past 10,000 years and have become increasingly prevalent.

Since ApoL1 protects against T.b. brucei, the researchers hypothesized G1 and G2 might be an adaptation to newly evolved trypanosome subspecies T.b. rhodesiense or T.b. gambiense, which are ApoL1-resistant.

“Because these parasites exist only in sub-Saharan Africa, we hypothesized that the APOL1 gene may have undergone natural selective pressure to counteract these trypanosome adaptations,” wrote Martin R. Pollak, M.D., chief of Nephrology at Beth Israel Deaconess Medical Center, and colleagues.

In laboratory tests, ApoL1 proteins purified from people who had one or both gene variants killed T.b. rhodesiense but not T.b. gambiense. Samples from people who lacked either gene variant killed neither. Surprisingly, genomic screening showed the Yoruba people carry genetic resistance to a T.b. rhodesiense, a subspecies that prevails in East Africa, a region outside their present day homeland. The researchers suggested changes in trypanosome biology or distribution or human migration might explain this contradiction.

“It will be interesting to determine the distribution of these mutations throughout sub-Saharan Africa,” wrote Pollak and colleagues. “Resistance to T.b. rhodesiense may not be the only factor causing these variants to be selected.” The authors suggested the possibility that ApoL1 may provide resistance to additional pathogens.

New treatments for African sleeping sickness are potential byproducts of the discovery. African sleeping sickness is a degenerative and potentially fatal disease affecting tens of thousands of people in sub-Saharan Africa. ApoL1 protein purified from the blood of people carrying the G1 or G2 mutation, or lab-created ApoL1, could potentially treat African sleeping sickness caused by T.b. rhodesiense, according to the report.

More research is needed to understand why APOL1 variants increase kidney disease risk. “Unraveling the molecular mechanisms by which they contribute to renal injury will be of great importance in understanding and potentially preventing renal disease in individuals of recent African Ancestry,” wrote Pollack and colleagues.

For more information about the 1000 Genomes Project, visit www.1000genomes.org.

The NIDDK has easy-to-read fact sheets and booklets about kidney diseases. For more information or to obtain copies, visit www.kidney.niddk.nih.gov.

Kidney Disease Research Updates Winter 2010