Genetics may underlie some kidney failure in blacks

In a case of natural selection with a twist, genetic variants that confer protection against disease in Africa seem to place African Americans half a world away at elevated risk of kidney failure, a new study finds.

U.S. blacks are three times as likely as whites to develop chronic kidney disease. “We think this explains perhaps most of it,” says study coauthor Martin Pollak, a nephrologist and geneticist at Harvard Medical School and Beth Israel Deaconess Medical Center in Boston.

The gene in question is called APOL-1, short for apolipoprotein L-1. Among people of African descent, APOL-1 can appear in two variant forms that protect against African sleeping sickness but also increase susceptibility to kidney failure, Pollak and his colleagues report online July 15 in Science.

Each parent provides one gene copy to offspring. The team analyzed blood from more than 1,400 African Americans and found that more than 30 percent carried at least one variant copy of APOL-1. About 10 percent harbored two variant copies.

Roughly half of the people in the study had kidney disease and half didn’t. The researchers found that those carrying two copies of an APOL-1 gene variant were 10.5 times as likely to have kidney disease marked by loss of blood filtration capacity compared with people who carried the normal APOL-1 gene. The double-copy carriers were 7.3 times more likely to have severe kidney disease marked by high blood pressure that necessitated dialysis or a transplant. People harboring two variant copies were also more prone to such end-stage disease compared with people having one variant copy. While harboring two copies of a variant seemed to increase risk, having one variant and one normal copy did not.

APOL-1 exists only in primates. The protein it encodes is a normal component of HDL, the good cholesterol, and might contribute to HDL’s activity in the body, says Chien-an Hu, a molecular biologist at the University of New Mexico School of Medicine in Albuquerque. Other work indicates that the APOL-1 protein might regulate a routine cell-recycling process called autophagy.

How variant APOL-1 proteins might damage the kidney remains unclear, but their effects could be related to a dysfunctional autophagy process, Hu surmises.

Deciphering the APOL-1 effect may someday benefit people at risk of kidney disease, Pollak says. But until the biological effects of the variants are known  genetic testing would be premature, he says.

Meanwhile, the double-edged nature of these APOL-1 genetic variants — fighting the parasite that causes sleeping sickness but apparently damaging kidneys — is eerily similar to the sickle-cell genetic trait. Many Africans have the sickle-cell mutation — inheriting a copy of it from one parent protects against malaria. Unfortunately, getting a copy from both parents results in sickle-cell disease.

Like sickle cell, the APOL-1 variants are closely tied to Africa. In the new study, roughly 40 percent of Nigerians tested carried at least one of the variants. The variant didn’t show up at all in Europeans, Japanese and Chinese.

“This whole story can be viewed as an outstanding illustration of the arms race taking place between [human] hosts and parasites during evolution,” says Luc Vanhamme, a microbiologist at the University of Brussels campus in Gosselies, Belgium. The biological record shows that long ago the single-celled parasite Trypanosoma brucei that causessleeping sickness developed a way to evade the human immune system. But people acquired a way to kill the parasite nevertheless, using a protein that’s not part of the immune system — the garden-variety APOL-1 protein.

The parasite retaliated. The current East African version of sleeping sickness is spread by a subspecies of the parasite, called T. brucei rhodesiense, that carries a mutation allowing it to dodge human APOL-1 protein and cause sleeping sickness. The new APOL-1 variants, which tests suggest can protect against this subspecies, represent the most recent skirmish in this war, Vanhamme says.

The increased kidney disease that they appear to foster, he says, “is an unfortunate side effect.”