The prevalence of end-stage renal disease is four times higher in African Americans than it is in European Americans. When I was an internal medicine resident in the late 1980s, I recall receiving several somewhat vague explanations as to why this was the case, basically suggesting that it was multifactorial, but that it could most often be blamed on untreated hypertension. What no one would have said then was that it was the fault of the tsetse fly.
Dr. Michael F. Murray
Before I get to the tsetse fly, let me briefly review the relationship between sickle hemoglobin and malaria, which is often used to explain heterozygous advantage. The observations underlying this example were made in the first half of the 20th century. To review, a point mutation in the HBB (beta hemoglobin) gene occurred in an individual in Western Africa and then – over centuries, and under the selective pressure of Plasmodium falciparum – the carrier state for this human genetic variant reached high levels. The human population’s advantage is that carriers are resistant to malaria; the human population’s cost is that sickle cell disease occurs in individuals who harbor two copies of the altered gene.
In this scenario, there is a homozygous disadvantage (that is, sickle cell anemia) for people who carry two copies of the altered gene, a homozygous disadvantage (susceptibility to malaria) for people who carry two copies of the unaltered gene, and a heterozygous advantage (resistance to malaria) for people who carry one copy of each.
In August 2010, Giulio Genovese, Ph.D., of Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, and his colleagues published an article entitled "Association of Trympanolytic APOL1 Variants with Kidney Disease in African Americans," (Science 2010;329:841-5). While I admit the title may not have grabbed the attention of the average clinician in practice, the story is truly amazing.
APOL1 is one of the human genes for an apolipoprotein, in this case one of the proteins on the surface of HDL cholesterol. It turns out that the parasite that causes African sleeping sickness (Trypanosoma brucei) is destroyed by lysis in the bloodstream of individuals with certain versions of this gene. Specifically, the variants of the APOL1 gene designated as the G1 and G2 alleles are associated with resistance to this fatal disease.
The APOL1–renal disease story appears to play out a bit like the HBB–sickle cell disease story. Like the mosquito, the tsetse fly is the disease vector that transmits disease when it bites humans. There is the homozygous disadvantage of susceptibility to sleeping sickness with the normal version of the APOL1 gene, and the heterozygous advantage of resistance to the infection with the genetic variant. And as the work of Dr. Genovese and colleagues suggests, there is the homozygous disadvantage of increased renal disease risk with two copies of the genetic variant.
So where does this research lead? In the years ahead, clinical research that looks at factors such as low-protein diets and intensified blood-pressure control in individuals with a genetic predisposition will likely yield answers about ways to modify the genetic risk. We hope such clinical research will lead to practical measures that will help counteract inherited risks for renal disease for many Americans.