Thursday, September 16, 2010

Kidney Disease as a Consequence of Genetic Resistance to a Parasite

It has been well established that carriers of the sickle cell trait – predominantly found in sub-Saharan African populations - have an innate resistance to malaria. There is now evidence of an analogous relationship between a genetically-determined resistance against an infective agent and disease - in this case involving kidney disease.

Research results coming out of the laboratory of Martin Pollak, a nephrologist and human geneticist from the Harvard Medical School in Boston, have established a link between certain renal (kidney) conditions and a parasite called Trypanosoma brucei that is spread in African populations by a tsetse fly vector and causes African sleeping sickness. The kidney diseases studied were focal segmental glomerulosclerosis and end stage kidney disease; both of these maladies are four or five times more prevalent in African American populations than those of European origins.

As a result of exhaustive genetic analysis, Pollak and his team identified two variants in the so-called APOL1 gene that strongly correlates with kidney illness. The variants were referred to as G1 and G2. G1 turned up in 52% of glomerulosclerosis patients as compared to 18% of controls, and the G2 variant was found to be 50% more common with either kidney disease. Furthermore, they went on to determine that if both of the APOL1 genes (genes normally exist in pairs – one residing on each member of a chromosome pair) carried one of the disease-bearing variants, the probability of expressing kidney disease would increase seven fold.

The APOL1 gene is responsible for the production of apolipoprotein L-1. It has been demonstrated that the apolipoprotein L-1 promotes degradation of the trypanosome parasite by forming pores in its membrane. Pollak and his colleagues discovered that individuals, who carried either G1 or G2 in their blood plasma, effectively killed a subspecies of parasite T. brucei rhodesiense that is resistant to the normal gene product as did the synthetic versions of the variant proteins.

These are very interesting findings that point to the complex relationship between parasites and the hosts they infect. In addition, the fact that the man-made variants G1 and G2 proved efficacious in killing the parasite may prove to be clinically useful.

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