Martin Pollak and his colleagues have shown that certain variants of the Apol1 serum factor confer trypanolytic capabilities and are associated with an increased risk of kidney disease in African-Americans. Genome Technology's Tracy Vence spoke with the chief of nephrology at Beth Israel Deaconess Medical Center about his team's findings, which were published in Science in August.
Genome Technology: Previous studies have shown an association between MYH9 and kidney disease, and evidence of natural selection at the genomic region containing MYH9 and APOL1. Why did you investigate whether there was a link between the two, and in African-Americans?
Martin Pollak: This paper extends some of those previous studies. Our work from doing genome-wide studies suggested to us that we had to look beyond just the MYH9 gene because we thought the selection pressure observed in this area could actually make the disease — the region that we needed to look at — bigger than previously was suspected. So we then broadened our search in terms of the size of the region that we were suspicious about, and we genotyped all [of] what we thought were suspicious variants in this region based on allele-frequency differences between ethnic groups. The region that we looked at, including APOL1, was by far the best associated variants in the genome.
GT: Why did you choose to analyze data from the 1,000 Genomes Project?
MP: Because this is a sequencing-based project looking at genome sequences from different ethnicities, if there was a common variant that was responsible for this phenotype, it should have been captured by those sequencing efforts. Rather than doing the sequencing ourselves, we could just use this existing important new resource to guide our studies.
GT: You found two APOL1 variants that are significantly associated with focal segmental glomerulosclerosis and hypertension-attributed end-stage kidney disease in African-Americans. You also found that only kidney disease associated Apol1 serum factor variants lyse Trypanosome brucei rhodensiense. What is the combined clinical significance of these results?
MP: Certainly I think there's significance in terms of the implications for African sleeping sickness. If this form of the [Apol1] protein really confers resistance, this could be useful in developing protein-based therapies. In terms of kidney disease, we need to now figure out if people with these variants respond differently to medicines, and whether we can tailor therapies differently. More importantly, in the long term, we can really — in a much more focused way — explore the biology of why African-Americans get so much more kidney disease than other ethnicities. Now we have a genetic understanding of why that is and we can do studies to understand how the -genetics changes the -biology.
GT: What about the evolutionary significance?
MP: We think this is very similar to sickle cell disease. It's an example of what we call "balancing selection." In Africa, there's been evolutionary pressure to select for people with these variants because of their effect on infectious disease. We're not sure that it's in fact Trypanosome brucei rhodensiense that's really the driving factor; it might be some other infectious agent or a combination of infectious agents. This needs further clarification, but we think that there is selection for these variants in Africa. But if a person inherits two copies of these variant alleles, then the person is now at a much greater risk for kidney disease.
GT: Do you plan to study these APOL1 variants further?
MP: We really know very little about the biology. We're going to do all sort of things [with] cell biologic and animal experiments to understand the connection between genotype and disease.