12 Aug Chronic Kidney Disease: Novel variants of APOL1 gene may play a role in susceptibility
MedicalResearch.com Interview with:
Dr. Wen-Ya Ko, Ph.D.
Postdoctoral Fellow, First author of the paper
Department of Genetics
School of Medicine
University of Pennsylvania
426 Clinical Research Building
415 Curie Boulevard
Philadelphia, PA 19104-6145
Dr. Sarah Tishkoff, Ph.D., Senior author of the paper
David and Lyn Silfen University Professor
Departments of Genetics and Biology
School of Medicine
School of Arts and Sciences
University of Pennsylvania
MedicalResearch.com: What are the main findings of the study?
Answer: In humans the APOL1 gene codes for Apolipoprotein L1, a major component of the trypanolytic factor in serum. The APOL1 gene harbors two risk alleles (G1 and G2) associated with chronic kidney disease (CKD) among individuals of recent African ancestry. We studied APOL1 across genetically and geographically diverse ethnic groups in Africa. We have discovered a number of novel variants at the APOL1 functional domains that are required to lyse trypanosome parasites inside human blood vessels.
We further identified signatures of natural selection influencing the pattern of variation on chromosomes carrying some of these variants. In particular, we have identified a haplotype (a cluster of genetic variants linked along a short region of a chromosome), termed G3, that has evolved adaptively in the Fulani population who have been practicing cattle herding which has been historically documented as early as in the medieval ages (but which could have begun thousands of years earlier). Many of the novel variants discovered in this study are candidates to play a role conferring protection against trypanosomiasis and/or to play a role in susceptibility of CKD in humans.
MedicalResearch.com: Were any of the findings unexpected?
Answer: We found that the genetic diversity of APOL1 is surprisingly high (at least 4-fold higher than the average levels of nonsynonymous (i.e. amino acid changing) polymorphisms in human genomes). We also found it surprising that the G1 and G2 alleles that had been associated with risk for kidney disease in African Americans were common only in one West African population from Nigeria called the Yoruba but were rare in other populations. Our results suggest that the picture of identifying risk alleles that contribute to CKD susceptibility is more complicated than we previously thought and, in addition to G1 and G2 risk alleles, there might be other functional variants that could play a role in human African trypanosomiasis infection and CKD risk.
MedicalResearch.com: What should clinicians and patients take away from your report?
Answer: We found that many of these candidate variants appear to be geographically restricted and, therefore, the probability of carrying a certain risk allele is likely to differ between ethnic groups. In particular, in our study, the allele frequency of the G1 risk allele differs greatly between the Yoruba (38%) and other populations (≤5.3%). It has been shown that African Americans have high levels of ancestry from western Africa (particularly from the Yoruba, in which the G3 haplotype is absent) but have only little Fulani ancestry where G3 is common. Therefore, the G3 haplotype might not play a major role contributing to CKD susceptibility in the majority of African Americans (although it could be playing a minor role). However, it could play a role in the susceptibility to CKD in some African populations that harbor this haplotypes.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Answer: Future studies should focus on studying the effect of the novel variants identified in this study on trypanolytic activity and statistical association with CKD. For example, it would be of great interest to study the functional consequences of the novel variant that we identified which occurs at the same codon coding for one of the two amino acid changes of the G1 risk allele. In addition, we have shown that the G3 haplotype may have evolved adaptively in the Cameroonian Fulani population that is currently exposed to T.b. rhodesiense. Therefore, it is also of great interest to test whether or not the serum of the G3 carriers can lyse T.b. rhodesiense. This is particularly important because the infection and resistance mechanisms of T.b. rhodesiense currently remain unclear.
Identifying Darwinian Selection Acting on Different Human APOL1 Variants among Diverse African Populations.
Ko WY, Rajan P, Gomez F, Scheinfeldt L, An P, Winkler CA, Froment A, Nyambo TB, Omar SA, Wambebe C, Ranciaro A, Hirbo JB, Tishkoff SA.
Department of Genetics, School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Centro de Investigação em Biodiversidade e Recursos Genéticos, Universidade do Porto, 4485-661 Vairão, Portugal.
Am J Hum Genet. 2013 Jul 11;93(1):54-66. doi: 10.1016/j.ajhg.2013.05.014.
Epub 2013 Jun 13.