Arrest of the true culprit and acquittal of the innocent? Genetic revelations charge APOL1 variants with kidney disease susceptibility

Excerpt

Until recently, the knowledge of genetic causes of focal and segmental glomerulosclerosis (FSGS) was limited to certain rare Mendelian diseases and a few gene variants with minor effects, together explaining only a small fraction of kidney diseases. However, striking racial disparities in the frequency of FSGS and other forms of kidney disease between African-Americans and European-Americans point to a common, relatively large genetic influence [1]. While previous studies based on genome-wide screens for association have consistently suggested that MYH9 gene variants confer the increased susceptibility for renal disease in African-Americans [2, 3], Martin Pollack and colleagues now provide compelling evidence that variants of APOL1 are in linkage disequilibrium with the previously identified MYH9 risk haplotype and may be regarded as the true culprit [4‐6]. They demonstrate that two APOL1 risk variants appear to entirely account for the strong association signal at the locus, and these encode for variant proteins conferring resistance against Trypanosoma brucei rhodesiense, a protozoa causing African sleeping disease. While the protective effect against trypanosomiasis appears to be present in heterozygous carriers, kidney disease susceptibility is largely restricted to individuals harboring two risk alleles. This heterozygous advantage model provides an explanation for a strong natural selection for the kidney disease risk alleles in the population exposed to the specific pathogen. However, the mechanisms by which the APOL1 variants contribute to renal injury remain to be unraveled. …