Genes and environment in chronic kidney disease hotspots

Abstract

Purpose of review: Chronic kidney disease (CKD) can cluster in geographic locations or in people of particular genetic ancestries. We explore APOL1 nephropathy and Balkan nephropathy as examples of CKD clustering that illustrate genetics and environment conspiring to cause high rates of kidney disease. Unexplained hotspots of kidney disease in Asia and Central America are then considered from the perspective of potential gene × environment interactions.

Recent findings: We report on evidence supporting both genes and environment in these CKD hotspots. Differing genetic susceptibility between populations and within populations may explain why causal environmental risk factors have been so hard to identify conclusively. Similarly, one cannot explain why these epidemics of kidney disease are happening now without invoking environmental changes.

Summary: Approaches to these CKD hotspots are of necessity becoming more holistic. Genetic studies may help us identify the environmental triggers by teaching us about disease biology and may empower environmental risk factor studies by allowing for stratification of study participants by genetic susceptibility.

Figure 1.. Kidney Disease in African Americans: a “hotspot” caused by genetic susceptibility.

Percentage of African Americans by state in the United States (CensusScope: www.censusscope.org). A strong correlation exists between rates of kidney disease and African American ancestry. Genetic variation in the APOL1 gene explains a large fraction of this disparity in kidney disease rates. Despite the very large risk of kidney disease conferred by the APOL1 risk alleles, most individuals with the high risk genotype do not develop kidney disease, suggesting that environmental triggers are also required.

Figure 2.. Defining genetic susceptibility in a CKD hotspot may make studies of environmental risk factors more powerful.

(top) Picture a population with very high rates of kidney disease. On the left hand side are disease cases and the right hand side are controls. The yellow spurs indicate individuals exposed to a particular environmental risk factor of interest. There appears to be some excess of exposures in the cases, but the data are not conclusive. (middle) A genetic study defines the genetically susceptible population. This could be either due to penetrant risk alleles at a single genetic locus or by an array of risk alleles, each of modest power, where the aggregate risk can be expressed in the form of a high polygenic risk score. (bottom) The overlap of genetic susceptibility and specific environmental exposure is illuminating. By comparing only susceptible cases with susceptible controls, strong differences in exposure to a putative environmental risk factor may become evident.