Approved Research

Examining the relationship between APOL1 and chronic kidney disease

University of Glasgow

Lay summary

There are two mutations (changes to the genetic sequence) in the APOL1 gene that are common in individuals with recent African genetic ancestry, but not present in humans who do not have this ancestry. Carrying one copy of the mutant APOL1 gene has been shown to give protection against human African trypanosomiasis (sleeping sickness). The frequency of these mutations has previously been calculated in various populations in Africa and in populations with recent African heritage in the Americas. Due to the benefit that this provides to carriers, natural selection has resulted in these mutations being common in areas where sleeping sickness is present, and in populations descended from such areas. However, previous studies of chronic kidney disease in African Americans have indicated that individuals who have two copies of mutant APOL1 have an increase susceptibility to chronic kidney disease.

We will determine the frequency of these mutations among individuals in the UK Biobank who have black ethnicity, and examine whether people in the UK Biobank who have two copies of mutant APOL1 are more likely to have impaired kidney function. We will also investigate whether there is a link between having one or two copies of the mutant APOL1 gene and other illnesses (such as heart conditions, strokes, and neurodegenerative diseases). Additionally we will investigate how factors that are responsible for chronic kidney disease differ across ethnicities.

We estimate that carrying out this analysis in full will take two years.

Having a greater understanding of the genetic basis of chronic kidney disease and how this and other relevant factors vary across ethnicities will enable predictions to be made about the likelihood that an individual might develop it, enable treatments and preventative measures to be better targeted, and provide information on inequalities between ethnicities in relation to health.

Scope extension:

We are interested in two variants (known as G1 and G2) that occur at the C-terminal end of the APOL1 gene. These variants are found only in individuals who have African genetic ancestry, and it has been shown in other populations (such as African Americans) that homozygotes for these variants have an increased likelihood of developing chronic kidney disease.

The aims of this study are:

To determine the frequency of APOL1 G1 and G2 among individuals in the UK Biobank who have black ethnicity.
To examine whether there is an observable relationship between APOL1 genotype and impaired kidney function.
To compare the predictors, modifiers, and comorbidities of kidney function across ethnicities.
To investigate whether APOL1 genotype has a relationship with additional morbidities and sequelae.

We would like to extend the scope of our study by using data from the UK Biobank to estimate how APOL1 G1 and G2 frequency varies across Africa. We would combine UK Biobank genotype data and ethnicity codes indicating African descent with our own datasets from previous analyses of African populations (Mulindwa et al., 2020: High Levels of Genetic Diversity within Nilo-Saharan Populations: Implications for Human Adaptation. Am J Hum Genet 107, 473-486). We would then perform principal component analysis on the combined dataset to estimate the location(s) within Africa most-associated with each individual's genetic heritage. We would then identify the proportion of APOL1 G1 and G2 alleles among people assigned to each location within Africa.

NEW SCOPE

Like APOL1, SMOC2 is implicated in both chronic kidney disease and human African trypanosomiasis (levels of SMOC2 increase in CKD, and we have identified a variant that is associated with protection in human African trypanosomiasis). Furthermore, it has been shown that APOL1 and SMOC2 interact. We would therefore like to extend our study to examine SMOC2 variants in a similar way to our APOL1 work:

- Determining the frequency of SMOC2 variants among individuals in the UK Biobank with recent African ancestry.

- Examining the relationship between SMOC2 genotype and APOL1 genotype, and how these combined genotypes impact on kidney function.

- Investigating whether SMOC2 genotype has a relationship with additional morbidities and sequelae.