Preliminary Report: Missense mutations in the APOL gene family are associated with end stage kidney disease risk previously attributed to the MYH9 gene

TL;DR

This study identifies specific APOL1 gene mutations in West Africans that are more strongly linked to end stage kidney disease than MYH9 variants, suggesting a new genetic risk factor related to pathogen defense adaptations.

Contribution

The paper demonstrates that APOL1 mutations, rather than MYH9 variants, are the primary genetic risk factors for ESKD in West African populations, revising previous genetic associations.

Findings

APOL1 missense mutations are strongly associated with ESKD.

Distribution of risk variants aligns with African ancestry patterns.

Other APOL gene family members also show associations.

Abstract

MYH9 has been proposed as a major genetic risk locus for a spectrum of non-diabetic end stage kidney disease (ESKD). We use recently released sequences from the 1000 Genomes Project to identify two western African specific missense mutations (S342G and I384M) in the neighbouring APOL1 gene, and demonstrate that these are more strongly associated with ESKD than previously reported MYH9 variants. We also show that the distribution of these risk variants in African populations is consistent with the pattern of African ancestry ESKD risk previously attributed to the MYH9 gene. Additional associations were also found among other members of the APOL gene family, and we propose that ESKD risk is caused by western African variants in members of the APOL gene family, which evolved to confer protection against pathogens, such as Trypanosoma.