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Review
. 2014 Sep;21(5):426-33.
doi: 10.1053/j.ackd.201406005.

APOL1 kidney risk alleles: population genetics and disease associations

Affiliations
Review

APOL1 kidney risk alleles: population genetics and disease associations

Sophie Limou et al. Adv Chronic Kidney Dis. 2014 Sep.

Abstract

APOL1 kidney disease is a unique case in the field of the genetics of common disease: 2 variants (termed G1 and G2) with high population frequency have been repeatedly associated with nondiabetic CKDs, with very strong effect size (odds ratios 3-29) in populations of sub-Saharan African descent. This review provides an update on the spectrum of APOL1 kidney disease and on the worldwide distribution of these kidney risk variants. We also summarize the proper way to run a recessive analysis on joint and independent effects of APOL1 G1 and G2 kidney risk variants.

Keywords: APOL1 demographics; African admixture; Apolipoprotein L1; Chronic kidney disease; Glomerular disease.

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Figures

Figure 1
Figure 1
ApoL1 protein structure and haplotype distribution among African Americans. (A) Domain structure of ApoL1 protein, with the location of the G1 allele (S342 G and I384 M) and G2 allele (NYK388–389K). (B) Haplotype and variant frequencies for the general African American population. For the G1 alleles, the G1GM refers to the genotype with both mutations and G1GI refers to S342 G without I384 M. Abbreviations: BH3, Bcl2 homology domain 3; SRA, serum resistance antigen (of Trypanosoma brucei rhodesiense).
Figure 2
Figure 2
Geographic distribution of APOL1 risk alleles and of Trypanosoma brucei subspecies. Shown are the distributions of G1 and G2 alleles among population groups, mostly in sub-Saharan Africa, together with the population ranges for Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. The Great Rift Valley is shown as line running from southwest to northeast. The population numbers refer to Table 1.
Figure 3
Figure 3
Importance of considering both G1 and G2 alleles in the genetic analysis. Spurious or attenuated associations occur when APOL1 G1 or G2 are considered separately. (A) Analysis by count of risk alleles; bars show frequency of each genotype among FSGS controls and cases. Genotypes with 2 risk alleles (red) are strongly associated; genotypes with 1 or no risk alleles (yellow) show weak or no associations. There is no significant difference in disease susceptibility between subjects carrying 1 and no risk alleles. Analysis that considersG1 or G2 separately confounds the association by bringing risk genotypes–genotype with 2 risk alleles–into the groups carrying 1 or no copies of G1 or G2, respectively. (B) Analysis considering the number of copies of G1. Here a significant difference is observed in frequency of FSGS between individuals with 1 copy of G1 and individuals with no copies, suggesting a dominant effect. However, this is driven by the high frequency of individuals with the G1/G2 genotype–individuals with 2 risk alleles, but only 1 copy of G1–among FSGS cases. (C) Analysis considering the number of copies of G2. A much weaker recessive disease association is seen–this is significant with the data shown but may not be with weaker data or smaller effect sizes for a particular phenotype–because of the rarity of the G2/G2 genotype and because the more frequent G1/G2 and G1/G1 genotypes occur only in the comparison (one and no copies of G2) groups.

References

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