Effect of Genetic African Ancestry on eGFR and Kidney Disease

Abstract

Self-reported ancestry, genetically determined ancestry, and APOL1 polymorphisms are associated with variation in kidney function and related disease risk, but the relative importance of these factors remains unclear. We estimated the global proportion of African ancestry for 9048 individuals at Mount Sinai Medical Center in Manhattan (3189 African Americans, 1721 European Americans, and 4138 Hispanic/Latino Americans by self-report) using genome-wide genotype data. CKD-EPI eGFR and genotypes of three APOL1 coding variants were available. In admixed African Americans and Hispanic/Latino Americans, serum creatinine values increased as African ancestry increased (per 10% increase in African ancestry, creatinine values increased 1% in African Americans and 0.9% in Hispanic/Latino Americans; P≤1x10(-7)). eGFR was likewise significantly associated with African genetic ancestry in both populations. In contrast, APOL1 risk haplotypes were significantly associated with CKD, eGFR<45 ml/min per 1.73 m(2), and ESRD, with effects increasing with worsening disease states and the contribution of genetic African ancestry decreasing in parallel. Using genetic ancestry in the eGFR equation to reclassify patients as black on the basis of ≥50% African ancestry resulted in higher eGFR for 14.7% of Hispanic/Latino Americans and lower eGFR for 4.1% of African Americans, affecting CKD staging in 4.3% and 1% of participants, respectively. Reclassified individuals had electrolyte values consistent with their newly assigned CKD stage. In summary, proportion of African ancestry was significantly associated with normal-range creatinine and eGFR, whereas APOL1 risk haplotypes drove the associations with CKD. Recalculation of eGFR on the basis of genetic ancestry affected CKD staging and warrants additional investigation.

Keywords: GFR; apolipoprotein L1; epidemiology and outcomes; ethnicity; genetic renal disease; renal function.

Figure 1.

Adjustment for proportion genetic African ancestry attenuates differences in serum creatinine between AAs and H/LAs, but not differences in eGFR. As shown in A, the natural log of serum creatinine values in H/LAs and AAs increase with proportion of genetic African ancestry (unadjusted β=0.02 units on log scale per 10% genetic African ancestry; P=2×10⁻⁵ in AAs; unadjusted β=0.01 units on log scale per 10% genetic African ancestry; P=8×10⁻⁵ in H/LAs). After adjusting for proportion of genetic African ancestry in a full model, there was no longer a significant difference in average creatinine levels between these populations (P>0.05). B shows that eGFR levels decrease with increased proportion of genetic African ancestry in both AAs and H/LAs (unadjusted β=−1.69 ml/min per 1.73 m² per 10% genetic African ancestry; P=2×10⁻⁷ in AAs; unadjusted β=−1.26 ml/min per 1.73 m² per 10% genetic African ancestry; P=7×10⁻¹² in H/LAs). However, unlike the analyses with creatinine, adjustment for genetic African ancestry did not attenuate the interpopulation differences in eGFR between AAs and H/LAs (P<10⁻¹⁰ in adjusted model).

Figure 2.

GFR in AAs and H/As calculated using the CKD-EPI equation is compared with a modification of the equation incorporating genetic African ancestry. Unadjusted eGFR (shown at the top of the figure) is higher on average in AAs than H/LAs, and this is seen in each category of proportion genetic African ancestry. The eGFR was then recalculated to incorporate genetic African ancestry, as follows. For self-reported AAs who were found by genetic ancestry to be <50% African, their current eGFR was divided by 1.159 to remove the black correction factor. In a similar fashion, for H/LAs who were found to be ≥50% African, their GFR was increased by a factor 1.159. With eGFR recalculated using genetic African ancestry, there was no longer a significant difference between eGFR values in AAs and H/LAs by category of percentage of African ancestry.