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 27 ).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.

Differential methylation between ethnic sub-groups reflects the effect of genetic ancestry and environmental exposures

“…To account for these heterogeneities and to avoid social and political controversies, the genetics community has grouped individuals by genetic ancestry instead of race and ethnicity (Yudell et al, 2016). Indeed, recent work from our group and others have demonstrated that genetic ancestry improves diagnostic precision compared to racial/ethnic categorizations for specific medical conditions and clinical decisions (Kumar et al, 2010; Udler et al., 2015; Nalls et al, 2008). …”

Creating ethnicity-specific reference intervals for lab tests from EHR data

“…However, in this test, race is binary (African-American or European), and recent work suggests that more granular categories and/or genetic ancestry could improve eGFR scaling (12). In other instances, differences in test distributions between SIRE are known in theory, but reference intervals are not altered in practice (13,14).…”

Clinical Decision Making in a Patient with Stage 5 CKD—Is eGFR Good Enough?

“…Few if any blacks were included in any of these reports, with the exception of a report from the AfricanAmerican Study of Hypertension and Kidney Disease Trial, which included derivation of its own formula for eGFR calculation in blacks (48). A recent report identified differences in eGFR and CKD staging on the basis of genetic determinants of the proportion of African ancestry in selfreported blacks and Hispanic/Latino Americans, further confounding GFR assessments in these populations (49).…”