APOL1 Nephropathy Risk Alleles and Mortality in African American Adults: A Cohort Study
Orlando M Gutiérrez1, Marguerite R Irvin2, Neil A Zakai3
1Department of Medicine, University of Alabama at Birmingham, Birmingham, AL; Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL.
Insights
APOL1 nephropathy risk alleles are linked to chronic kidney disease (CKD) in African Americans. High-risk APOL1 genotypes were associated with lower mortality, especially in those with CKD, after accounting for genetic ancestry.
Area of Science:
- Genetics and genomics
- Nephrology
- Epidemiology
Background:
- APOL1 nephropathy risk alleles are associated with chronic kidney disease (CKD) in African Americans.
- The link between APOL1 risk alleles and mortality is not well-established, despite CKD being a known mortality risk factor.
Purpose of the Study:
- To investigate the association between APOL1 high-risk genotypes and all-cause and cause-specific mortality in African Americans.
- To compare mortality risks associated with APOL1 genotypes between African Americans and white Americans.
Main Methods:
- A prospective cohort study of 10,380 African American and 17,485 white American participants from the REGARDS Study.
- Cox proportional hazards models were used to analyze the association of APOL1 high-risk (2 risk alleles) versus low-risk (0/1 risk allele) genotypes with mortality.
- Adjustments were made for sociodemographic variables, comorbid conditions, kidney function, and genetic ancestry.
Main Results:
- APOL1 high-risk participants were younger and had higher albuminuria prevalence.
- No significant association between APOL1 high-risk genotypes and all-cause mortality was found in initial models.
- After adjusting for genetic ancestry, APOL1 high-risk genotypes showed a significantly lower risk of all-cause mortality (HR, 0.81; 95% CI, 0.69-0.96).
- This association was significant for individuals with CKD (HR, 0.78; 95% CI, 0.62-0.99) but not those without CKD.
- African Americans with high-risk genotypes had similar mortality rates compared to white Americans, while those with low-risk genotypes had higher rates.
Conclusions:
- African Americans with high-risk APOL1 genotypes demonstrated a lower mortality risk compared to those with low-risk genotypes when genetic ancestry was considered.
- The findings suggest a complex interplay between APOL1 genetics, CKD, and mortality risk in African Americans.
Rationale & Objective:
APOL1 nephropathy risk alleles are associated with the development of chronic kidney disease (CKD) in African Americans. Although CKD is an established risk factor for mortality, associations of APOL1 risk alleles with mortality are uncertain.
Study Design:
Prospective cohort.
Settings & Participants:
10,380 African American and 17,485 white American participants in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study.
Exposures:
APOL1 nephropathy risk alleles.
Outcomes:
All-cause and cause-specific mortality.
Analytical Approach:
Cox proportional hazards models were used to examine the association of APOL1 high-risk genotypes (2 risk alleles) versus APOL1 low-risk genotypes (0/1 risk allele) with all-cause and cause-specific mortality in African Americans and examine the risk for all-cause mortality in African Americans with high-risk genotypes versus African Americans with low-risk genotypes and white Americans.
Results:
APOL1 high-risk participants were younger and had a higher prevalence of albuminuria than low-risk participants. There was no statistically significant association of APOL1 high- versus low-risk genotypes with all-cause mortality in models adjusted for sociodemographic variables, comorbid conditions, and kidney function (HR, 0.88; 95% CI, 0.77-1.01). After further adjustment for genetic ancestry in a subset with available data, a statistically significant association emerged (HR, 0.81; 95% CI, 0.69-0.96). Associations differed by CKD status (Pinteraction=0.04), with African Americans with high-risk genotypes having lower risk for mortality than those with low-risk genotypes in fully adjusted models (HR, 0.78; 95% CI, 0.62-0.99) among those with CKD, but not those without CKD (HR, 0.84; 95% CI, 0.66-1.05). Compared with white Americans, African Americans with high-risk genotypes had a similar rate of mortality, whereas African Americans with low-risk genotypes had a higher rate of mortality (HR, 1.07; 95% CI, 1.00-1.14) in fully adjusted models.
Limitations:
Lack of follow-up measures of kidney function.
Conclusions:
African Americans with high-risk APOL1 genotypes had lower mortality than those with low-risk genotypes in multivariable-adjusted models including genetic ancestry.
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