Advisory Committee Chair
Marguerite Ryan Irvin
Advisory Committee Members
Orlando M Gutierrez
Bertha A Hidalgo
Nita A Limdi
Richard J Reynolds Iv
Hemant K Tiwari
Document Type
Dissertation
Date of Award
2021
Degree Name by School
Doctor of Philosophy (PhD) School of Public Health
Abstract
Over the past decade, the discovery of novel genetic loci on chromosome 22q, apolipoprotein-L1 (APOL1), has given insights into the racial differences in kidney outcomes at the population level. APOL1 risk alleles are unique to African ancestry and confer increased susceptibility to end-stage kidney disease (ESKD) especially among individuals without diabetes. However, the diseases do not occur in all who inherit these alleles. Current efforts are driven towards identifying the factors that can interact with APOL1 in the development of kidney diseases. This dissertation investigated whether the association between APOL1 and kidney outcomes is affected by inflammatory markers (AIM1), high-density lipoproteins (HDL) or HDL sub-fractions (AIM2), and other genes (AIM3) using data from the Reasons for Geographic and Racial Differences in Stroke(REGARDS) study(N=10,605). The primary kidney outcomes were incident ESKD (N=421) using linkage with the USRDS and incident CKD (N=781) using estimated glomerular filtration rate (eGFR) value across two REGARDS study visits. In AIM1, using data on C reactive protein, white blood cell count, and serum albumin, we found that APOL1 risk alleles were associated with lowers odds of low (or abnormal) serum albumin. However, serum albumin did not mediate the relationship between APOL1 and incident kidney outcomes. In AIM2, APOL1 risk alleles moderated the association between HDL sub-fractions and incident ESKD. Among individuals with high-risk APOL1 genotype, higher levels of small and total HDL sub-fractions were independently associated with incident ESKD while the same relationship was not observed among those without the high risk APOL1 genotype. In AIM3, we conducted a genome-wide association gene-APOL1 interactive analysis using REGARDs genotype. Only one SNPs met the statistical significance threshold of P<5E-08. With a liberal threshold of P<1E-05, 183 SNPs interacted with APOL1 high risk status under a recessive genetic model. On replication analysis in the Genetics of Hypertension Associated Treatment study (N=6,791), we identified a potential APOL1-renal risk modifying variant (rs2181251) near SMOC2 on chromosome 6. In conclusion, we have uncovered additional novel information that may inform APOL1-kidney risk among the AAs population. The replication of these findings in other cohorts can continue to clarify the most essential driving factor
Recommended Citation
Chaudhary, Ninad S., "How Inflammation, High-Density Lipoproteins, And Genes Affect The Relationship Between Apol1 And Kidney Outcomes" (2021). All ETDs from UAB. 3487.
https://digitalcommons.library.uab.edu/etd-collection/3487