HBACopy Number and Kidney Disease Risk among Black Americans: a Longitudinal Cohort Study

ABSTRACT Background Alpha globin gene ( HBA) copy number is variable among people of African descent. HBA limits endothelial nitric oxide signaling and variation in gene copy number could modify kidney disease risk in this population. Objective To examine the association of HBA copy number with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). We hypothesized that higher HBA copy number would be associated with greater CKD prevalence and ESKD incidence. Design Prospective, longitudinal cohort from the REasons for Geographic and Racial Differences in Stroke (REGARDS) study which enrolled participants from 2003 through 2007 and conducted follow-up through June 2014. Data were analyzed from January 2018 through January 2021. Setting Community-dwelling participants enrolled throughout the contiguous United States Participants Black Americans age 45 years and older Measurements HBA copy number was measured using droplet-digital PCR on genomic DNA; copy number ranged from 2 to ≥ 5 copies. The prevalence ratio (PR) of CKD and relative risk (RR) of incident reduced estimated glomerular filtration rate (eGFR) were calculated using modified Poisson multivariable regression employing a log-linear effect of HBA allele count. The hazard ratio (HR) of incident ESKD was calculated using Cox proportional hazards multivariable regression. Results Among 9,918 participants, HBA gene copy number frequencies were 4%, 28%, 67%, and 1% for 2, 3, 4, and ≥5 copies, respectively. After adjusting for demographic, clinical, and genetic risk factors, each additional copy of HBA was associated with 14% greater prevalence of CKD (PR = 1.14, 95% CI 1.07 to 1.21; P < 0.0001). While there was no significant association with incident reduced eGFR (RR = 1.06, 95% CI 0.94 to 1.18; p = 0.36), the hazard of incident ESKD was 28% higher for each additional copy of HBA (HR = 1.28, 95% CI 1.01 to 1.61; P = 0.04). Limitations This study did not identify the mechanism by which HBA copy number modifies kidney disease risk. This study focused on Black Americans, a population with a high frequency of the 3.7 kb gene deletion; it is unknown whether HBA modifies kidney disease risk in other populations with the 3.7 kb deletion. Conclusions Increasing HBA copy number was associated with greater prevalent CKD and incident ESKD in a national longitudinal study of Black Americans. Funding Source National Institutes of Health