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

Abstract

ABSTRACTBackgroundAlpha globin gene (HBA)copy number is variable among people of African descent.HBAlimits endothelial nitric oxide signaling and variation in gene copy number could modify kidney disease risk in this population.ObjectiveTo examine the association ofHBAcopy number with chronic kidney disease (CKD) and end-stage kidney disease (ESKD). We hypothesized that higherHBAcopy number would be associated with greater CKD prevalence and ESKD incidence.DesignProspective, 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.SettingCommunity-dwelling participants enrolled throughout the contiguous United StatesParticipantsBlack Americans age 45 years and olderMeasurementsHBAcopy 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 ofHBAallele count. The hazard ratio (HR) of incident ESKD was calculated using Cox proportional hazards multivariable regression.ResultsAmong 9,918 participants,HBAgene 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 ofHBAwas 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 ofHBA(HR = 1.28, 95% CI 1.01 to 1.61;P= 0.04).LimitationsThis study did not identify the mechanism by whichHBAcopy 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 whetherHBAmodifies kidney disease risk in other populations with the 3.7 kb deletion.ConclusionsIncreasingHBAcopy number was associated with greater prevalent CKD and incident ESKD in a national longitudinal study of Black Americans.Funding SourceNational Institutes of Health