Alpha Globin Gene Copy Number Is Associated with Kidney Disease Among Black Individuals

Introduction: In addition to forming hemoglobin in red blood cells, alpha globin (HBA) has non-erythroid effects and is expressed in vascular endothelial cells where it interacts with endothelial nitric oxide (NO) synthase (eNOS) to limit nitric oxide diffusion across the myoendothelial junction. Reduced expression of HBA or disruption of HBA/eNOS interactions increases endothelial nitric oxide signaling. Humans have 0 to 3 copies of HBA per chromosome and Black individuals have increased variation in HBA allele count. Moreover, Black individuals are more likely to develop end-stage kidney disease (ESKD) and unexplained genetic factors may contribute to racial disparities in kidney disease not attributable to socioeconomic factors. Given that decreased endothelial NO signaling accelerates renal disease in mouse models, we hypothesized that lower HBA gene copy number would be associated with lower risk of kidney disease among Black individuals.

Methods: We used droplet digital PCR to measure HBA copy number in Black individuals enrolled in the REasons for Geographic and Racial Differences in Stroke cohort. This national, prospective observational study enrolled 30,239 men and women >45 years of age from the 48 contiguous United States. Prevalent chronic kidney disease (CKD) was defined as eGFR <60 ml/min/1.73m²or urine albumin/creatinine ratio ≥30 mg/g at enrollment. Incident end-stage kidney disease (ESKD) was identified by linkage to the United States Renal Data System. The relative risk (RR) of prevalent CKD was calculated using modified Poisson multivariable regression employing a linear effect of HBA allele count and adjusting for 13 pre-specified genetic, biomedical, and socioeconomic factors. The hazard ratio (HR) for incident ESKD was calculated using Cox proportional hazards regression with the same covariates.

Results: HBA copy number ranged from 2 to 6 among 9,918 Black participants (4% with 2 copies, 28% with 3, 67% with 4, and 1% with ≥ 5), with 25% of all participants having CKD at baseline. Participants were followed for a median (25^th, 75^thpercentile) of 10.1 (5.5, 12.5) years for the development of ESKD, with 2.4% of all participants developing ESKD. As shown in the table, after multivariable adjustment and calculated relative to the most common copy number (4), model-estimated CKD risk was 23% lower among those with 2 copies and 12% lower among those with 3 copies of HBA, while CKD risk was 14% higher among those with 5 or 6 copies of HBA. In addition, relative to 4 copies, ESKD risk was 40% lower among those with 2 copies and 22% lower among those with 3 copies, while the risk of ESKD increased by 29% in those with 5 or 6 copies of HBA.

Conclusions: We identified a novel, independent genetic association of HBA copy number with CKD prevalence and ESKD incidence among Black individuals in a national, prospective cohort study in the US. The findings are consistent with our hypothesis that decreased alpha globin gene expression could increase endothelial NO signaling in small renal arteries and confer protection against renovascular injury, while increased alpha globin gene expression couldlimit endothelial NO signaling. These findings suggest that further study of the impact of HBA expression on normal renal physiology and susceptibility to injury is needed.

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