Alpha globin gene copy number and hypertension risk among Black Americans

Ruhl, A. Parker; Jeffries, Neal; Yu, Yang; Gutiérrez, Orlando M.; Muntner, Paul; Naik, Rakhi P.; Pecker, Lydia H.; Mott, Bryan T.; Zakai, Neil A.; Safford, Monika M.; Lange, Leslie A.; Winkler, Cheryl A.; Irvin, Marguerite R.; Cushman, Mary; Ackerman, Hans

doi:10.1371/journal.pone.0271031

Cited by 3 publications

(1 citation statement)

References 41 publications

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“…This finding is consistent with a prior study demonstrating no association between HBA copy number and hypertension but differs from a study demonstrating an association with chronic and end-stage kidney disease in which HBA gene deletions are protective. 6,10 Together, these population studies suggest that the physiological roles of alpha globin may differ between the renal and cerebral vascular beds.…”

Section: Resultsmentioning

confidence: 97%

Alpha globin gene copy number and incident ischemic stroke risk among Black Americans

Ruhl

Jeffries

et al. 2023

Preprint

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Introduction: People with African ancestry have greater stroke risk and greater heritability of stroke risk than people of other ancestries. Given the importance of NO in stroke, we examined the association between alpha globin gene (HBA) copy number and incident ischemic stroke in the Reasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Methods: Among 9,999 Black REGARDS participants9 withHBAandHBBgenotyping available, 8,947 participants had no self-reported history of stroke at baseline and complete follow-up data. Incident ischemic stroke was defined as non-hemorrhagic stroke with a focal neurological deficit lasting ≥ 24 hours confirmed by the medical record or a focal or non-focal neurological deficit with positive imaging confirmed with medical records. Genomic DNA was analyzed using droplet digital PCR 6 to determineHBAcopy number. Multivariable Cox proportional hazards regression was used to estimate the hazard ratio (HR) ofHBAcopy number on time to first ischemic stroke. Results: Four-hundred seventy-nine (5.3%) participants had an ischemic stroke over a median (IQR) of 11.0 (5.7, 14.0) years follow-up.HBAgene copy number ranged from 2 to 6: 368 (4%) -α/-α, 2,480 (28%) -α/αα, 6,014 (67%) αα/αα, 83 (1%) ααα/αα and 2 (<1%) ααα/ααα. The HR of ischemic stroke withHBAcopy number, adjusted for age, sex, hypertension, atrial fibrillation, LVH, diabetes, and smoking, was 1.04; 95%CI 0.89, 1.21; p = 0.66. Conclusions: Although a reduction inHBAcopy number is expected to increase endothelial nitric oxide signaling in the human vascular endothelium,HBAcopy number was not associated with incident ischemic stroke in this large longitudinal cohort of Black Americans. This finding is consistent with a prior study demonstrating no association betweenHBAcopy number and hypertension but differs from a study demonstrating an association with chronic and end-stage kidney disease in whichHBAgene deletions are protective. Together, these population studies suggest that the physiological roles of alpha globin may differ between the renal and cerebral vascular beds.

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Section: Resultsmentioning

confidence: 97%

Alpha globin gene copy number and incident ischemic stroke risk among Black Americans

Ruhl

Jeffries

et al. 2023

Preprint

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A moonlighting job for α-globin in blood vessels

Abbineni,

Baid,

Weiss

2024

Blood

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Red blood cells (RBC) express high levels of hemoglobin A tetramer (HbA, 22) to facilitate oxygen (O2) transport. Hemoglobin and related proteins are also expressed at lower levels in other tissues across the animal kingdom. Physiological functions for most non-erythroid globins likely derive from their ability to catalyze reduction-oxidation (redox) reactions via electron transfer through heme-associated iron. An interesting example is illustrated by the recent discovery that -globin without -globin is expressed in some arteriolar endothelial cells (ECs). -Globin binds EC nitric oxide synthase (eNOS) and degrades its enzymatic product nitric oxide (NO), a potent vasodilator. Thus, depletion of -globin in ECs or inhibition of its association with eNOS causes arteriolar relaxation and lowering of blood pressure in mice. Some of these findings have been replicated in isolated human blood vessels and genetic studies are tractable in populations where -thalassemia alleles are prevalent. Two small studies identified associations between loss of -genes in humans and NO-regulated vascular responses elicited by local hypoxia-induced blood flow or thermal stimulation. In a few larger population-based studies, no associations were detected between loss of -globin genes and blood pressure, ischemic stroke or pulmonary hypertension. In contrast, a significant positive association between -globin gene copy number and kidney disease was detected in an African American cohort. Further studies are required to define comprehensively the expression of -globin and related globin proteins in different vascular beds and ascertain their overall impact on normal and pathological vascular physiology.

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Alpha globin gene copy number and incident ischemic stroke risk among Black Americans

Ruhl

Jeffries

et al. 2023

Front. Stroke

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IntroductionPeople with African ancestry have greater stroke risk and greater heritability of stroke risk than people of other ancestries. Given the importance of nitric oxide (NO) in stroke, and recent evidence that alpha globin restricts nitric oxide release from vascular endothelial cells, we hypothesized that alpha globin gene (HBA) deletion would be associated with reduced risk of incident ischemic stroke.MethodsWe evaluated 8,947 participants self-reporting African ancestry in the national, prospective Reasons for Geographic And Racial Differences in Stroke (REGARDS) cohort. Incident ischemic stroke was defined as non-hemorrhagic stroke with focal neurological deficit lasting ≥24 h confirmed by the medical record or focal or non-focal neurological deficit with positive imaging confirmed with medical records. Genomic DNA was analyzed using droplet digital PCR to determine HBA copy number. Multivariable Cox proportional hazards regression was used to estimate the hazard ratio (HR) of HBA copy number on time to first ischemic stroke.ResultsFour-hundred seventy-nine (5.3%) participants had an incident ischemic stroke over a median (IQR) of 11.0 (5.7, 14.0) years' follow-up. HBA copy number ranged from 2 to 6: 368 (4%) -α/-α, 2,480 (28%) -α/αα, 6,014 (67%) αα/αα, 83 (1%) ααα/αα, and 2 (<1%) ααα/ααα. The adjusted HR of ischemic stroke with HBA copy number was 1.04; 95%CI 0.89, 1.21; p = 0.66.ConclusionsAlthough a reduction in HBA copy number is expected to increase endothelial nitric oxide signaling in the human vascular endothelium, HBA copy number was not associated with incident ischemic stroke in this large cohort of Black Americans.

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Alpha globin gene copy number and hypertension risk among Black Americans

Cited by 3 publications

References 41 publications

Alpha globin gene copy number and incident ischemic stroke risk among Black Americans

Alpha globin gene copy number and incident ischemic stroke risk among Black Americans

A moonlighting job for α-globin in blood vessels

Alpha globin gene copy number and incident ischemic stroke risk among Black Americans

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