Loss of alpha globin genes is associated with improved microvascular function in patients with sickle cell anemia

Romana, Marc; Reminy, K.; Moeckesch, Berenike; Charlot, Keyne; Hardy‐Dessources, Marie‐Dominique; Doumdo, Lydia; Tressières, Benoît; Etienne‐Julan, Maryse; Lemonne, Nathalie; Denton, Christopher; Coates, Thomas D.; Petras, Marie; Antoine‐Jonville, Sophie; Connes, Philippe

doi:10.1002/ajh.26126

Cited by 8 publications

(16 citation statements)

References 11 publications

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“…Thus, compensation may obscure the effect of reduced endothelial alpha globin gene expression on blood pressure. Third, while deletion of HBA has been associated with enhanced dynamic vasodilation [ 14 , 15 ], blood pressure is regulated by multiple pathways that are integrated across the renal, cardiovascular, and nervous systems. Thus changes in arterial nitric oxide signaling could be overcome by other regulatory systems to maintain a blood pressure set point [ 32 , 33 ].…”

Section: Discussionmentioning

confidence: 99%

“…The 3.7 kb alpha globin gene deletion is associated with enhanced dynamic vasodilation in adults of African or Asian ancestry [ 14 , 15 ]; however, the same deletion is not associated with blood pressure in healthy Kenyan adolescents [ 16 ]. We recently discovered this deletion to be associated with protection from chronic kidney disease and end-stage kidney disease in the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study cohort, a large population-based cohort study of older Black adults [ 17 ]; however, the question of whether HBA copy number is associated with hypertension risk or blood pressure in this cohort remains unaddressed.…”

Section: Introductionmentioning

confidence: 99%

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Alpha globin gene copy number and hypertension risk among Black Americans

Ruhl

Jeffries

et al. 2022

PLoS ONE

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Background Alpha globin is expressed in the endothelial cells of human resistance arteries where it binds to endothelial nitric oxide synthase and limits release of the vasodilator nitric oxide. Genomic deletion of the alpha globin gene (HBA) is common among Black Americans and could lead to increased endothelial nitric oxide signaling and reduced risk of hypertension. Methods Community-dwelling US adults aged 45 years or older were enrolled and examined from 2003 to 2007, followed by telephone every 6 months, and reexamined from 2013 to 2016. At both visits, trained personnel performed standardized, in-home blood pressure measurements and pill bottle review. Prevalent hypertension was defined as systolic blood pressure ≥ 140mmHg or diastolic blood pressure ≥ 90mmHg or anti-hypertensive medication use. Droplet digital PCR was used to determine HBA copy number. The associations of HBA copy number with prevalent hypertension, resistant hypertension, and incident hypertension were estimated using multivariable regression. Results Among 9,684 Black participants, 7,439 (77%) had hypertension at baseline and 1,044 of those had treatment-resistant hypertension. 1,000 participants were not hypertensive at baseline and participated in a follow up visit; 517 (52%) developed hypertension over median 9.2 years follow-up. Increased HBA copy number was not associated with prevalent hypertension (PR = 1.00; 95%CI 0.98,1.02), resistant hypertension (PR = 0.95; 95%CI 0.86,1.05), or incident hypertension (RR = 0.96; 95%CI 0.86,1.07). Conclusions There were no associations between increased HBA copy number and risk of hypertension. These findings suggest that variation in alpha globin gene copy number does not modify the risk of hypertension among Black American adults.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Alpha globin gene copy number and hypertension risk among Black Americans

Ruhl

Jeffries

et al. 2022

PLoS ONE

View full text Add to dashboard Cite

show abstract

“…Thus, compensation may obscure the effect of reduced endothelial alpha globin gene expression on blood pressure. Third, while deletion of HBA has been associated with enhanced dynamic vasodilation [14,15], blood pressure is regulated by multiple pathways that are integrated across the renal, cardiovascular, and nervous systems. Thus changes in arterial nitric oxide signaling could be overcome by other regulatory systems to maintain a blood pressure set point [33,34].…”

Section: Discussionmentioning

confidence: 99%

“…The 3.7 kb alpha globin gene deletion has been found to be associated with enhanced dynamic vasodilation in adults of African or Asian ancestry; 14,15 however, the same deletion was not associated with blood pressure in a study of healthy Kenyan adolescents. 16 We recently discovered that this deletion was associated with protection from chronic kidney disease and end-stage kidney disease in a large population-based cohort study of older Black adults 17 ; however, the question of whether HBA copy number is associated with hypertension risk or blood pressure in this cohort remains unaddressed.…”

Section: Introductionmentioning

confidence: 93%

“…These genes vary in functional copy number due to genomic deletions and insertions that are prevalent in people of African, Southeast Asian, Middle Eastern, Mediterranean, or Indian descent, [9][10][11] but are less common in people of European descent. 11 The most common alpha globin gene deletion (-3.7 kb) was recently found to be associated with enhanced vasodilation in people of African and Asian ancestry; 12,13 however, the same deletion was not associated with ambulatory blood pressure in a study of healthy Kenyan adolescents. 14 The question of whether this alpha globin gene insertion/deletion is associated with hypertension risk or blood pressure among older adults with multiple medical comorbidities remains unaddressed.…”

Section: Introductionmentioning

confidence: 99%

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Alpha globin gene copy number and hypertension risk among Black Americans

Ruhl

Jeffries

et al. 2022

Preprint

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BACKGROUND: Alpha globin is expressed in the endothelial cells of human resistance arteries where it binds to endothelial nitric oxide synthase and limits release of the vasodilator nitric oxide. Genomic deletion of the alpha globin gene (HBA) is common among Black Americans and could lead to increased endothelial nitric oxide signaling and reduced risk of hypertension. METHODS: Community-dwelling US adults aged 45 years or older were enrolled and examined from 2003 to 2007, followed by telephone every 6 months, and reexamined from 2013 to 2016. At both visits, trained personnel performed standardized, in-home blood pressure measurements and pill bottle review. Prevalent hypertension was defined as systolic blood pressure ≥ 140mmHg or diastolic blood pressure ≥ 90mmHg or anti-hypertensive medication use. Droplet digital PCR was used to determine HBA copy number. The associations of HBA copy number with prevalent hypertension, resistant hypertension, and incident hypertension were estimated using multivariable regression. RESULTS: Among 9,684 Black participants, 7,439 (77%) had hypertension at baseline and 1,044 of those had treatment-resistant hypertension. 1,000 participants were not hypertensive at baseline and participated in a follow up visit; 517 (52%) developed hypertension over median 9.2 years follow-up. Increased HBA copy number was not associated with prevalent hypertension (PR=1.00; 95%CI 0.98,1.02), resistant hypertension (PR=0.95; 95%CI 0.86,1.05), or incident hypertension (RR=0.96; 95%CI 0.86,1.07). CONCLUSIONS: There were no associations between increased HBA copy number and risk of hypertension. These findings suggest that genetic variation in alpha globin gene expression does not modify the risk of hypertension among Black American adults.

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Genetic Variation and Sickle Cell Disease Severity

Kirkham,

Estepp,

Weiss

et al. 2023

JAMA Netw Open

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ImportanceSickle cell disease (SCD) is a monogenic disorder, yet clinical outcomes are influenced by additional genetic factors. Despite decades of research, the genetics of SCD remain poorly understood.ObjectiveTo assess all reported genetic modifiers of SCD, evaluate the design of associated studies, and provide guidelines for future analyses according to modern genetic study recommendations.Data SourcesPubMed, Web of Science, and Scopus were searched through May 16, 2023, identifying 5290 publications.Study SelectionAt least 2 reviewers identified 571 original, peer-reviewed English-language publications reporting genetic modifiers of human SCD phenotypes, wherein the outcome was not treatment response, and the comparison was not between SCD subtypes or including healthy controls.Data Extraction and SynthesisData relevant to all genetic modifiers of SCD were extracted, evaluated, and presented following STREGA and PRISMA guidelines. Weighted z score meta-analyses and pathway analyses were conducted.Main Outcomes and MeasuresOutcomes were aggregated into 25 categories, grouped as acute complications, chronic conditions, hematologic parameters or biomarkers, and general or mixed measures of SCD severity.ResultsThe 571 included studies reported on 29 670 unique individuals (50% ≤ 18 years of age) from 43 countries. Of the 17 757 extracted results (4890 significant) in 1552 genes, 3675 results met the study criteria for meta-analysis: reported phenotype and genotype, association size and direction, variability measure, sample size, and statistical test. Only 173 results for 62 associations could be cross-study combined. The remaining associations could not be aggregated because they were only reported once or methods (eg, study design, reporting practice) and genotype or phenotype definitions were insufficiently harmonized. Gene variants regulating fetal hemoglobin and α-thalassemia (important markers for SCD severity) were frequently identified: 19 single-nucleotide variants in BCL11A, HBS1L-MYB, and HBG2 were significantly associated with fetal hemoglobin (absolute value of Z = 4.00 to 20.66; P = 8.63 × 10−95 to 6.19 × 10−5), and α-thalassemia deletions were significantly associated with increased hemoglobin level and reduced risk of albuminuria, abnormal transcranial Doppler velocity, and stroke (absolute value of Z = 3.43 to 5.16; P = 2.42 × 10−7 to 6.00 × 10−4). However, other associations remain unconfirmed. Pathway analyses of significant genes highlighted the importance of cellular adhesion, inflammation, oxidative and toxic stress, and blood vessel regulation in SCD (23 of the top 25 Gene Ontology pathways involve these processes) and suggested future research areas.Conclusions and RelevanceThe findings of this comprehensive systematic review and meta-analysis of all published genetic modifiers of SCD indicated that implementation of standardized phenotypes, statistical methods, and reporting practices should accelerate discovery and validation of genetic modifiers and development of clinically actionable genetic profiles.

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Loss of alpha globin genes is associated with improved microvascular function in patients with sickle cell anemia

Abstract: analyzed and interrupted the results; Kunming Qi, Gang Wang, Qingyun Wu and Zhenyu Li designed the figures; Jiang Cao and Shiyuan Wang wrote the manuscript. All authors critically reviewed the final draft prior to submission.

Cited by 8 publications

References 11 publications

Alpha globin gene copy number and hypertension risk among Black Americans

Alpha globin gene copy number and hypertension risk among Black Americans

Alpha globin gene copy number and hypertension risk among Black Americans

Genetic Variation and Sickle Cell Disease Severity

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