A Parker Ruhl1,2, Neal Jeffries3, Yu Yang4, Rakhi P Naik5, Amit Patki6, Lydia H Pecker5, Bryan T Mott7, Neil A Zakai8,9, Cheryl A Winkler10, Jeffrey B Kopp11, Leslie A Lange12, Marguerite R Irvin13, Orlando M Gutierrez13,14, Mary Cushman8,9, Hans C Ackerman1. 1. Laboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland parker.ruhl@nih.gov hans.ackerman@nih.gov. 2. Pulmonary Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland. 3. Office of Biostatistics Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland. 4. Division of Blood Diseases and Resources, National Heart, Lung, and Blood Institute, Rockville, Maryland. 5. Division of Hematology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland. 6. Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama. 7. University of Alabama at Birmingham School of Medicine, Birmingham, Alabama. 8. Department of Medicine, Larner College of Medicine at the University of Vermont, Burlington, Vermont. 9. Department of Pathology & Laboratory Medicine, Larner College of Medicine at the University of Vermont, Burlington, Vermont. 10. Basic Research Program, National Cancer Institute, Frederick National Laboratory for Cancer Research, Frederick, Maryland. 11. Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland. 12. Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado, Denver, Colorado. 13. Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, Alabama. 14. Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.
Abstract
BACKGROUND: α-Globin is expressed in endothelial cells of resistance arteries, where it limits endothelial nitric oxide signaling and enhances α-adrenergic-mediated vasoconstriction. α-Globin gene (HBA) copy number is variable in people of African descent and other populations worldwide. Given the protective effect of nitric oxide in the kidney, we hypothesized that HBA copy number would be associated with kidney disease risk. METHODS: Community-dwelling Black Americans aged ≥45 years old were enrolled in a national longitudinal cohort from 2003 through 2007. HBA copy number was measured using droplet digital PCR. The prevalence ratio (PR) of CKD and the relative risk (RR) of incident reduced eGFR were calculated using modified Poisson multivariable regression. The hazard ratio (HR) of incident ESKD was calculated using Cox proportional hazards multivariable regression. RESULTS: Among 9908 participants, HBA copy number varied from 2 to 6. In analyses adjusted for demographic, clinical, and genetic risk factors, a one-copy increase in HBA was associated with 14% greater prevalence of CKD (PR, 1.14; 95% CI, 1.07 to 1.21; P<0.0001). While HBA copy number was not associated with incident reduced eGFR (RR, 1.06; 95% CI, 0.94 to 1.19; P=0.38), the hazard of incident ESKD was 32% higher for each additional copy of HBA (HR, 1.32; 95% CI, 1.09 to 1.61; P=0.005). CONCLUSIONS: Increasing HBA copy number was associated with a greater prevalence of CKD and incidence of ESKD in a national longitudinal cohort of Black Americans.
BACKGROUND: α-Globin is expressed in endothelial cells of resistance arteries, where it limits endothelial nitric oxide signaling and enhances α-adrenergic-mediated vasoconstriction. α-Globin gene (HBA) copy number is variable in people of African descent and other populations worldwide. Given the protective effect of nitric oxide in the kidney, we hypothesized that HBA copy number would be associated with kidney disease risk. METHODS: Community-dwelling Black Americans aged ≥45 years old were enrolled in a national longitudinal cohort from 2003 through 2007. HBA copy number was measured using droplet digital PCR. The prevalence ratio (PR) of CKD and the relative risk (RR) of incident reduced eGFR were calculated using modified Poisson multivariable regression. The hazard ratio (HR) of incident ESKD was calculated using Cox proportional hazards multivariable regression. RESULTS: Among 9908 participants, HBA copy number varied from 2 to 6. In analyses adjusted for demographic, clinical, and genetic risk factors, a one-copy increase in HBA was associated with 14% greater prevalence of CKD (PR, 1.14; 95% CI, 1.07 to 1.21; P<0.0001). While HBA copy number was not associated with incident reduced eGFR (RR, 1.06; 95% CI, 0.94 to 1.19; P=0.38), the hazard of incident ESKD was 32% higher for each additional copy of HBA (HR, 1.32; 95% CI, 1.09 to 1.61; P=0.005). CONCLUSIONS: Increasing HBA copy number was associated with a greater prevalence of CKD and incidence of ESKD in a national longitudinal cohort of Black Americans.
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