BACKGROUND: Nitric oxide has a range of biological activity in the lung and the fractional exhalation of nitric oxide (FeNO) is useful in patients with asthma in whom treatment is being considered. Normal variation in FeNO may impact the interpretation of this physiologic measurement, yet little is known about genetic factors that influence FeNO, particularly among Black populations. Growing evidence that globins are co-expressed with NOS in airway epithelium, along with the structural similarity of iNOS and eNOS, imply that globins may regulate NO signaling not only in the vascular endothelium, but in the airway epithelium as well. Given that Black individuals have increased HBA allele count variation, we assessed the role of alpha globin in airway nitric oxide physiology, we examined the association of alpha globin gene deletions with FeNO in healthy Black individuals. METHODS: We measured HBA copy number via droplet digital PCR in Black healthy volunteers age 18-40 years were enrolled in a multi-center, cross-sectional cohort from 4 sites near Durham, North Carolina. Subjects self-reported health status, age, sex, race, and ethnicity. Only non-Hispanic African American subjects were enrolled in the original study. Exclusion criteria for this analysis were: 1) not consenting to future research and 2) serum cotinine level >25 ng/mL to exclude active tobacco use. For continuous measures, medians and 25th and 75th percentiles were calculated by alpha globin genotype. Differences between groups were assessed by Kruskal-Wallis test. Categorical variables were assessed by Fisher&#39s exact test. IgE and FeNO were log transformed due to skewness. The association of HBA copy number with FeNO was evaluated using multivariable linear regression employing a linear effect of HBA allele count (2-5 HBA copies). RESULTS: Among DNA specimens from 643 Black individuals, HBA genotype frequencies were: 30 (4.7%) -a/-a, 197 (30.6%) -a/aa, 405 (63%) aa/aa, and 8 (1.2%) aa/aaa, with the median (25th, 75th percentile) measured FeNO value of 20 (13, 31) ppb. Subjects were 35% male with median age 20 (19, 22) years and median IgE level of 58 (22, 160) kU/L. After adjustment for sex, age, and log transformed total IgE, the coefficient for HBA copy number with FeNO was -0.005 (95% CI: -0.042, 0.033, p=0.81). CONCLUSIONS: No clear association between HBA copy number and FeNO was found among healthy Black adults in this cohort. Many questions regarding the roles of alpha and beta globin in epithelial NO signaling and pulmonary pathophysiology remain unanswered.

The authors have declared no competing interest.

The original study was supported by project ES011185 from the National Institute of Environmental Health Sciences; and MO1-RR-30 from the National Center for Research Resources, Clinical Research Centers Program, National Institutes of Health. The current analysis was supported in part by the Divisions of Intramural Research, National Institute of Allergy and Infectious Diseases project AI001150 (A.P.R., J.M.J, C.M.C, J.G.N., M.P. F., H.C.A), National Heart, Lung, and Blood Institute (NHLBI) project HL006196 (A.P.R., H.C.A.). This work was also funded in part by NHLBI grants NIH R01-HL107590 and R01HL153641 (L.G.Q.) and the Durham VA Medical Center Research Service (J.B.W.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIAID or NHLBI. The content of this publication does not necessarily reflect the view or policy of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the government. The interpretation and reporting of these data are the responsibility of the author(s) and in no way should be seen as an official policy or interpretation of the U.S. government.

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