Ancestry and genetic associations with bronchopulmonary dysplasia in preterm infants

Bronchopulmonary dysplasia in premature infants is a common and often severe lung disease with long-term sequelae. A genetic component is suspected but not fully defined. We performed an ancestry and genome-wide association study to identify variants, genes, and pathways associated with survival without bronchopulmonary dysplasia in 387 high-risk infants treated with inhaled nitric oxide in the Trial of Late Surfactant study. Global African genetic ancestry was associated with increased survival without bronchopulmonary dysplasia among infants of maternal self-reported Hispanic white race/ethnicity [odds ratio (OR) = 4.5, P = 0.01]. Admixture mapping found suggestive outcome associations with local African ancestry at chromosome bands 18q21 and 10q22 among infants of maternal self-reported African-American race/ethnicity. For all infants, the top individual variant identified was within the intron of NBL1, which is expressed in midtrimester lung and is an antagonist of bone morphogenetic proteins ( rs372271081 , OR = 0.17, P = 7.4 × 10−7). The protective allele of this variant was significantly associated with lower nitric oxide metabolites in the urine of non-Hispanic white infants ( P = 0.006), supporting a role in the racial differential response to nitric oxide. Interrogating genes upregulated in bronchopulmonary dysplasia lungs indicated association with variants in CCL18, a cytokine associated with fibrosis and interstitial lung disease, and pathway analyses implicated variation in genes involved in immune/inflammatory processes in response to infection and mechanical ventilation. Our results suggest that genetic variation related to lung development, drug metabolism, and immune response contribute to individual and racial/ethnic differences in respiratory outcomes following inhaled nitric oxide treatment of high-risk premature infants.

Download Full-text

Ancestry and Genetic Associations with Bronchopulmonary Dysplasia in Preterm Infants

10.1101/263814 ◽

2018 ◽

Cited By ~ 1

Author(s):

Dara G. Torgerson ◽

Philip L. Ballard ◽

Roberta L. Keller ◽

Sam S. Oh ◽

Scott Huntsman ◽

...

Keyword(s):

Nitric Oxide ◽

High Risk ◽

Lung Disease ◽

Bronchopulmonary Dysplasia ◽

Premature Infants ◽

Genome Wide Association Study ◽

African Ancestry ◽

Inhaled Nitric Oxide ◽

Race Ethnicity ◽

Hispanic White

ABSTRACTBronchopulmonary dysplasia in premature infants is a common and often severe lung disease with long term sequelae. A genetic component is suspected but not fully defined. We performed an ancestry and genome-wide association study to identify variants, genes and pathways associated with survival without bronchopulmonary dysplasia in 387 high-risk infants treated with inhaled nitric oxide in the Trial of Late Surfactant study. Global African genetic ancestry was associated with increased survival without bronchopulmonary dysplasia among infants of maternal self-reported Hispanic White race/ethnicity (OR=4.5, p=0.01). Admixture mapping found suggestive outcome associations with local African ancestry at 18q21 and 10q22 among infants of maternal self-reported African American race/ethnicity. For all infants, the top individual variant identified was within the intron of NBL1, which is expressed in mid-trimester lung and is an antagonist of bone morphogenetic proteins (rs372271081, OR=0.17, p=7.4 × 10−7). The protective allele of this variant was significantly associated with lower nitric oxide metabolites in the urine of non-Hispanic white infants (p= 0.006), supporting a role in the racial differential response to nitric oxide. Interrogating genes upregulated in bronchopulmonary dysplasia lungs indicated association with variants in CCL18, a cytokine associated with fibrosis and interstitial lung disease, and pathway analyses implicated variation in genes involved in immune/inflammatory processes in response to infection and mechanical ventilation. Our results suggest that genetic variation related to lung development, drug metabolism, and immune response contribute to individual and racial/ethnic differences in respiratory outcomes following inhaled nitric oxide treatment of high-risk premature infants.

Download Full-text

Inhaled nitric oxide (iNO) for preventing prematurity-related bronchopulmonary dysplasia (BPD): 7-year follow-up of the European Union Nitric Oxide (EUNO) trial

Journal of Perinatal Medicine ◽

10.1515/jpm-2020-0164 ◽

2021 ◽

Vol 49 (1) ◽

pp. 104-110

Author(s):

Anne Greenough ◽

Fabrice Decobert ◽

David Field ◽

Mikko Hallman ◽

Helmut D. Hummler ◽

...

Keyword(s):

Nitric Oxide ◽

Bronchopulmonary Dysplasia ◽

Premature Infants ◽

Oxygen Therapy ◽

Well Being ◽

Inhaled Nitric Oxide ◽

Current Evidence ◽

Home Oxygen Therapy

AbstractObjectivesMost studies of inhaled nitric oxide (iNO) for prevention of bronchopulmonary dysplasia (BPD) in premature infants have focused on short-term mortality and morbidity. Our aim was to determine the long-term effects of iNO.MethodsA 7-year follow-up was undertaken of infants entered into a multicenter, double-blind, randomized, placebo-controlled trial of iNO for prevention of BPD in premature infants born between 24 and 28 weeks plus six days of gestation. At 7 years, survival and hospital admissions since the 2-year follow-up, home oxygen therapy in the past year, therapies used in the previous month and growth assessments were determined. Questionnaires were used to compare general health, well-being, and quality of life.ResultsA total of 305 children were assessed. No deaths were reported. Rates of hospitalization for respiratory problems (6.6 vs. 10.5%, iNO and placebo group, respectively) and use of respiratory medications (6.6 vs. 9.2%) were similar. Two patients who received iNO and one who received placebo had received home oxygen therapy. There were no significant differences in any questionnaire-documented health outcomes.ConclusionsiNO for prevention of BPD in very premature infants with respiratory distress did not result in long-term benefits or adverse long-term sequelae. In the light of current evidence, routine use of iNO cannot be recommended for prevention of BPD in preterm infants.

Download Full-text