Ancestry and genetic associations with bronchopulmonary dysplasia in preterm infants

TOLSURF Study Group

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)L858-L869
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume315
Issue number5
DOIs
StatePublished - Nov 1 2018

Fingerprint

Bronchopulmonary Dysplasia
Premature Infants
Nitric Oxide
Lung
Odds Ratio
Mothers
Genes
Bone Morphogenetic Proteins
Genome-Wide Association Study
Interstitial Lung Diseases
Second Pregnancy Trimester
Artificial Respiration
Hispanic Americans
Surface-Active Agents
African Americans
Introns
Lung Diseases
Fibrosis
Chromosomes
Alleles

Keywords

  • Bronchopulmonary dysplasia
  • Drug response
  • Genetic ancestry
  • Genome- wide association study
  • Preterm infants

PubMed: MeSH publication types

  • Journal Article
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Ancestry and genetic associations with bronchopulmonary dysplasia in preterm infants. / TOLSURF Study Group.

In: American Journal of Physiology - Lung Cellular and Molecular Physiology, Vol. 315, No. 5, 01.11.2018, p. L858-L869.

Research output: Contribution to journalArticle

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abstract = "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.",
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author = "{TOLSURF Study Group} and Torgerson, {Dara G.} and Ballard, {Philip L.} and Keller, {Roberta L.} and Oh, {Sam S.} and Scott Huntsman and Donglei Hu and Celeste Eng and Burchard, {Esteban G.} and Ballard, {Roberta A.} and Steinhorn, {Robin H.} and Bendel, {Catherine M.} and Bendel-Stenzel, {Ellen M.} and Courtney, {Sherry E.} and Ramasubbareddy Dhanireddy and Koch, {Frances R.} and Hudak, {Mark L.} and Mayock, {Dennis E.} and Rajan Wadhawan and Bendel, {Catherine M} and McKay, {Victor J.} and Merrill, {Jeffrey D.} and Eichenwald, {Eric C.} and Truog, {William E.} and Mammel, {Mark C.} and Rogers, {Elizabeth E.} and Ryan, {Rita M.} and Durand, {David J.} and {Michael O’Shea}, T. and Black, {Dennis M.} and Strong, {Suzanne Hamilton} and Jill Immamura-Ching and Margaret Orfanos-Villalobos and Cassandra Williams and Lisa Palermo and Dolia Horton and Loretta Pacello and April Willard and Cheryl Gauldin and Anne Holmes and Patrice Johnson and Kerrie Meinert and Reynolds, {Anne Marie} and Janine Lucie and Patrick Conway and Michael Sacilowski and Michael Leadersdorff and Pam Orbank and Karen Wynn and Maria DeUngria and Georgieff, {Michael K}",
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AU - Oh, Sam S.

AU - Huntsman, Scott

AU - Hu, Donglei

AU - Eng, Celeste

AU - Burchard, Esteban G.

AU - Ballard, Roberta A.

AU - Steinhorn, Robin H.

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AU - Dhanireddy, Ramasubbareddy

AU - Koch, Frances R.

AU - Hudak, Mark L.

AU - Mayock, Dennis E.

AU - Wadhawan, Rajan

AU - Bendel, Catherine M

AU - McKay, Victor J.

AU - Merrill, Jeffrey D.

AU - Eichenwald, Eric C.

AU - Truog, William E.

AU - Mammel, Mark C.

AU - Rogers, Elizabeth E.

AU - Ryan, Rita M.

AU - Durand, David J.

AU - Michael O’Shea, T.

AU - Black, Dennis M.

AU - Strong, Suzanne Hamilton

AU - Immamura-Ching, Jill

AU - Orfanos-Villalobos, Margaret

AU - Williams, Cassandra

AU - Palermo, Lisa

AU - Horton, Dolia

AU - Pacello, Loretta

AU - Willard, April

AU - Gauldin, Cheryl

AU - Holmes, Anne

AU - Johnson, Patrice

AU - Meinert, Kerrie

AU - Reynolds, Anne Marie

AU - Lucie, Janine

AU - Conway, Patrick

AU - Sacilowski, Michael

AU - Leadersdorff, Michael

AU - Orbank, Pam

AU - Wynn, Karen

AU - DeUngria, Maria

AU - Georgieff, Michael K

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N2 - 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.

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KW - Drug response

KW - Genetic ancestry

KW - Genome- wide association study

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