Ancestry and genetic associations with bronchopulmonary dysplasia in preterm infants

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.

Keywords: bronchopulmonary dysplasia; drug response; genetic ancestry; genome-wide association study; preterm infants.

Fig. 1.

Global ancestry proportions and survival without bronchopulmonary dysplasia (BPD). Proportions shown are of global African (A) and European (B) ancestry in preterm infants participating in the Trial of Late Surfactant (TOLSURF) study by maternal self-reported race/ethnicity. Global ancestry was inferred using ADMIXTURE. Box plots compare global African ancestry and survival without BPD in infants of maternal self-reported black/African-American race/ethnicity (C; logistic regression: P = 0.97, β = −0.015 ± 0.37) and Hispanic white race/ethnicity (D; P = 0.01, β = −1.5 ± 0.60).

Fig. 2.

Results of admixture mapping comparing local African ancestry and survival without bronchopulmonary dysplasia in 133 infants with maternal self-reported black/African-American race/ethnicity (82 cases, 51 controls). Top associations were observed at chromosome bands 10q21 (odds ratio = 0.17, P = 4.4 × 10⁻⁴) and 18q21 (odds ratio = 4.6, P = 2.7 × 10⁻⁴).

Fig. 3.

Manhattan plot (A) and quantile-quantile plot (B) showing the results of a weighted meta-analysis for survival without bronchopulmonary dysplasia (BPD) across 3 maternal self-reported racial/ethnic groups, including non-Hispanic white (136 BPD/death infants, 41 no BPD), black/African American (82 BPD/death infants, 51 no BPD), and Hispanic white (28 BPD/death infants, 14 no BPD).

Fig. 4.

A: LocusZoom plot of the region flanking the top association at rs372271081, an intronic variant of NBL1. Mb, megabase. B: expression of genes by RNA sequencing within this locus in fetal lung at 23 wk gestation.

Fig. 5.

A: box plot showing levels of urinary NO metabolites by genotype at rs372271081 in preterm infants following treatment with inhaled nitric oxide at 5 ppm. B: frequency of rs372271081 in populations from the Phase 3 1000 Genomes Project. A and G, alleles; AFR, African; AMR, Admixed American; EAS, East Asian; EUR, European; SAS, South Asian.