Identification of SPOCK2 as a susceptibility gene for bronchopulmonary dysplasia

Alice Hadchouel*, Xavier Durrmeyer, Emmanuelle Bouzigon, Roberto Incitti, Johanna Huusko, Pierre Henri Jarreau, Richard Lenclen, Florence Demenais, Marie Laure Franco-Montoya, Inès Layouni, Juliana Patkai, Jacques Bourbon, Mikko Hallman, Claude Danan, Christophe Delacourt

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

69 Scopus citations

Abstract

Rationale: Bronchopulmonary dysplasia is the most commonchronic respiratory disease in premature infants. Genetic factors might contribute to bronchopulmonary dysplasia susceptibility. Objectives: To identify genetic variants involved in bronchopulmonary dysplasia through a genome-wide association study. Methods: We prospectively evaluated 418 premature neonates (gestational age <28 wk), of whom 22% developed bronchopulmonary dysplasia. Two discovery series were created, using a DNA pooling strategy in neonates from white and African ancestry. Polymorphisms associated with the disease were confirmed in an independent replication population. Genes were then explored by fine mapping and associations were replicated in an external Finnish population of 213 neonates. Validated genes expression patterns were studied in rat lung, after air or hyperoxia exposure. Measurements and Main Results: SPOCK2 gene was identified by both discovery series. The most significant polymorphism (rs1245560; P=1.66 × 10 -7) was confirmed by individual genotyping, and in the replication population (P = 0.002). Fine mapping confirmed the association of rs1245560 with bronchopulmonary dysplasia in both white and African populations with adjusted odds ratios of 2.96 (95% confidence interval [CI], 1.37-6.40) and 4.87 (95% CI, 1.88-12.63), respectively. In white neonates, rs1049269 was also associated with the disease (odds ratio, 3.21; 95% CI, 1.51-6.82). These associations were replicated in the Finnish population. In newborn rat lungs, SPOCK2 mRNA levels markedly increased during the alveolar stage of lung development. After rat exposure to hyperoxia, SPOCK2 expression increased relative to air-exposed controls. Conclusions: We identified SPOCK2 as a new possible candidate susceptibility gene for bronchopulmonary dysplasia. Its lung expression pattern points toward a potential role in alveolarization.

Original languageEnglish (US)
Pages (from-to)1164-1170
Number of pages7
JournalAmerican Journal of Respiratory and Critical Care Medicine
Volume184
Issue number10
DOIs
StatePublished - Nov 15 2011

Keywords

  • DNA microarrays
  • Development
  • Infant
  • Lung
  • Premature

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

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