title: Identification of SPOCK2 as a susceptibility gene for bronchopulmonary dysplasia.
abstract: BACKGROUND
  Bronchopulmonary dysplasia is the most common chronic respiratory disease in premature infants. Genetic factors might contribute to bronchopulmonary dysplasia susceptibility.
  
  
  OBJECTIVE
  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.
  
  
  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.
authors.affiliation: Inserm, U955, Créteil, France. alice.hadchouel-duverge@nck.aphp.fr
authors.forename: Alice
authors.initials: A
authors.lastname: Hadchouel
authors.forename: Xavier
authors.initials: X
authors.lastname: Durrmeyer
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bouzigon
authors.forename: Roberto
authors.initials: R
authors.lastname: Incitti
authors.forename: Johanna
authors.initials: J
authors.lastname: Huusko
authors.forename: Pierre-Henri
authors.initials: PH
authors.lastname: Jarreau
authors.forename: Richard
authors.initials: R
authors.lastname: Lenclen
authors.forename: Florence
authors.initials: F
authors.lastname: Demenais
authors.forename: Marie-Laure
authors.initials: ML
authors.lastname: Franco-Montoya
authors.forename: Inès
authors.initials: I
authors.lastname: Layouni
authors.forename: Juliana
authors.initials: J
authors.lastname: Patkai
authors.forename: Jacques
authors.initials: J
authors.lastname: Bourbon
authors.forename: Mikko
authors.initials: M
authors.lastname: Hallman
authors.forename: Claude
authors.initials: C
authors.lastname: Danan
authors.forename: Christophe
authors.initials: C
authors.lastname: Delacourt
mesh_terms: D000818:Animals; D000831:Animals, Newborn / Q000235:genetics; D044383:Black People / Q000235:genetics; D001997:Bronchopulmonary Dysplasia / Q000235:genetics*; D005260:Female; D005387:Finland; D015870:Gene Expression; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D008168:Lung / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011509:Proteoglycans / Q000235:genetics* / Q000502:physiology; D051381:Rats / Q000235:genetics; D044465:White People / Q000235:genetics
chemical_list: D011509:Proteoglycans; C504404:SPOCK2 protein, human