Association of polymorphisms in genes of factors involved in regulation of splicing of cystic fibrosis transmembrane conductance regulator mRNA with acute respiratory distress syndrome in children with pneumonia.
Previous work has demonstrated a strong association between lung injury in African American children with pneumonia and a polymorphic (TG)mTn region in cystic fibrosis transmembrane conductance (CFTR) involved in the generation of a nonfunctional CFTR protein lacking exon 9. A number of splicing factors that regulate the inclusion/exclusion of exon 9 have been identified. The objective of this study was to determine whether genetic variants in these splicing factors were associated with acute respiratory distress syndrome (ARDS) in children with pneumonia.



This is a prospective cohort genetic association study of lung injury in African American and non-Hispanic Caucasian children with community-acquired pneumonia evaluated in the emergency department or admitted to the hospital. Linkage-disequilibrium-tag single nucleotide polymorphisms (LD-tag SNPs) in genes of the following splicing factors (followed by gene name) involved in exon 9 skipping PTB1 (PTBP1), SRp40 (SFRS1), SR2/ASF (SFRS5), TDP-43 (TARDBP), TIA-1 (TIA1), and U2AF(65) (U2AF2) were genotyped. SNPs in the gene of the splicing factor CELF2 (CELF2) were selected by conservation score. Multivariable analysis was used to examine association between genotypes and ARDS.



The African American cohort (n = 474) had 29 children with ARDS and the non-Hispanic Caucasian cohort (n = 304) had 32 children with ARDS. In the African American group multivariable analysis indicated that three variants in CELF2, rs7068124 (p = 0.004), rs3814634 (p = 0.032) and rs10905928 (p = 0.044), and two in TIA1, rs2592178 (p = 0.005) and rs13402990 (p = 0.018) were independently associated with ARDS. In the non-Hispanic Caucasian group, a single variant in CELF2, rs2277212 (p = 0.014), was associated with increased risk of developing ARDS.



The data indicate that SNPs in CELF2 may be associated with the risk of developing ARDS in both African American and non-Hispanic Caucasian children with pneumonia and suggest that the potential role of the splicing factor CELF2 in ARDS should be explored further.
Section of Critical Care Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.
Francesca
F
Perez-Marques
Section of Quantitative Health Sciences, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.|Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI, USA.|Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA.
Pippa
P
Simpson
Section of Quantitative Health Sciences, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI, USA.|Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI, USA.
Ke
K
Yan
Division of Pediatric Critical Care, Department of Pediatrics and Communicable Diseases, University of Michigan, 1500 East Medical Center Dr, SPC 5243, Ann Arbor, MI, 48109-5243, USA.
Michael W
MW
Quasney
Division of Pediatric Critical Care, Department of Pediatrics and Communicable Diseases, University of Michigan, 1500 East Medical Center Dr, SPC 5243, Ann Arbor, MI, 48109-5243, USA.
Nadine
N
Halligan
Section of Critical Care Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.|Children's Research Institute, Medical College of Wisconsin, Milwaukee, WI, USA.
Daniel
D
Merchant
Division of Pediatric Critical Care, Department of Pediatrics and Communicable Diseases, University of Michigan, 1500 East Medical Center Dr, SPC 5243, Ann Arbor, MI, 48109-5243, USA. mkdahmer@umich.edu.
Mary K
MK
Dahmer
D000293:Adolescent; D001741:Black or African American / Q000208:ethnology / Q000235:genetics; D000067878:CELF Proteins; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003550:Cystic Fibrosis / Q000235:genetics / Q000503:physiopathology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics / Q000502:physiology*; D005260:Female; D005820:Genetic Testing / Q000379:methods; D014644:Genetic Variation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D015999:Multivariate Analysis; D009419:Nerve Tissue Proteins; D011014:Pneumonia / Q000208:ethnology / Q000235:genetics / Q000503:physiopathology; D020641:Polymorphism, Single Nucleotide / Q000502:physiology*; D011446:Prospective Studies; D012333:RNA, Messenger / Q000235:genetics*; D012128:Respiratory Distress Syndrome / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D044465:White People / Q000208:ethnology / Q000235:genetics
D000067878:CELF Proteins; C117363:CELF2 protein, human; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D019005:Cystic Fibrosis Transmembrane Conductance Regulator
ALI; ARDS; Acute lung injury; Genetic association study; Pediatrics; Pneumonia