title: Variants in Solute Carrier SLC26A9 Modify Prenatal Exocrine Pancreatic Damage in Cystic Fibrosis.
abstract: OBJECTIVE
  To test the hypothesis that multiple constituents of the apical plasma membrane residing alongside the causal cystic fibrosis (CF) transmembrane conductance regulator protein, including known CF modifiers SLC26A9, SLC6A14, and SLC9A3, would be associated with prenatal exocrine pancreatic damage as measured by newborn screened (NBS) immunoreactive trypsinogen (IRT) levels.
  
  
  METHODS
  NBS IRT measures and genome-wide genotype data were available on 111 subjects from Colorado, 37 subjects from Wisconsin, and 80 subjects from France. Multiple linear regression was used to determine whether any of 8 single nucleotide polymorphisms (SNPs) in SLC26A9, SLC6A14, and SLC9A3 were associated with IRT and whether other constituents of the apical plasma membrane contributed to IRT.
  
  
  RESULTS
  In the Colorado sample, 3 SLC26A9 SNPs were associated with NBS IRT (min P=1.16×10(-3); rs7512462), but no SLC6A14 or SLC9A3 SNPs were associated (P>.05). The rs7512462 association replicated in the Wisconsin sample (P=.03) but not in the French sample (P=.76). Furthermore, rs7512462 was the top-ranked apical membrane constituent in the combined Colorado and Wisconsin sample.
  
  
  CONCLUSIONS
  NBS IRT is a biomarker of prenatal exocrine pancreatic disease in patients with CF, and a SNP in SLC26A9 accounts for significant IRT variability. This work suggests SLC26A9 as a potential therapeutic target to ameliorate exocrine pancreatic disease.
authors.affiliation: Program in Genetics and Genome Biology, the Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Melissa R
authors.initials: MR
authors.lastname: Miller
authors.affiliation: Program in Genetics and Genome Biology, the Hospital for Sick Children, Toronto, Ontario, Canada; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Soave
authors.affiliation: Program in Genetics and Genome Biology, the Hospital for Sick Children, Toronto, Ontario, Canada; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Weili
authors.initials: W
authors.lastname: Li
authors.affiliation: Program in Genetics and Genome Biology, the Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Jiafen
authors.initials: J
authors.lastname: Gong
authors.affiliation: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Rhonda G
authors.initials: RG
authors.lastname: Pace
authors.affiliation: Pierre et Marie Curie University-Paris 6, Paris, France; Biostatistics Department, St Antoine Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP); Institut National de la Santé et la Recherche Médicale (INSERM), UMR-S 1136, Paris, France.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Boëlle
authors.affiliation: Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD; McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Garry R
authors.initials: GR
authors.lastname: Cutting
authors.affiliation: Departments of Pediatrics and Genetics, Case Western Reserve University, Cleveland, OH.
authors.forename: Mitchell L
authors.initials: ML
authors.lastname: Drumm
authors.affiliation: Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Knowles
authors.affiliation: Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; Department of Statistical Sciences, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Lei
authors.initials: L
authors.lastname: Sun
authors.affiliation: Program in Genetics and Genome Biology, the Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Johanna M
authors.initials: JM
authors.lastname: Rommens
authors.affiliation: Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO; Department of Pediatrics, Children's Hospital of Colorado, Aurora, CO.
authors.forename: Frank
authors.initials: F
authors.lastname: Accurso
authors.affiliation: Program in Physiology and Experimental Medicine, the Hospital for Sick Children, Toronto, Ontario, Canada; Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Durie
authors.affiliation: Pierre et Marie Curie University-Paris 6, Paris, France; Pediatric Pulmonology Department, Trousseau Hospital, AP-HP, Inserm U938, Paris, France.
authors.forename: Harriet
authors.initials: H
authors.lastname: Corvol
authors.affiliation: Department of Pediatrics, Section of Pulmonary and Sleep Medicine, Medical College of Wisconsin, Milwaukee, WI; Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI.
authors.forename: Hara
authors.initials: H
authors.lastname: Levy
authors.affiliation: Department of Pediatrics, Children's Hospital of Colorado, Aurora, CO; Department of Epidemiology, Colorado School of Public Health University of Colorado Denver, Aurora, CO.
authors.forename: Marci K
authors.initials: MK
authors.lastname: Sontag
authors.affiliation: Program in Genetics and Genome Biology, the Hospital for Sick Children, Toronto, Ontario, Canada; Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. Electronic address: Lisa.Strug@utoronto.ca.
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Strug
mesh_terms: D017920:Antiporters / Q000235:genetics*; D015415:Biomarkers / Q000097:blood; D002462:Cell Membrane / Q000378:metabolism; D003120:Colorado; D003550:Cystic Fibrosis / Q000235:genetics*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D005260:Female; D005602:France; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D007231:Infant, Newborn; D016014:Linear Models; D008297:Male; D009154:Mutation; D015997:Neonatal Screening; D046790:Pancreas, Exocrine / Q000002:abnormalities*; D020641:Polymorphism, Single Nucleotide; D011786:Quality Control; D000076988:Sulfate Transporters; D014362:Trypsinogen / Q000097:blood; D014922:Wisconsin
chemical_list: D017920:Antiporters; D015415:Biomarkers; C505032:CFTR protein, human; C455628:SLC26A9 protein, human; D000076988:Sulfate Transporters; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014362:Trypsinogen