Variants in Solute Carrier SLC26A9 Modify Prenatal Exocrine Pancreatic Damage in Cystic Fibrosis - 24/04/15

Doi : 10.1016/j.jpeds.2015.01.044

Melissa R. Miller, PhD ¹, David Soave, MS ^1,², Weili Li, MS ^1,², Jiafen Gong, PhD ¹, Rhonda G. Pace, BS ³, Pierre-Yves Boëlle, PhD ^4,⁵, Garry R. Cutting, MD ^6,⁷, Mitchell L. Drumm, PhD ⁸, Michael R. Knowles, MD ³, Lei Sun, PhD ^2,⁹, Johanna M. Rommens, PhD ^1,¹⁰, Frank Accurso, MD ^11,¹², Peter R. Durie, MD, FRCP(C) ^13,¹⁴, Harriet Corvol, MD, PhD ^4,¹⁵, Hara Levy, MD ^16,¹⁷, Marci K. Sontag, PhD ^12,¹⁸, Lisa J. Strug, PhD ^1,^2,^⁎
¹ Program in Genetics and Genome Biology, the Hospital for Sick Children, Toronto, Ontario, Canada
² Division of Biostatistics, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada
³ Marsico Lung Institute/UNC CF Research Center, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC
⁴ Pierre et Marie Curie University-Paris 6, Paris, France
⁵ 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
⁶ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
⁷ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD
⁸ Departments of Pediatrics and Genetics, Case Western Reserve University, Cleveland, OH
⁹ Department of Statistical Sciences, University of Toronto, Toronto, Ontario, Canada
¹⁰ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
¹¹ Department of Pediatrics, University of Colorado Denver School of Medicine, Aurora, CO
¹² Department of Pediatrics, Children's Hospital of Colorado, Aurora, CO
¹³ Program in Physiology and Experimental Medicine, the Hospital for Sick Children, Toronto, Ontario, Canada
¹⁴ Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
¹⁵ Pediatric Pulmonology Department, Trousseau Hospital, AP-HP, Inserm U938, Paris, France
¹⁶ Department of Pediatrics, Section of Pulmonary and Sleep Medicine, Medical College of Wisconsin, Milwaukee, WI
¹⁷ Children's Research Institute, Children's Hospital of Wisconsin, Milwaukee, WI
¹⁸ Department of Epidemiology, Colorado School of Public Health University of Colorado Denver, Aurora, CO

^∗Reprint requests: Lisa J. Strug, PhD, Peter Gilgan Centre for Research & Learning, Room 12.9834, 686 Bay Street, Toronto, ON M5G 0A4.

Abstract

Objectives

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.

Study design

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.

Le texte complet de cet article est disponible en PDF.

Keyword : 660W, CF, CFTR, IRT, NBS, Omni5, QC, SNP

Plan

Methods

Quality Control and DNA Collection

NBS IRT Measurement and Assay

Statistical Analyses

Results

Discussion

Funding support information is available at www.jpeds.com (Appendix). The authors declare no conflicts of interest.

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Vol 166 - N° 5

P. 1152 - mai 2015 Retour au numéro

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Variants in Solute Carrier SLC26A9 Modify Prenatal Exocrine Pancreatic Damage in Cystic Fibrosis - 24/04/15

Abstract

Objectives

Study design

Results

Conclusions

Plan

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