In Cftr−/− mice that mostly die because of intestinal obstruction, intestinal expression of Clca3 is decreased, whereas upregulation of Clca3 results in amelioration of intestinal disease. The aim of the study was to investigate whether the p.S357N variant in CLCA1, the human orthologue of Clca3, acts as a modifier gene in a cohort of 682 European patients with cystic fibrosis (CF)–99 patients with meconium ileus. The 357SS genotype was significantly overrepresented in both patients with meconium ileus and also with a severe CFTR genotype (P = 0.009) and in p.F508del homozygotes (P = 0.002). This suggests that CLCA1 has similar important functions in CF-related intestinal obstruction in humans as in Cftr−/− mice.
*Departments of Pediatric Gastroenterology, The Netherlands
†Pediatric Pulmonology, The Netherlands
§Complex Genetics Section, DBG-Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
‡Departments of Pediatric Pulmonology and Immunology, Germany
#Hepatology and Gastroenterology, Charité Universitätsmedizin, Berlin, Germany
||Molecular Genetics Laboratory, Italy
¶Department of Pediatric Gastroenterology, Fondazione IRCCS, Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, University of Milan, Milan, Italy. Dr Witt is now with Department of Pediatrics, Klinik und Poliklinik für Kinder- und Jugendmedizin des Klinikums rechts der Isar, Technische Universität München (TUM), Munich, Germany.
Received 25 September, 2008
Accepted 19 May, 2009
Address correspondence and reprint requests to H.P.J. van der Doef, MD, Department of Pediatric Gastroenterology [KE.04.133.1], University Medical Center Utrecht, Lundlaan 6, 3584 EA Utrecht, The Netherlands (e-mail: firstname.lastname@example.org).
The study was funded by the Wilhelmina Research Fund, grant number OZF 2005/04, and by a grant from The Netherlands Organization for Health Research and Development (ZonMW), grant number 920-03-295.
The authors report no conflicts of interest.