OBJECTIVE: In chronic pancreatitis (CP), alterations in several genes have so far been described, but only small cohorts have been extensively investigated for all predisposing genes. DESIGN: 660 patients with idiopathic or hereditary CP and up to 1758 controls were enrolled. PRSS1, SPINK1 and CTRC were analysed by DNA sequencing, and cystic fibrosis transmembrane conductance regulator (CFTR) by melting curve analysis. RESULTS: Frequencies of CFTR variants p.R75Q, p.I148T, 5T-allele and p.E528E were comparable in patients and controls. We identified 103 CFTR variants, which represents a 2.7-fold risk increase (p<0.0001). Severe cystic fibrosis (CF)-causing variants increased the risk of developing CP 2.9-fold, and mild CF-causing variants 4.5-fold (p<0.0001 for both). Combined CF-causing variants increased CP risk 3.4-fold (p<0.0001), while non-CF-causing variants displayed a 1.5-fold over-representation in patients (p=0.14). CFTR compound heterozygous status with variant classes CF-causing severe and mild represented an OR of 16.1 (p<0.0001). Notably, only 9/660 (1.4%) patients were compound heterozygotes in this category. Trans-heterozygosity increased CP risk, with an OR of 38.7, with 43/660 (6.5%) patients and 3/1667 (0.2%) controls being trans-heterozygous (p<0.0001). CONCLUSIONS: Accumulation of CFTR variants in CP is less pronounced than reported previously, with ORs between 2.7 and 4.5. Only CF-causing variants reached statistical significance. Compound and trans-heterozygosity is an overt risk factor for the development of CP, but the number of CFTR compound heterozygotes in particular is rather low. In summary, the study demonstrates the complexity of genetic interactions in CP and a minor influence of CFTR alterations in CP development.
OBJECTIVE: In chronic pancreatitis (CP), alterations in several genes have so far been described, but only small cohorts have been extensively investigated for all predisposing genes. DESIGN: 660 patients with idiopathic or hereditary CP and up to 1758 controls were enrolled. PRSS1, SPINK1 and CTRC were analysed by DNA sequencing, and cystic fibrosis transmembrane conductance regulator (CFTR) by melting curve analysis. RESULTS: Frequencies of CFTR variants p.R75Q, p.I148T, 5T-allele and p.E528E were comparable in patients and controls. We identified 103 CFTR variants, which represents a 2.7-fold risk increase (p<0.0001). Severe cystic fibrosis (CF)-causing variants increased the risk of developing CP 2.9-fold, and mild CF-causing variants 4.5-fold (p<0.0001 for both). Combined CF-causing variants increased CP risk 3.4-fold (p<0.0001), while non-CF-causing variants displayed a 1.5-fold over-representation in patients (p=0.14). CFTR compound heterozygous status with variant classes CF-causing severe and mild represented an OR of 16.1 (p<0.0001). Notably, only 9/660 (1.4%) patients were compound heterozygotes in this category. Trans-heterozygosity increased CP risk, with an OR of 38.7, with 43/660 (6.5%) patients and 3/1667 (0.2%) controls being trans-heterozygous (p<0.0001). CONCLUSIONS: Accumulation of CFTR variants in CP is less pronounced than reported previously, with ORs between 2.7 and 4.5. Only CF-causing variants reached statistical significance. Compound and trans-heterozygosity is an overt risk factor for the development of CP, but the number of CFTR compound heterozygotes in particular is rather low. In summary, the study demonstrates the complexity of genetic interactions in CP and a minor influence of CFTR alterations in CP development.
Authors: Heiko Witt; Sebastian Beer; Jonas Rosendahl; Jian-Min Chen; Giriraj Ratan Chandak; Atsushi Masamune; Melinda Bence; Richárd Szmola; Grzegorz Oracz; Milan Macek; Eesh Bhatia; Sandra Steigenberger; Denise Lasher; Florence Bühler; Catherine Delaporte; Johanna Tebbing; Maren Ludwig; Claudia Pilsak; Karolin Saum; Peter Bugert; Emmanuelle Masson; Sumit Paliwal; Seema Bhaskar; Agnieszka Sobczynska-Tomaszewska; Daniel Bak; Ivan Balascak; Gourdas Choudhuri; D Nageshwar Reddy; G Venkat Rao; Varghese Thomas; Kiyoshi Kume; Eriko Nakano; Yoichi Kakuta; Tooru Shimosegawa; Lukasz Durko; András Szabó; Andrea Schnúr; Péter Hegyi; Zoltán Rakonczay; Roland Pfützer; Alexander Schneider; David Alexander Groneberg; Markus Braun; Hartmut Schmidt; Ulrike Witt; Helmut Friess; Hana Algül; Olfert Landt; Markus Schuelke; Renate Krüger; Bertram Wiedenmann; Frank Schmidt; Klaus-Peter Zimmer; Peter Kovacs; Michael Stumvoll; Matthias Blüher; Thomas Müller; Andreas Janecke; Niels Teich; Robert Grützmann; Hans-Ulrich Schulz; Joachim Mössner; Volker Keim; Matthias Löhr; Claude Férec; Miklós Sahin-Tóth Journal: Nat Genet Date: 2013-08-18 Impact factor: 38.330
Authors: Niloofar Y Jalaly; Robert A Moran; Farshid Fargahi; Mouen A Khashab; Ayesha Kamal; Anne Marie Lennon; Christi Walsh; Martin A Makary; David C Whitcomb; Dhiraj Yadav; Liudmila Cebotaru; Vikesh K Singh Journal: Am J Gastroenterol Date: 2017-04-25 Impact factor: 10.864
Authors: Matthew J Giefer; Mark E Lowe; Steven L Werlin; Bridget Zimmerman; Michael Wilschanski; David Troendle; Sarah Jane Schwarzenberg; John F Pohl; Joseph Palermo; Chee Y Ooi; Veronique D Morinville; Tom K Lin; Sohail Z Husain; Ryan Himes; Melvin B Heyman; Tanja Gonska; Cheryl E Gariepy; Steven D Freedman; Douglas S Fishman; Melena D Bellin; Bradley Barth; Maisam Abu-El-Haija; Aliye Uc Journal: J Pediatr Date: 2017-05-10 Impact factor: 4.406