James R A Skipworth1, Rian M Nijmeijer, Hjalmar C van Santvoort, Marc G H Besselink, Hans-Ulrich Schulz, Mika Kivimaki, Meena Kumari, Jackie A Cooper, Jay Acharya, Arjun Shankar, Massimo Malago, Steve E Humphries, Steven W M Olde Damink, Hugh E Montgomery. 1. *Department of Surgery and Interventional Science, University College London, London, United Kingdom †Department of Hepatopancreaticobiliary Surgery, Royal Free Hospital NHS Trust, London, United Kingdom ‡UCL Institute of Human Health & Performance, University College London, London, United Kingdom §Department of Internal Medicine, Rijnstate Hospital, Arnhem, The Netherlands ¶Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands ∥Department of Surgery, G4-196, AMC Amsterdam, Amsterdam, The Netherlands **General Surgery Department, Medical Faculty of Otto-von-Guericke University, Magdeburg, Germany ††Department of Epidemiology and Public Health, University College London, London, United Kingdom ‡‡Centre for Cardiovascular Genetics, University College London, London, United Kingdom §§Department of Surgery, Maastricht University Medical Centre, Maastricht, The Netherlands.
Abstract
OBJECTIVES: We sought association of genetic variants in the renin-angiotensin system (RAS) and vitamin D system with acute pancreatitis (AP) development and severity. BACKGROUND: The endocrine RAS is involved in circulatory homeostasis through the pressor action of angiotensin II at its AT1 receptor. However, local RAS regulate growth and inflammation in diverse cells and tissues, and their activity may be suppressed by vitamin D. Intrapancreatic angiotensin II generation has been implicated in the development of AP. METHODS: Five hundred forty-four white patients with AP from 3 countries (United Kingdom, 22; Germany, 136; and The Netherlands 386) and 8487 control subjects (United Kingdom 7833, The Netherlands 717) were genotyped for 8 polymorphisms of the RAS/vitamin D systems, chosen on the basis of likely functionality. RESULTS: The angiotensin-converting enzyme I (rather than D) allele was significantly associated with alcohol-related AP when all cohorts were combined (P = 0.03). The renin rs5707 G (rather than A) allele was associated with AP (P = 0.002), infected necrosis (P = 0.025) and mortality (P = 0.046). CONCLUSIONS: The association of 2 RAS polymorphisms with AP suggests the need for further detailed analysis of the role of RAS/vitamin D in the genesis or severity of AP, particularly given the ready potential for pharmacological manipulation of this system using existing marketed agents. However, further replication studies will be required before any such association is considered robust, particularly given the significant heterogeneity of AP causation and clinical course.
OBJECTIVES: We sought association of genetic variants in the renin-angiotensin system (RAS) and vitamin D system with acute pancreatitis (AP) development and severity. BACKGROUND: The endocrine RAS is involved in circulatory homeostasis through the pressor action of angiotensin II at its AT1 receptor. However, local RAS regulate growth and inflammation in diverse cells and tissues, and their activity may be suppressed by vitamin D. Intrapancreatic angiotensin II generation has been implicated in the development of AP. METHODS: Five hundred forty-four white patients with AP from 3 countries (United Kingdom, 22; Germany, 136; and The Netherlands 386) and 8487 control subjects (United Kingdom 7833, The Netherlands 717) were genotyped for 8 polymorphisms of the RAS/vitamin D systems, chosen on the basis of likely functionality. RESULTS: The angiotensin-converting enzyme I (rather than D) allele was significantly associated with alcohol-related AP when all cohorts were combined (P = 0.03). The renin rs5707 G (rather than A) allele was associated with AP (P = 0.002), infected necrosis (P = 0.025) and mortality (P = 0.046). CONCLUSIONS: The association of 2 RAS polymorphisms with AP suggests the need for further detailed analysis of the role of RAS/vitamin D in the genesis or severity of AP, particularly given the ready potential for pharmacological manipulation of this system using existing marketed agents. However, further replication studies will be required before any such association is considered robust, particularly given the significant heterogeneity of AP causation and clinical course.
Authors: Marc Gh Besselink; Hjalmar C van Santvoort; Erik Buskens; Marja A Boermeester; Harry van Goor; Harro M Timmerman; Vincent B Nieuwenhuijs; Thomas L Bollen; Bert van Ramshorst; Ben Jm Witteman; Camiel Rosman; Rutger J Ploeg; Menno A Brink; Alexander Fm Schaapherder; Cornelis Hc Dejong; Peter J Wahab; Cees Jhm van Laarhoven; Erwin van der Harst; Casper Hj van Eijck; Miguel A Cuesta; Louis Ma Akkermans; Hein G Gooszen Journal: Lancet Date: 2008-02-14 Impact factor: 79.321
Authors: Maria L Mansego; Josep Redon; Rosa Marin; Verónica González-Albert; Juan C Martin-Escudero; Maria Jose Fabia; Fernando Martinez; F Javier Chaves Journal: J Hypertens Date: 2008-02 Impact factor: 4.844
Authors: Robson A S Santos; Ana C Simoes e Silva; Christine Maric; Denise M R Silva; Raquel Pillar Machado; Insa de Buhr; Silvia Heringer-Walther; Sergio Veloso B Pinheiro; Myriam Teresa Lopes; Michael Bader; Elizabeth P Mendes; Virgina Soares Lemos; Maria Jose Campagnole-Santos; Heinz-Peter Schultheiss; Robert Speth; Thomas Walther Journal: Proc Natl Acad Sci U S A Date: 2003-06-26 Impact factor: 11.205