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The Effect of Renin Angiotensin System Genetic Variants in Acute Pancreatitis

Skipworth, James R. A. MBBS, BSc, MRCS*,†,‡; Nijmeijer, Rian M. PhD§; van Santvoort, Hjalmar C. PhD; Besselink, Marc G. H. PhD; Schulz, Hans-Ulrich PhD**; Kivimaki, Mika PhD††; Kumari, Meena PhD††; Cooper, Jackie A. MSc‡‡; Acharya, Jay PhD‡‡; Shankar, Arjun MD; Malago, Massimo PhD*,†; Humphries, Steve E. PhD‡‡; Olde Damink, Steven W. M. PhD*,†,§§; Montgomery, Hugh E. MD*,‡

doi: 10.1097/SLA.0000000000000655
Original Articles

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.

Local renin-angiotensin systems (RAS) regulate growth and inflammation in diverse cells and tissues, and their activity has been implicated in the development of acute pancreatitis (AP). We genotyped 544 patients with AP from 3 European countries to identify an association between 2 of the RAS polymorphisms and AP.

*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.

Reprints: James R. A. Skipworth, MBBS, BSc, MRCS, Department of Surgery and Interventional Science, University College London, 74 Huntley St, London WC1E 6AU, United Kingdom. E-mail: jamesskipworth@doctors.org.uk.

Disclosure: JRAS is supported by the “No Surrender Charitable Trust” as the inaugural recipient of the “Jason Boas Fellowship.” S.E.H. holds a Chair funded by the British Heart Foundation and is personally supported by the BHF (grant nos. BHFPG08/008). The NPHSII study was supported by the Medical Research Council, the US National Institutes of Health (NHLBI 33014) and DuPont Pharma. The WHII study has been supported by grants from the Medical Research Council; British Heart Foundation; Health and Safety Executive; Department of Health; National Heart Lung and Blood Institute (grant no. NHLBI: HL36310) and National Institute on Aging (AG13196), US NIH; Agency for Health Care Policy Research (grant no. HS06516); and the John D. and Catherine T. MacArthur Foundation Research Networks on Successful Midlife Development and Socioeconomic Status and Health. All authors read and approved the final manuscript. The authors declare no conflicts of interests.

© 2015 by Lippincott Williams & Wilkins.