DOP011. A genome wide association study identifying association of the MHC region with 5-amino-salicylate (5-ASA) induced nephrotoxicity in inflammatory bowel disease
G. Heap1, C. Bewshea1, A. Singh1, M. Weedon2, J. Goldstein3, N. Ebney4, C. Mulgrew4, R. D'Souza4, R. Oram4, T. Orchard5, T. Shirazi6, E. Wesley7, K. So8, E. Wesley7, P. Irving9, A. Cole10, S. Sebastian11, D. Gaya12, C. Lees13, I. Lawrence8, C. Hawkey14, J. Mansfield15, M. Parkes16, G. Radford-Smith17, E. Tsianos18, V. Annese19, G.C. Sturniolo20, R. Weersma21, M. D'Amato22, M. Silverberg23, A. Hart24, A. Holden25, UK IBDGC26, The International Serious Adverse Events Consortium27, T. Ahmad1, 1Royal Devon and Exeter NHS Foundation Trust, IBD Pharmacogenetics, Exeter, United Kingdom, 2University of Exeter, Biomedical Informatics Hub, Exeter, United Kingdom, 3The Broad Institute, Analytical and Translational Genetics Unit, Boston, United States, 4Royal Devon and Exeter NHS Foundation Trust, Renal Medicine, Exeter, United Kingdom, 5Imperial College, St Mary's Campus, London, United Kingdom, 6Royal Devon and Exeter NHS Foundation Trust, Gastroenterology, Exeter, United Kingdom, 7Taunton and Somerset NHS Trust, Musgrove Park Hospital, Gastroenterology, Taunton, United Kingdom, 8Fremantle Hospital, Centre for Inflammatory Bowel Disease, Fremantle, Australia, 9Guy's & St Thomas' NHS Foundation Trust, Gastroenterology, London, United Kingdom, 10Royal Derby Hospital, Gastroenterology, Derby, United Kingdom, 11Hull and East Yorkshire Hospitals NHS Trust, Gastroenterology, Hull, United Kingdom, 12Glasgow Royal Infirmary, Gastroenterology, Glasgow, United Kingdom, 13Western General Hospital, Gastrointestinal Unit, Edinburgh, United Kingdom, 14Nottingham University Hospital NHS Trust, Nottingham Digestive Diseases Centre, Nottingham, United Kingdom, 15Newcastle Upon Tyne Hospitals NHS Foundation Trust, Gastroenterology, Newcastle Upon Tyne, United Kingdom, 16Cambridge University Hospitals, Biomedical Campus, Cambridge, United Kingdom, 17Royal Brisbane and Women's Hospital, Gastroenterology and Hepatalogy Department, Brisbane, Australia, 18University of Ioannina School of Medicine, Department of Internal Medicine, Ioannina, Greece, 19AOU Careggi, Largo Brambilla, Gastroenterologia, Firenze, Italy, 20Univerita di Padova, Gastroenterologia, Padova, Italy, 21University Medical Centre Groningen, Department of Gastroenterology and Hepatology, Groningen, Netherlands, 22Department of Biosciences and Nutrition, Karolinska Institute, Stockholm, Sweden, 23Mount Sinai Hospital, Division of Gastroenterology, Toronto Ontario, Canada, 24St Mark's Hospital, Gastroenterology, London, United Kingdom, 25International Serious Adverse Event Consortium (iSAEC), Bryn Mawr Avenue, Chicago, United States, 26The UK IBD Genetic Consortium, United Kingdom, 27SAEC Consortium, Ltd, Bryn Mawr Avenue, Chicago, United States
Nephrotoxicity is a rare idiosyncratic reaction to 5-ASA therapy. The precise pathogenic mechanisms are unknown. This study aims to a) describe the clinical features of this rare complication b) explore underlying mechanisms and c) identify clinically useful predictive genetic markers so these drugs can be avoided, or monitoring intensified in high-risk patients.
Patients were identified and recruited from 185 sites (130 UK). Inclusion criteria included normal renal function prior to commencing 5-ASA, greater than 50% rise in creatinine after starting 5-ASA and medical opinion implicating 5-ASA justified drug withdrawal. An adjudication panel assessed causality from case report forms using the validated Liverpool Adverse Drug Reaction Causality Assessment Tool.
200 patients were recruited. 50 patients were excluded following adjudication. The cohort included patients with Crohn's disease, ulcerative colitis and indeterminate colitis (38%, 58%, 4% respectively). 68% of cases were male. Nephrotoxicity was seen with all aminosalicylates including 1 patient treated with topical therapy only. Nephrotoxicity occurred at a median age of 36.2 years (range 9.3–87.8 years). Only 28% of cases recovered completely after drug withdrawal, with 14 requiring renal replacement therapy (13 requiring transplantation). 72.3% of renal biopsies demonstrated an immune interstitial nephritis. There was no evidence that early withdrawal of 5-ASA led to a higher likelihood of complete recovery. A genome wide association study was conducted on 140 5ASA patients (after removal of ethnic outliers and related individuals) compared to a 4,109 controls, matched for disease, imputed to the 1000 genome project and a dedicated HLA-typed cohort. An association signal was identified within the Class II MHC region at rs3135356 (p = 3.99×10−8) with an odds ratio of 2.07. This was robust to principle component correction. Confirmatory single SNP genotyping was undertaken to demonstrate the validity of the imputed genotypes.
This is the largest and most detailed study of 5-ASA induced nephrotoxicity to date. Whilst the incidence is low, the morbidity is high with 9% of patients requiring renal replacement therapy and 72% of patients failing to return to a normal creatinine after 5-ASA withdrawal. The genome-wide association study identified association within the Class II MHC region highlighting the underlying adaptive immune system pathogenesis.
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