Year: 2016
Type: article
Study design: Observational Study
Abstract: The aryl hydrocarbon receptor interacting protein (AIP) founder mutation R304* (or p.R304*; NM_003977.3:c.910C>T, p.Arg304Ter) identified in Northern Ireland (NI) predisposes to acromegaly/gigantism; its population health impact remains unexplored. We measured R304* carrier frequency in 936 Mid Ulster, 1,000 Greater Belfast (both in NI) and 2,094 Republic of Ireland (ROI) volunteers and in 116 NI or ROI acromegaly/gigantism patients. Carrier frequencies were 0.0064 in Mid Ulster (95%CI = 0.0027–0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011–0.0047) and zero in ROI (0–0.0014). R304* prevalence was elevated in acromegaly/gigantism patients in NI (11/87, 12.6%, P < 0.05), but not in ROI (2/29, 6.8%) versus non-Irish patients (0–2.41%). Haploblock conservation supported a common ancestor for all the 18 identified Irish pedigrees (81 carriers, 30 affected). Time to most recent common ancestor (tMRCA) was 2550 (1,275–5,000) years. tMRCA-based simulations predicted 432 (90–5,175) current carriers, including 86 affected (18–1,035) for 20% penetrance. In conclusion, R304* is frequent in Mid Ulster, resulting in numerous acromegaly/gigantism cases. tMRCA is consistent with historical/folklore accounts of Irish giants. Forward simulations predict many undetected carriers; geographically targeted population screening improves asymptomatic carrier identification, complementing clinical testing of patients/relatives. We generated disease awareness locally, necessary for early diagnosis and improved outcomes of AIP-related disease.
Source: Human Mutation
DOI: 10.1002/humu.23121
Authors: Serban Radian, Yoan Diekmann, Plamena Gabrovska, Brendan Holland, Lisa Bradley, Helen Wallace, Karen Stals, Anna-Marie Bussell, Karen McGurren, Martin Cuesta, Anthony W. Ryan, Maria Herincs, Laura C. Hernández-Ramírez, Aidan Holland, Jade Samuels, Elena Daniela Aflorei, Sayka Barry, Judit Dénes, Ida Pernicova, Craig E. Stiles, Giampaolo Trivellin, Ronan McCloskey, Michal Ajzensztejn, Noina Abid, Scott A. Akker, Moises Mercado, Mark Cohen, Rajesh V. Thakker, Stephanie Baldeweg, Ariel Barkan, Madalina Musat, Miles Levy, Stephen M. Orme, Martina Unterländer, Joachim Burger, Ajith V. Kumar, Sian Ellard, Joseph McPartlin, Ross McManus, Gerard J. Linden, Brew Atkinson, David J. Balding, Amar Agha, Chris J. Thompson, Steven J. Hunter, Mark G. Thomas, Patrick J. Morrison, Márta Korbonits
Institutions: Carol Davila University of Medicine and Pharmacy, Queen Mary University of London, Institutul Național de Endocrinologie C.I. Parhon, William Harvey Research Institute, University College London, Belfast Health and Social Care Trust, Royal Victoria Hospital, University of Exeter, Royal Devon & Exeter NHS Foundation Trust, Royal College of Surgeons in Ireland, Beaumont Hospital, Trinity College Dublin, St. James's Hospital, Royal Belfast Hospital for Sick Children, Mexican Social Security Institute, Centro Medico Nacional Siglo XXI, Barnet Hospital, University of Oxford, Oxford Centre for Diabetes, Endocrinology and Metabolism, University College Hospital, University of Michigan, University Hospitals of Leicester NHS Trust, St James's University Hospital, Johannes Gutenberg University Mainz, Great Ormond Street Hospital, Queen's University Belfast, The University of Melbourne
Language: English
Subfield: Endocrinology, Diabetes and Metabolism
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $2,781
Funders: Pfizer, Wellcome Trust, National Institute for Health and Care Research, European Commission, Rosetrees Trust, Science Foundation Ireland, Public Health Agency, Consejo Nacional de Ciencia y Tecnología, Consejo Nacional de Ciencia y Tecnología, Guatemala, Pfizer UK, Medical Research Council, Research Executive Agency
Awards: G1445708506, The effect of AIP mutations on the apoptotic RET pathway in pituitary adenomas, G3713042667, G4434592721, Human Adaptation to Changing Diet and Infectious Disease Loads, from the Origins of Agriculture to the Present., AIP gene regulation and its implications in pituitary tumorigenesis, Post-genomic investigation of celiac disease susceptibility genes, Analysis of the involvement of AIP in tumourigenic signalling pathways in pituitary tumours and its role as a circulating peptide., G9000249302
OpenAlex ID: W2522067506