Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland.
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
Journal: Human mutation
2018;38(1):78-85
PMID: 27650164
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.
© 2016 The Authors. **Human Mutation published by Wiley Periodicals, Inc.
Address:
Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.; Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, C.I. Parhon National Institute of Endocrinology, Bucharest, Romania.; Research Department of Genetics, Evolution and Environment, University College London, London, UK.; Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.; Department of Medical Genetics, Belfast HSC Trust, Belfast, UK.; Regional Centre for Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, UK.; Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust/ Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.; Department of Endocrinology and Diabetes, Beaumont Hospital/RCSI Medical School, Dublin, Ireland.; Department of Clinical Medicine and Institute of Molecular Medicine, Trinity College Dublin, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland.; Royal Belfast Hospital for Sick Children, Belfast, UK.; Endocrinology Service/Experimental Endocrinology Unit, Hospital de Especialidades, Centro Medico Nacional Siglo XXI, IMSS, Mexico City, Mexico.; Department of Endocrinology and Diabetes, Barnet General Hospital, London, UK.; Academic Endocrine Unit, OCDEM, University of Oxford, Oxford, UK.; Department of Endocrinology and Diabetes, University College London Hospitals, London, UK.; Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA.; Department of Endocrinology, Carol Davila University of Medicine and Pharmacy, C.I. Parhon National Institute of Endocrinology, Bucharest, Romania.; Department of Endocrinology, University Hospitals of Leicester, Leicester, UK.; Department of Endocrinology, St James's University Hospital, Leeds, UK.; Institute of Anthropology, Johannes Gutenberg University, Mainz, Germany.; North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK.; Trinity Biobank, Institute of Molecular Medicine, Trinity College Dublin, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland.; Centre for Public Health, School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.; Research Department of Genetics, Evolution and Environment, University College London, London, UK.; School of Biosciences, University of Melbourne, Parkville, Victoria, Australia.; Schools of Mathematics and Statistics, University of Melbourne, Parkville, Victoria, Australia.; Department of Medical Genetics, Belfast HSC Trust, Belfast, UK.; Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK.
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MeSH Terms:
Acromegaly,
Adolescent,
Adult,
Aged,
Aged, 80 and over,
Alleles,
Amino Acid Substitution,
Chromosome Mapping,
Cross-Sectional Studies,
Female,
Gene Frequency,
Genetic Predisposition to Disease,
Genotype,
Gigantism,
Heterozygote,
Humans,
Intracellular Signaling Peptides and Proteins,
Ireland,
Male,
Mass Screening,
Middle Aged,
Phenotype,
Risk,
Young Adult