title: Increased Population Risk of AIP-Related Acromegaly and Gigantism in Ireland.
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.
authors.affiliation: 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.
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authors.affiliation: Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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authors.affiliation: Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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authors.affiliation: Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust/ Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK.
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authors.affiliation: Department of Endocrinology and Diabetes, Beaumont Hospital/RCSI Medical School, Dublin, Ireland.
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authors.affiliation: Department of Endocrinology and Diabetes, Beaumont Hospital/RCSI Medical School, Dublin, Ireland.
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authors.affiliation: Department of Clinical Medicine and Institute of Molecular Medicine, Trinity College Dublin, Trinity Centre for Health Sciences, St James's Hospital, Dublin, Ireland.
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authors.affiliation: Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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authors.affiliation: Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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authors.affiliation: Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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authors.affiliation: Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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authors.affiliation: Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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authors.affiliation: Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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authors.affiliation: Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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authors.affiliation: Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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authors.affiliation: Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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authors.affiliation: Centre of Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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authors.affiliation: 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.
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authors.affiliation: Department of Medical Genetics, Belfast HSC Trust, Belfast, UK.|Centre for Cancer Research and Cell Biology, Queens University Belfast, Belfast, UK.
authors.forename: Patrick J
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mesh_terms: D000172:Acromegaly / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D019943:Amino Acid Substitution; D002874:Chromosome Mapping; D003430:Cross-Sectional Studies; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005877:Gigantism / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007494:Ireland / Q000453:epidemiology; D008297:Male; D008403:Mass Screening; D008875:Middle Aged; D010641:Phenotype; D012306:Risk; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C103265:aryl hydrocarbon receptor-interacting protein
keywords: AIP; acromegaly and gigantism; evolutionary genetics; founder mutation; population screening