Increased population risk of AIP-related acromegaly and gigantism in Ireland
| Autor: | 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 |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Adult
Male Risk Heterozygote Adolescent Genotype evolutionary genetics Gigantism Young Adult Gene Frequency Humans Mass Screening Genetic Predisposition to Disease AIP Alleles Research Articles Aged acromegaly and gigantism Aged 80 and over Intracellular Signaling Peptides and Proteins Chromosome Mapping Middle Aged Cross-Sectional Studies Phenotype Amino Acid Substitution population screening Acromegaly founder mutation Female Ireland Research Article |
| Zdroj: | Human Mutation |
| Popis: | 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, 1000 Greater Belfast (both in NI) and 2094 Republic of Ireland (ROI) volunteers and in 116 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%) vs. 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 (1275-5000) years. tMRCA-based simulations predicted 432 (90-5175) current carriers, including 86 affected (18-1035) 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. This article is protected by copyright. All rights reserved. |
| Databáze: | OpenAIRE |
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