Increased Population Risk ofAIP-Related Acromegaly and Gigantism in Ireland
Open Access
- 4 October 2016
- journal article
- research article
- Published by Wiley in Human Mutation
- Vol. 38 (1) , 78-85
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.Keywords
Funding Information
- Wellcome Trust (097970/Z/11/Z, 100719/Z/12/Z, 098395/Z/12/A)
- European Commission Research Executive Agency (303006/2011)
- Barts and The London Charity
- Pfizer UK (WS 733753)
- Science Foundation Ireland (09/IN.1/B2640)
- Secretaría de Ciencia, Humanidades, Tecnología e Innovación (scholarship to L.C.H.R.)
- FIPA Patients Charity
- Belfast City Hospital Charitable fund
- Holland family
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