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Increased Population Risk of AIPâ Related Acromegaly and Gigantism in Ireland
dc.contributor.authorRadian, Serban
dc.contributor.authorDiekmann, Yoan
dc.contributor.authorGabrovska, Plamena
dc.contributor.authorHolland, Brendan
dc.contributor.authorBradley, Lisa
dc.contributor.authorWallace, Helen
dc.contributor.authorStals, Karen
dc.contributor.authorBussell, Anna‐marie
dc.contributor.authorMcGurren, Karen
dc.contributor.authorCuesta, Martin
dc.contributor.authorRyan, Anthony W.
dc.contributor.authorHerincs, Maria
dc.contributor.authorHernández‐ramírez, Laura C.
dc.contributor.authorHolland, Aidan
dc.contributor.authorSamuels, Jade
dc.contributor.authorAflorei, Elena Daniela
dc.contributor.authorBarry, Sayka
dc.contributor.authorDénes, Judit
dc.contributor.authorPernicova, Ida
dc.contributor.authorStiles, Craig E.
dc.contributor.authorTrivellin, Giampaolo
dc.contributor.authorMcCloskey, Ronan
dc.contributor.authorAjzensztejn, Michal
dc.contributor.authorAbid, Noina
dc.contributor.authorAkker, Scott A.
dc.contributor.authorMercado, Moises
dc.contributor.authorCohen, Mark
dc.contributor.authorThakker, Rajesh V.
dc.contributor.authorBaldeweg, Stephanie
dc.contributor.authorBarkan, Ariel
dc.contributor.authorMusat, Madalina
dc.contributor.authorLevy, Miles
dc.contributor.authorOrme, Stephen M.
dc.contributor.authorUnterländer, Martina
dc.contributor.authorBurger, Joachim
dc.contributor.authorKumar, Ajith V.
dc.contributor.authorEllard, Sian
dc.contributor.authorMcPartlin, Joseph
dc.contributor.authorMcManus, Ross
dc.contributor.authorLinden, Gerard J.
dc.contributor.authorAtkinson, Brew
dc.contributor.authorBalding, David J.
dc.contributor.authorAgha, Amar
dc.contributor.authorThompson, Chris J.
dc.contributor.authorHunter, Steven J.
dc.contributor.authorThomas, Mark G.
dc.contributor.authorMorrison, Patrick J.
dc.contributor.authorKorbonits, Márta
dc.date.accessioned2017-01-10T19:10:27Z
dc.date.available2018-03-01T16:43:49Zen
dc.date.issued2017-01
dc.identifier.citationRadian, Serban; Diekmann, Yoan; Gabrovska, Plamena; Holland, Brendan; Bradley, Lisa; Wallace, Helen; Stals, Karen; Bussell, Anna‐marie ; McGurren, Karen; Cuesta, Martin; Ryan, Anthony W.; Herincs, Maria; Hernández‐ramírez, Laura C. ; Holland, Aidan; Samuels, Jade; Aflorei, Elena Daniela; Barry, Sayka; Dénes, Judit ; Pernicova, Ida; Stiles, Craig E.; Trivellin, Giampaolo; McCloskey, Ronan; Ajzensztejn, Michal; Abid, Noina; Akker, Scott A.; Mercado, Moises; Cohen, Mark; Thakker, Rajesh V.; Baldeweg, Stephanie; Barkan, Ariel; Musat, Madalina; Levy, Miles; Orme, Stephen M.; Unterländer, Martina ; Burger, Joachim; Kumar, Ajith V.; Ellard, Sian; McPartlin, Joseph; McManus, Ross; Linden, Gerard J.; Atkinson, Brew; Balding, David J.; Agha, Amar; Thompson, Chris J.; Hunter, Steven J.; Thomas, Mark G.; Morrison, Patrick J.; Korbonits, Márta (2017). "Increased Population Risk of AIPâ Related Acromegaly and Gigantism in Ireland." Human Mutation 38(1): 78-85.
dc.identifier.issn1059-7794
dc.identifier.issn1098-1004
dc.identifier.urihttps://hdl.handle.net/2027.42/135617
dc.description.abstractThe 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 = 0.0027â 0.013; P = 0.0005 vs. ROI), 0.001 in Greater Belfast (0.00011â 0.0047) and zero in ROI (0â 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 nonâ Irish patients (0â 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 (1,275â 5,000) years. tMRCAâ based simulations predicted 432 (90â 5,175) current carriers, including 86 affected (18â 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 AIPâ related disease.Combining patient and general population screening in Ireland with a novel coalescentâ based population genetics approach, we revealed that AIPâ related pituitary adenomas are frequent in Mid Ulster region of Northern Ireland and almost exclusively due to a founder AIP mutation, R304*. Forward simulation predicted many undiagnosed carriers. We demonstrated that geographicallyâ targeted population screening complements clinical testing for carrier identification. Benefitting from patient and general public involvement, our study contributed to disease awareness locally, necessary for early diagnosis and improved patient outcomes.
dc.publisherWiley Periodicals, Inc.
dc.publisherWhite Row Press Ltd
dc.subject.otherevolutionary genetics
dc.subject.otheracromegaly and gigantism
dc.subject.otherAIP
dc.subject.otherpopulation screening
dc.subject.otherfounder mutation
dc.titleIncreased Population Risk of AIPâ Related Acromegaly and Gigantism in Ireland
dc.typeArticleen_US
dc.rights.robotsIndexNoFollow
dc.subject.hlbsecondlevelGenetics
dc.subject.hlbtoplevelHealth Sciences
dc.subject.hlbtoplevelScience
dc.description.peerreviewedPeer Reviewed
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/135617/1/humu23121_am.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/135617/2/humu23121-sup-0002-SuppMat.pdf
dc.description.bitstreamurlhttp://deepblue.lib.umich.edu/bitstream/2027.42/135617/3/humu23121.pdf
dc.identifier.doi10.1002/humu.23121
dc.identifier.sourceHuman Mutation
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