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.

Keywords: AIP; acromegaly and gigantism; evolutionary genetics; founder mutation; population screening.

Figure 1

Geographical distribution of R304^* allele carriers in Ireland, compared to AIPmut–negative patients with somatotrophinomas. R304^* carriers, unaffected (R304^* unaffected, green columns) and patients with somatotrophinomas (R304^* GH, red columns) were compared to AIPmut–negative patients with somatotrophinomas (AIP–neg GH, blue columns). Only subjects currently residing in Ireland were included; R304^*–positive patients with other PA types (n = 5) are not shown. The map was arbitrarily divided into regions separated by dotted borders, red for Mid Ulster. Ninety percent of the Mid Ulster screening subjects resided here, including all six R304^* carriers. Each small graph summarizes data from the region indicated by the corresponding arrow; the y–axis scale is identical for all graphs.

Figure 2

Microsatellite haplotypes of chromosome 11q12.2–13.3 of R304^*–positive pedigrees. Irish (first two rows) and non–Irish pedigrees (third row) are shown. Marker alleles are displayed as amplicon sizes. Dark shading: haploblock shared between all Irish pedigrees (0.2–1.95 Mbp long); light shading: additional shared haploblocks. Thick horizontal lines represent AIP alleles (black = wild–type, yellow = R304^*); intervals between markers are not drawn to scale. Sp, sporadic PA. Haplotypes of 18th century patient, FIPA 1, 2, 3, 6, 7, FIPA UK, Romania, US (Italian), Sp India and Sp Mexico pedigrees have been previously published (Chahal et al., 2011; Stals et al., 2011; Ramirez‐Renteria et al., 2016).

Figure 3

New evidence of historical Irish giants. (A) Subject 15 (Supp. Table S7), 211cm tall, from Maghera, Mid Ulster, uncle of a screening participant, died of a hypertensive crisis one month after photograph was taken – 13^th May 1918, Daily Sketch (Canadian newspaper). (B) Group of Irish immigrants from Garvagh (a town close to Mid Ulster) after arrival in Western Australia, 1910. At center with the pole, Subject 16 (Supp. Table S7), 213 cm tall; standing far left—unrelated subject with pronounced acromegalic features and tall stature (photograph from Garvagh Museum, NI).