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1. Multi-trait analysis characterizes the genetics of thyroid function and identifies causal associations with clinical implications

Author

Sterenborg, R.B.T.M., Steinbrenner, I., Li, Yong, Bujnis, M.N., Naito, T., Marouli, E., Galesloot, T.E., Babajide, O., Andreasen, L., Astrup, A., Åsvold, B.O., Bandinelli, S., Beekman, M., Beilby, J.P., Bork-Jensen, J., Boutin, T., Brody, J.A., Brown, S.J., Brumpton, B., Campbell, P.J., Cappola, A.R., Ceresini, G., Chaker, L., Chasman, D.I., Concas, M.P., Coutinho de Almeida, Rodrigo, Cross, S.M., Cucca, F., Deary, I.J., Kjaergaard, A.D., Echouffo Tcheugui, J.B., Ellervik, C., Eriksson, J.G., Ferrucci, L., Freudenberg, J., Fuchsberger, C., Gieger, C., Giulianini, F., Gögele, M., Graham, S.E., Grarup, N., Gunjača, I., Hansen, T., Harding, B.N., Harris, S.E., Haunsø, S., Hayward, C., Hui, J., Ittermann, T., Jukema, J.W., Kajantie, E., Kanters, J.K., Kårhus, L.L., Kiemeney, L.A.L.M., Kühnel, B., Lahti, J., Langenberg, C., Lapauw, B., Leese, G., Li, Shuo, Liewald, D.C.M., Linneberg, A., Lominchar, J.V.T., Luan, Jian'an, Martin, N.G., Matana, A., Meima, M.E., Meitinger, T., Meulenbelt, I., Mitchell, B.D., Møllehave, L.T., Mora, S., Naitza, S., Nauck, M., Netea-Maier, R.T., Noordam, R., Nursyifa, C., Okada, Y., Onano, S., Papadopoulou, A., Palmer, C.N.A., Pattaro, C., Pedersen, O., Peters, A., Pietzner, M., Polašek, O., Pramstaller, P.P., Psaty, B.M., Punda, A., Ray, D., Redmond, P., Richards, J.B., Ridker, P.M., Russ, T.C., Ryan, K.A., Olesen, M.S., Schultheiss, U.T., Selvin, E., Siddiqui, M.K., Teumer, A., Medici, M., Sterenborg, R.B.T.M., Steinbrenner, I., Li, Yong, Bujnis, M.N., Naito, T., Marouli, E., Galesloot, T.E., Babajide, O., Andreasen, L., Astrup, A., Åsvold, B.O., Bandinelli, S., Beekman, M., Beilby, J.P., Bork-Jensen, J., Boutin, T., Brody, J.A., Brown, S.J., Brumpton, B., Campbell, P.J., Cappola, A.R., Ceresini, G., Chaker, L., Chasman, D.I., Concas, M.P., Coutinho de Almeida, Rodrigo, Cross, S.M., Cucca, F., Deary, I.J., Kjaergaard, A.D., Echouffo Tcheugui, J.B., Ellervik, C., Eriksson, J.G., Ferrucci, L., Freudenberg, J., Fuchsberger, C., Gieger, C., Giulianini, F., Gögele, M., Graham, S.E., Grarup, N., Gunjača, I., Hansen, T., Harding, B.N., Harris, S.E., Haunsø, S., Hayward, C., Hui, J., Ittermann, T., Jukema, J.W., Kajantie, E., Kanters, J.K., Kårhus, L.L., Kiemeney, L.A.L.M., Kühnel, B., Lahti, J., Langenberg, C., Lapauw, B., Leese, G., Li, Shuo, Liewald, D.C.M., Linneberg, A., Lominchar, J.V.T., Luan, Jian'an, Martin, N.G., Matana, A., Meima, M.E., Meitinger, T., Meulenbelt, I., Mitchell, B.D., Møllehave, L.T., Mora, S., Naitza, S., Nauck, M., Netea-Maier, R.T., Noordam, R., Nursyifa, C., Okada, Y., Onano, S., Papadopoulou, A., Palmer, C.N.A., Pattaro, C., Pedersen, O., Peters, A., Pietzner, M., Polašek, O., Pramstaller, P.P., Psaty, B.M., Punda, A., Ray, D., Redmond, P., Richards, J.B., Ridker, P.M., Russ, T.C., Ryan, K.A., Olesen, M.S., Schultheiss, U.T., Selvin, E., Siddiqui, M.K., Teumer, A., and Medici, M.

Abstract

Contains fulltext : 304858.pdf (Publisher’s version ) (Open Access), To date only a fraction of the genetic footprint of thyroid function has been clarified. We report a genome-wide association study meta-analysis of thyroid function in up to 271,040 individuals of European ancestry, including reference range thyrotropin (TSH), free thyroxine (FT4), free and total triiodothyronine (T3), proxies for metabolism (T3/FT4 ratio) as well as dichotomized high and low TSH levels. We revealed 259 independent significant associations for TSH (61% novel), 85 for FT4 (67% novel), and 62 novel signals for the T3 related traits. The loci explained 14.1%, 6.0%, 9.5% and 1.1% of the total variation in TSH, FT4, total T3 and free T3 concentrations, respectively. Genetic correlations indicate that TSH associated loci reflect the thyroid function determined by free T3, whereas the FT4 associations represent the thyroid hormone metabolism. Polygenic risk score and Mendelian randomization analyses showed the effects of genetically determined variation in thyroid function on various clinical outcomes, including cardiovascular risk factors and diseases, autoimmune diseases, and cancer. In conclusion, our results improve the understanding of thyroid hormone physiology and highlight the pleiotropic effects of thyroid function on various diseases.

Published
2024

2. Cardiovascular and metabolic effects of metformin in patients with type 1 diabetes (REMOVAL): a double-blind, randomised, placebo-controlled trial

Author

Nickerson, H, Lou, O, Dutta, S, Haw, J, Anderson, C, Kean, S, Thomson, E, Gillespie, L, Gibb, J, Greenlaw, N, Keech, A, Jenkins, A, March, K, Williams, S, Coady, E, Bots, M, Dreyer, J, Jan, T, Sheffy, K, Lusky, R, Peleg, S, Shore, A, Carty, D, Donnan, P, Witham, M, Adler, A, Lonn, E, Rauchhaus, P, Lindsay, R, Brouwers, M, Van-Melckebeke, J, Hamill, T, Cuthbertson, L, Murray, A, Jolly, L, Miller, E, Hair, J, Bell, A, Carmichael, S, Douglas, E, Surtees, P, Dinnett, E, Allan, J, Watson, C, McLaughlin, M, Brindley, G, Smillie, E, Motherwell, D, MacDonald, S, Ellis, P, Stuart, D, Travers, M, Brearley, S, Greig, L, Colman, P, Nankervis, A, Forulanos, S, West, D, Vaughan, S, Bjorasen, M, Donlan, J, Vrazas, J, O'Neal, D, Horsburgh, J, Pater, H, Kent, S, Twigg, S, Fulcher, G, Denner, R, Piotrowicz, A, Januszewski, A, Coy, A, Paul, T, McDonald, C, Tereschyn, S, Schmidt, N, Weingert, M, Heard, H, Burke, S, Ooi, TC, Lochnan, H, Sorisky, A, Keely, E, Malcolm, J, Maranger, J, Favreau, C, Petherick, S, Boles, K, Rossing, P, Hansen, TW, Lund, S, Hemmingsen, B, Thorogood, N, Green, K, Robinson, T, Abouglilia, K, Nayman, D, Miller, C, Warren, R, Aizawa, K, Balasubramani, M, Toth, S, Harvey, K, Birch, G, Atkin, S, Sathyapalan, T, James, A, Javed, Z, Wilding, J, Martin, B, Birch, S, Wilcox, A, Watson, N, Oliver, N, Jugnee, N, Rutter, M, Turgut, T, Shaju, A, Yau, S, Subin, S, Walker, M, Wake, D, Millward, A, Chong, P, Hibbert, M, George, J, Schaper, N, Pinxt, J, op het Roodt, J, Phillips, Sam, Murray, L, Sleigh, L, Collier, A, Sit, LE, Allan, K, Cook, J, Campbell, K, Hodge, L, Leese, G, Reekie, G, Jaap, A, Sudworth, A, White, A, McKnight, J, Steven, L, McKay, G, Llano, A, Currie, G, Lennon, E, Johnstone, J, Shields, K, Petrie, John R, Chaturvedi, Nishi, Ford, Ian, Brouwers, Martijn C G J, Greenlaw, Nicola, Tillin, Therese, Hramiak, Irene, Hughes, Alun D, Jenkins, Alicia J, Klein, Barbara E K, Klein, Ronald, Ooi, Teik C, Rossing, Peter, Stehouwer, Coen D A, Sattar, Naveed, and Colhoun, Helen M

Published
2017
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12. Predicted impact of extending the screening interval for diabetic retinopathy: the Scottish Diabetic Retinopathy Screening programme

Author

Looker, H. C., Nyangoma, S. O., Cromie, D. T., Olson, J. A., Leese, G. P., Philip, S., Black, M. W., Doig, J., Lee, N., Briggs, A., Hothersall, E. J., Morris, A. D., Lindsay, R. S., McKnight, J. A., Pearson, D. W. M., Sattar, N. A., Wild, S. H., McKeigue, P., Colhoun, H. M., and on behalf of the Scottish Diabetes Research Network (SDRN) Epidemiology Group and the Scottish Diabetic Retinopathy Collaborative

Published
2013
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13. Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs

Author

Colhoun, H. M., Livingstone, S. J., Looker, H. C., Morris, A. D., Wild, S. H., Lindsay, R. S., Reed, C., Donnan, P. T., Guthrie, B., Leese, G. P., McKnight, J., Pearson, D. W. M., Pearson, E., Petrie, J. R., Philip, S., Sattar, N., Sullivan, F. M., McKeigue, P., and on behalf of the Scottish Diabetes Research Network Epidemiology Group

Published
2012
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16. Diabetic retinopathy at diagnosis of type 2 diabetes in Scotland

Author

Looker, H. C., Nyangoma, S. O., Cromie, D., Olson, J. A., Leese, G. P., Black, M., Doig, J., Lee, N., Lindsay, R. S., McKnight, J. A., Morris, A. D., Philip, S., Sattar, N., Wild, S. H., Colhoun, H. M., and on behalf of the Scottish Diabetic Retinopathy Screening Collaborative and the Scottish Diabetes Research Network Epidemiology Group

Published
2012
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21. Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Author

Marques, P, Caimari, F, Hernández-Ramírez, LC, Collier, D, Iacovazzo, D, Ronaldson, A, Magid, K, Lim, CT, Stals, K, Ellard, S, Grossman, AB, Korbonits, M, Abraham, P, Aflorei, E, Agha, A, Ahlquist, J, Akker, SA, Alexandraki, K, Alföldi, S, Anselmo, J, Arlt, W, Atkinson, B, Aulinas-Masó, A, Aylwin, SJ, Baborie, A, Backeljauw, PF, Badiu, C, Baldeweg, S, Ball, S, Bano, G, Barkan, A, Barton, J, Barwell, J, Bates, P, Bernal-González, C, Besser, M, Bevan, JS, Bickerton, A, Blair, J, Bolanowski, M, Bouloux, P, Bradley, L, Bradley, K, Brain, C, Brooke, A, Brown, R, Buchfelder, M, Burren, C, Cakir, M, Canham, N, Capraro, J, Carroll, P, Carter, P, Carty, D, Cavlan, D, Chahal, HS, Cheetham, T, Chentli, F, Choong, C, Christ-Crain, M, Chung, T-T, Clayton, P, Clayton, RN, Cohen, M, Courtney, H, Cove, D, Crowne, E, Cuthbertson, D, Dal, J, Dalantaeva, N, Damjanovic, S, Daousi, C, Darzy, K, Dattani, M, Davies, M, Davies, J, Davis, J, de Castro, M, de Marinis, L, Deal, C, Dénes, J, Dimitri, P, Dorward, N, Dow, G, Drake, W, Druce, M, Drummond, J, Dutta, P, Dzeranova, L, Edén-Engström, B, Eeles, R, Elfving, M, Ellis, K, Elston, M, Emmerson, L, Ezzat, S, Fersht, N, Fica, S, Fischli, S, Fleseriu, M, Forsythe, E, Foulkes, W, Freda, P, Friedman, T, Gadelha, M, Gainsborough, M, Gallacher, S, Gallego, P, Gan, H-W, Georgescu, C, Gevers, E, Gilkes, C, Glynn, N, Goldman, JE, Goldstone, AP, Góth, M, Green, A, Greenhalgh, L, Grieve, J, Griz, L, Guitelman, M, Gürlek, A, Gurnell, M, Hamblin, PS, Hana, V, Harding, P, Hay, E, Hilton, DA, Ho, W, Hong, G, Horváth, K, Howell, S, Howlett, TA, Höybye, C, Hunter, S, Idampitiya, C, Igaz, P, Imran, A, Inder, WJ, Iwata, T, Izatt, L, Jagadeesh, S, Johnston, C, Jose, B, Kaltsas, G, Kaplan, F, Karavitaki, N, Kastelan, D, Katz, M, Kearney, T, Kershaw, M, Khoo, B, Kiraly-Borri, C, Knispelis, R, Kovács, GL, Kumar, A, Kumar, AV, Kun, IZ, Kyriaku, A, Lambrescu, I, Lampe, AK, Laws, ER, Lebek-Szatanska, A, Lechan, RM, Leese, G, Levy, A, Levy, MJ, Lewandowski, K, Lin, E, Lo, J, Lyons, C, Maartens, N, Maghnie, M, Makaya, T, Marcus, H, Niedziela, M, Martin, N, Matsuno, A, McGowan, B, McQuaid, SE, Medic-Stojanoska, M, Mendoza, N, Mercado-Atri, M, Mettananda, S, Mezősi, E, Miljic, D, Miller, KK, Modenesi, S, Molitch, ME, Monson, J, Morris, DG, Morrison, PJ, Mosterman, B, Munir, A, Murray, RD, Musat, M, Musolino, N, Nachtigall, L, Nagi, D, Nair, R, Nelson, R, Newell-Price, J, Nikookam, K, Ogilivie, A, Orme, SM, O´Weickert, M, Pal, A, Pascanu, I, Patócs, A, Patterson, C, Pearce, SH, Giraldi, FP, Penney, L, Perez-Rivas, LG, Pfeifer, M, Pirie, F, Poplawski, N, Popovic, V, Powell, M, Pullan, P, Quinton, R, Radian, S, Randeva, H, Reddy, N, Rees, A, Renals, V, de Oliveira, AR, Richardson, T, Rodd, C, Ross, RJM, Roncaroli, F, Ryan, F, Salvatori, R, Schöfl, C, Shears, D, Shotliff, K, Skelly, R, Snape, K, Soares, BS, Somasundaram, N, Spada, A, Sperber, J, Spoudeas, H, Stelmachowska-Banas, M, Stewart, S, Storr, HL, Strasburger, C, Street, ME, Suter-Widmer, I, Suthers, G, Swords, F, Syro, LV, Swantje, B, Sze, C, Taylor, J, Thakker, RV, Tham, E, Thompson, C, Thorner, MO, Tóth, M, Trainer, PJ, Tsagarakis, S, Twine, G, Tzanela, M, Vadasz, J, Vaidya, B, Vaks, V, Vance, ML, Verkauskiene, R, Von Esch, H, Wass, JA, Waterhouse, M, Webb, S, Weber, A, Wernig, F, Widell, H, Yamada, S, Yap, P, Yarman, S, Yeoh, P, Yoshimoto, K, Yuen, K, and Zammitt, NN

Abstract

Context\ud \ud Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs).\ud \ud \ud \ud Objective\ud \ud To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients.\ud \ud \ud \ud Design\ud \ud 12-year prospective, observational study.\ud \ud \ud \ud Participants & Setting\ud \ud We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases.\ud \ud \ud \ud Interventions & Outcome\ud \ud AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310).\ud \ud \ud \ud Results\ud \ud Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650).\ud \ud \ud \ud Conclusions\ud \ud Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.

Published
2020

45. Risk of diabetic retinopathy at first screen in children at 12 and 13 years of age

Author

Scanlon, P, Stratton, I, Bachmann, M, Jones, C, Leese, G, and Group, Four Nations Diabetic Retinopathy Screening Study

Subjects
Male, medicine.medical_specialty, Pediatrics, Adolescent, Endocrinology, Diabetes and Metabolism, Age at diagnosis, 030209 endocrinology & metabolism, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Vision Screening, Risk Factors, Ophthalmology, Diabetes mellitus, Internal Medicine, Medicine, Humans, Age of Onset, Child, Care Delivery, Research Articles, Diabetic Retinopathy, business.industry, Incidence (epidemiology), Incidence, Eye screening, Diabetic retinopathy, medicine.disease, RA645.D54, Confidence interval, United Kingdom, Diabetes Mellitus, Type 1, Early Diagnosis, Diabetes Mellitus, Type 2, 030221 ophthalmology & optometry, RE, Female, Age of onset, business, Short Report: Care Delivery, Retinopathy
Abstract

Aims To investigate the relationships between age at diagnosis of diabetes, age at diabetic eye screening and severity of diabetic retinopathy at first and subsequent screenings in children aged 12 or 13 years. Methods Data were extracted from four English screening programmes and from the Scottish, Welsh and Northern Irish programmes on all children with diabetes invited for their first and subsequent screening episodes from the age of 12 years. Retinopathy levels at first and subsequent screens, time from diagnosis of diabetes to first screening and age at diagnosis in years were calculated. Results Data were available for 2125 children with diabetes screened for the first time at age 12 or 13 years. In those diagnosed with diabetes at 2 years of age or less, the proportion with retinopathy in one or both eyes was 20% and 11%, respectively, decreasing to 8% and 2% in those diagnosed between 2 and 12 years (P < 0.0001). Only three children (aged 8, 10 and 11 years at diagnosis of diabetes) had images graded with referable retinopathy and, of these, two had non‐referable diabetic retinopathy at all subsequent screenings. Of 1703 children with subsequent images, 25 were graded with referable diabetic retinopathy over a mean follow‐up of 3.1 years, an incidence rate of 4.7 (95% confidence interval, 3.1–7.0) per 1000 per year. Conclusions In this large cohort of children, the low prevalence and incidence rates of referable diabetic retinopathy suggest that screening earlier than age 12 is not necessary., What's new? This is the largest reported study in the literature of baseline levels of diabetic retinopathy in the age group 12 or 13 years.This is the largest reported study showing the rate of progression of diabetic retinopathy in adolescents.Of 2125 children with diabetes screened for the first time at age 12 or 13 years, three were found to have referable disease.The absence of referable disease in subsequent screens in two of the children and of pre‐proliferative changes in the third child suggest that it is unlikely that any treatment is required.

Published
2019

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