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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

3. The optimal healthy ranges of thyroid function defined by the risk of cardiovascular disease and mortality: systematic review and individual participant data meta-analysis

Author

Xu, Y.F., Derakhshan, A., Hysaj, O., Wildisen, L., Ittermann, T., Pingitore, A., Abolhassani, N., Medici, M., Kiemeney, L.A., Riksen, N.P., Dullaart, R.P.F., Trompet, S., Dörr, M., Brown, S.J., Schmidt, Börge, Führer-Sakel, D., Vanderpump, M.P.J., Muendlein, A., Drexel, H., Fink, H.A., Ikram, M.K., Kavousi, M., Rhee, C.M., Bensenor, I.M., Azizi, F., Hankey, G.J., Iacoviello, M., Imaizumi, M., Ceresini, G., Ferrucci, L., Sgarbi, J.A., Bauer, D.C., Wareham, N., Boelaert, K., Bakker, S.J.L., Jukema, J.W., Vaes, B., Iervasi, G., Yeap, B.B., Westendorp, R.G.J., Korevaar, T.I.M., Völzke, H., Razvi, S., Gussekloo, J., Walsh, J.P., Cappola, A.R., Rodondi, N., Peeters, R.P., Chaker, L., Xu, Y.F., Derakhshan, A., Hysaj, O., Wildisen, L., Ittermann, T., Pingitore, A., Abolhassani, N., Medici, M., Kiemeney, L.A., Riksen, N.P., Dullaart, R.P.F., Trompet, S., Dörr, M., Brown, S.J., Schmidt, Börge, Führer-Sakel, D., Vanderpump, M.P.J., Muendlein, A., Drexel, H., Fink, H.A., Ikram, M.K., Kavousi, M., Rhee, C.M., Bensenor, I.M., Azizi, F., Hankey, G.J., Iacoviello, M., Imaizumi, M., Ceresini, G., Ferrucci, L., Sgarbi, J.A., Bauer, D.C., Wareham, N., Boelaert, K., Bakker, S.J.L., Jukema, J.W., Vaes, B., Iervasi, G., Yeap, B.B., Westendorp, R.G.J., Korevaar, T.I.M., Völzke, H., Razvi, S., Gussekloo, J., Walsh, J.P., Cappola, A.R., Rodondi, N., Peeters, R.P., and Chaker, L.

Abstract

Contains fulltext : 297328.pdf (Publisher’s version ) (Closed access), BACKGROUND: Reference intervals of thyroid-stimulating hormone (TSH) and free thyroxine (FT(4)) are statistically defined by the 2·5-97·5th percentiles, without accounting for potential risk of clinical outcomes. We aimed to define the optimal healthy ranges of TSH and FT(4) based on the risk of cardiovascular disease and mortality. METHODS: This systematic review and individual participant data (IPD) meta-analysis identified eligible prospective cohorts through the Thyroid Studies Collaboration, supplemented with a systematic search via Embase, MEDLINE (Ovid), Web of science, the Cochrane Central Register of Controlled Trials, and Google Scholar from Jan 1, 2011, to Feb 12, 2017 with an updated search to Oct 13, 2022 (cohorts found in the second search were not included in the IPD). We included cohorts that collected TSH or FT(4), and cardiovascular outcomes or mortality for adults (aged ≥18 years). We excluded cohorts that included solely pregnant women, individuals with overt thyroid diseases, and individuals with cardiovascular disease. We contacted the study investigators of eligible cohorts to provide IPD on demographics, TSH, FT(4), thyroid peroxidase antibodies, history of cardiovascular disease and risk factors, medication use, cardiovascular disease events, cardiovascular disease mortality, and all-cause mortality. The primary outcome was a composite outcome including cardiovascular disease events (coronary heart disease, stroke, and heart failure) and all-cause mortality. Secondary outcomes were the separate assessment of cardiovascular disease events, all-cause mortality, and cardiovascular disease mortality. We performed one-step (cohort-stratified Cox models) and two-step (random-effects models) meta-analyses adjusting for age, sex, smoking, systolic blood pressure, diabetes, and total cholesterol. The study was registered with PROSPERO, CRD42017057576. FINDINGS: We identified 3935 studies, of which 53 cohorts fulfilled the inclusion criteria and 26 co

Published
2023

4. Incorporating Baseline Outcome Data in Individual Participant Data Meta-Analysis of Non-randomized Studies

Author

Syrogiannouli, L., Wildisen, L., Meuwese, C., Bauer, D.C., Cappola, A.R., Gussekloo, J., Elzen, W.P.J. den, Trompet, S., Westendorp, R.G.J., Jukema, J.W., Ferrucci, L., Ceresini, G., Asvold, B.O., Chaker, L., Peeters, R.P., Imaizumi, M., Ohishi, W., Vaes, B., Volzke, H., Sgarbi, J.A., Walsh, J.P., Dullaart, R.P.F., Bakker, S.J.L., Iacoviello, M., Rodondi, N., Giovane, C. del, Thyroid Studies Collaboration, Epidemiology, Internal Medicine, Laboratory for Endocrinology, APH - Personalized Medicine, APH - Aging & Later Life, Groningen Institute for Organ Transplantation (GIOT), and Groningen Kidney Center (GKC)

Subjects
baseline imbalance, cohorts, continuous outcome, individual participant data, non-randomized studies, Prevention, Clinical Sciences, 360 Soziale Probleme, Sozialdienste, 610 Medicine & health, Psychiatry and Mental health, SDG 3 - Good Health and Well-being, 360 Social problems & social services, Public Health and Health Services, Psychology, 610 Medizin und Gesundheit
Abstract

BackgroundIn non-randomized studies (NRSs) where a continuous outcome variable (e.g., depressive symptoms) is assessed at baseline and follow-up, it is common to observe imbalance of the baseline values between the treatment/exposure group and control group. This may bias the study and consequently a meta-analysis (MA) estimate. These estimates may differ across statistical methods used to deal with this issue. Analysis of individual participant data (IPD) allows standardization of methods across studies. We aimed to identify methods used in published IPD-MAs of NRSs for continuous outcomes, and to compare different methods to account for baseline values of outcome variables in IPD-MA of NRSs using two empirical examples from the Thyroid Studies Collaboration (TSC).MethodsFor the first aim we systematically searched in MEDLINE, EMBASE, and Cochrane from inception to February 2021 to identify published IPD-MAs of NRSs that adjusted for baseline outcome measures in the analysis of continuous outcomes. For the second aim, we applied analysis of covariance (ANCOVA), change score, propensity score and the naïve approach (ignores the baseline outcome data) in IPD-MA from NRSs on the association between subclinical hyperthyroidism and depressive symptoms and renal function. We estimated the study and meta-analytic mean difference (MD) and relative standard error (SE). We used both fixed- and random-effects MA.ResultsTen of 18 (56%) of the included studies used the change score method, seven (39%) studies used ANCOVA and one the propensity score (5%). The study estimates were similar across the methods in studies in which groups were balanced at baseline with regard to outcome variables but differed in studies with baseline imbalance. In our empirical examples, ANCOVA and change score showed study results on the same direction, not the propensity score. In our applications, ANCOVA provided more precise estimates, both at study and meta-analytical level, in comparison to other methods. Heterogeneity was higher when change score was used as outcome, moderate for ANCOVA and null with the propensity score.ConclusionANCOVA provided the most precise estimates at both study and meta-analytic level and thus seems preferable in the meta-analysis of IPD from non-randomized studies. For the studies that were well-balanced between groups, change score, and ANCOVA performed similarly.

Published
2022
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5. Subclinical thyroid dysfunction and incident diabetes: a systematic review and an individual participant data analysis of prospective cohort studies

Author

Alwan, H., Villoz, F., Feller, M., Dullaart, R.P.F., Bakker, S.J.L., Peeters, R.P., Kavousi, M., Bauer, D.C., Cappola, A.R., Yeap, B.B., Walsh, J.P., Brown, S.J., Ceresini, G., Ferrucci, L., Gussekloo, J., Trompet, S., Iacoviello, M., Moon, J.H., Razvi, S., Bensenor, I.M., Azizi, F., Amouzegar, A., Valdes, S., Colomo, N., Wareham, N.J., Jukema, J.W., Westendorp, R.G.J., Kim, K.W., Rodondi, N., Giovane, C. del, Thyroid Studies Collaboration, Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), Internal Medicine, Epidemiology, Alwan, Heba [0000-0001-5516-6022], Bakker, Stephan JL [0000-0003-3356-6791], Peeters, Robin P [0000-0001-7732-9371], Yeap, Bu B [0000-0002-7612-5892], Razvi, Salman [0000-0002-9047-1556], Amouzegar, Atieh [0000-0001-9433-9408], and Apollo - University of Cambridge Repository

Subjects
Adult, Data Analysis, Male, Endocrinology, Diabetes and Metabolism, Clinical Sciences, Thyrotropin, 610 Medicine & health, Hyperthyroidism, Paediatrics and Reproductive Medicine, Cohort Studies, Endocrinology & Metabolism, Endocrinology, SDG 3 - Good Health and Well-being, Hypothyroidism, 360 Social problems & social services, Clinical Research, Diabetes Mellitus, Humans, Prospective Studies, Metabolic and endocrine, screening and diagnosis, Prevention, Diabetes, General Medicine, Middle Aged, Thyroid Diseases, Detection, Female, 4.2 Evaluation of markers and technologies
Abstract

ObjectiveFew prospective studies have assessed whether individuals with subclinical thyroid dysfunction are more likely to develop diabetes, with conflicting results. In this study, we conducted a systematic review of the literature and an individual participant data analysis of multiple prospective cohorts to investigate the association between subclinical thyroid dysfunction and incident diabetes.MethodsWe performed a systematic review of the literature in Medline, Embase, and the Cochrane Library from inception to February 11, 2022. A two-stage individual participant data analysis was conducted to compare participants with subclinical hypothyroidism and subclinical hyperthyroidism vs euthyroidism at baseline and the adjusted risk of developing diabetes at follow-up.ResultsAmong 61 178 adults from 18 studies, 49% were females, mean age was 58 years, and mean follow-up time was 8.2 years. At the last available follow-up, there was no association between subclinical hypothyroidism and incidence of diabetes (odds ratio (OR) = 1.02, 95% CI: 0.88–1.17, I2 = 0%) or subclinical hyperthyroidism and incidence of diabetes (OR = 1.03, 95% CI: 0.82–1.30, I2 = 0%), in age- and sex-adjusted analyses. Time-to-event analysis showed similar results (hazard ratio for subclinical hypothyroidism: 0.98, 95% CI: 0.87–1.11; hazard ratio for subclinical hyperthyroidism: 1.07, 95% CI: 0.88–1.29). The results were robust in all sub-group and sensitivity analyses.ConclusionsThis is the largest systematic review and individual participant data analysis to date investigating the prospective association between subclinical thyroid dysfunction and diabetes. We did not find an association between subclinical thyroid dysfunction and incident diabetes. Our results do not support screening patients with subclinical thyroid dysfunction for diabetes.Significance statementEvidence is conflicting regarding whether an association exists between subclinical thyroid dysfunction and incident diabetes. We therefore aimed to investigate whether individuals with subclinical thyroid dysfunction are more prone to develop diabetes in the long run as compared to euthyroid individuals. We included data from 18 international cohort studies with 61 178 adults and a mean follow-up time of 8.2 years. We did not find an association between subclinical hypothyroidism or subclinical hyperthyroidism at baseline and incident diabetes at follow-up. Our results have clinical implications as they neither support screening patients with subclinical thyroid dysfunction for diabetes nor treating them in the hope of preventing diabetes in the future. Objective: Few prospective studies have assessed whether individuals with subclinical thyroid dysfunction are more likely to develop diabetes, with conflicting results. In this study, we conducted a systematic review of the literature and an individual participant data analysis of multiple prospective cohorts to investigate the association between subclinical thyroid dysfunction and incident diabetes. Methods: We performed a systematic review of the literature in Medline, Embase, and the Cochrane Library from inception to February 11, 2022. A two-stage individual participant data analysis was conducted to compare participants with subclinical hypothyroidism and subclinical hyperthyroidism vs euthyroidism at baseline and the adjusted risk of developing diabetes at follow-up. Results: Among 61 178 adults from 18 studies, 49% were females, mean age was 58 years, and mean follow-up time was 8.2 years. At the last available follow-up, there was no association between subclinical hypothyroidism and incidence of diabetes (odds ratio (OR) = 1.02, 95% CI: 0.88-1.17, I2 = 0%) or subclinical hyperthyroidism and incidence of diabetes (OR = 1.03, 95% CI: 0.82-1.30, I2 = 0%), in age- and sex-adjusted analyses. Time-to-event analysis showed similar results (hazard ratio for subclinical hypothyroidism: 0.98, 95% CI: 0.87-1.11; hazard ratio for subclinical hyperthyroidism: 1.07, 95% CI: 0.88-1.29). The results were robust in all sub-group and sensitivity analyses. Conclusions: This is the largest systematic review and individual participant data analysis to date investigating the prospective association between subclinical thyroid dysfunction and diabetes. We did not find an association between subclinical thyroid dysfunction and incident diabetes. Our results do not support screening patients with subclinical thyroid dysfunction for diabetes. Significance statement: Evidence is conflicting regarding whether an association exists between subclinical thyroid dysfunction and incident diabetes. We therefore aimed to investigate whether individuals with subclinical thyroid dysfunction are more prone to develop diabetes in the long run as compared to euthyroid individuals. We included data from 18 international cohort studies with 61 178 adults and a mean follow-up time of 8.2 years. We did not find an association between subclinical hypothyroidism or subclinical hyperthyroidism at baseline and incident diabetes at follow-up. Our results have clinical implications as they neither support screening patients with subclinical thyroid dysfunction for diabetes nor treating them in the hope of preventing diabetes in the future.

Published
2022
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6. Concurrent change in dehydroepiandrosterone sulfate and functional performance in the oldest old: results from the cardiovascular health study all stars study

Author

Sanders, J.L., Cappola, A.R., Arnold, A.M., Boudreau, R.M., Chaves, P.H., Robbins, J., Cushman, M., and Newman, A.B.

Subjects
Biological markers -- Properties, Cardiovascular system -- Research, Dehydroepiandrosterone -- Physiological aspects, Health, Seniors
Abstract

Introduction. The correlation between dehydroepiandrosterone sulfate (DHEAS) decline and age led to the hypothesis that DHEAS might be a marker of primary aging, though conflicting data from observational studies of mortality do not support this. We evaluated concurrent DHEAS and functional decline in a very old cohort to test if DHEAS change tracks with functional change during aging. Methods. DHEAS and functional performance (gait speed, grip strength, Modified Mini-Mentul State Examination [3MSE] score, and digit symbol substitution test [DSST] score) were measured in 1996-1997 and 2005-2006 in 989 participants in the Cardiovascular Health Study All Stars study (mean age 85.2 years in 2005-2006, 63.5% women and 16.5% African American). We used multivariable linear regression to test the association of DHEAS decline with functional decline. Results. After adjustment, each standard deviation decrease in DHEAS was associated with greater declines in gait speed (0.12 m/s, p = .01), grip strength (0.09 kg, p = .03), 3MSE score (0.13 points, p < .001), and DSST score (0.14 points, p = .001) in women only. Additional adjustment for baseline DHEAS attenuated the association with grip strength but did not alter other estimates appreciably, and baseline DHEAS was unassociated with functional decline. Conclusions. In this cohort of very old individuals, DHEAS decline tracked with declines in gait speed, 3MSE score, and DSST score, but not grip strength, in women independent of baseline DHEAS level. DHEAS decline might be a marker for age-associated performance decline, but its relevance is specific to women. Key Words: Aging--Biomarker--Dehydroepiandrosterone sulfate--Function. doi: 10.1093/gerona/glq072

Published
2010

7. Relationship of 25-hydroxyvitamin D with all-cause and cardiovascular disease mortality in older community-dwelling adults

Author

Semba, R.D, Houston, D.K., Bandinelli, S., Sun, K., Cherubini, A., Cappola, A.R., Guralnik, J.M., and Ferrucci, L.

Subjects
Aged -- Health aspects -- Food and nutrition, Aging -- Health aspects, Mortality -- Risk factors -- Italy, Vitamin D deficiency -- Demographic aspects -- Statistics -- Risk factors -- Complications and side effects, Cardiovascular diseases -- Demographic aspects, Food/cooking/nutrition, Health
Abstract

Background/Objectives: Vitamin D deficiency is associated with cardiovascular disease, osteoporosis, poor muscle strength, falls, fractures and mortality. Although older adults are at a higher risk of vitamin D deficiency, the relationship of serum 25-hydroxyvitamin D (25(OH)D) with all-cause and cardiovascular disease mortality has not been well characterized in the elderly. We hypothesized that low serum 25(OH)D levels predicted mortality in older adults. Subjects/Methods: Serum 25(OH)D as well as all-cause and cardiovascular disease mortality were examined in 1006 adults, aged ≥ 65 years, who participated in the InCHIANTI (Invecchiare in Chianti, Aging in the Chianti Area) study, a population-based, prospective cohort study of aging in Tuscany, Italy. Serum 25(OH)D levels were measured at the time of enrollment in 1998-1999, and participants were followed up for mortality. Results: During 6.5 years of follow-up, 228 (22.7%) participants died, of whom 107 died due to cardiovascular diseases. Compared with participants in the highest quartile of serum 25(OH)D (>26.5 ng/ml) (to convert to nmol/l, multiply by 2.496), those in the lowest quartile ( Conclusions: Older community-dwelling adults with low serum 25(OH)D levels are at higher risk of all-cause and cardiovascular disease mortality. European Journal of Clinical Nutrition (2010) 64, 203-209; doi: 10.1038/ejcn.2009.140; published online 2 December 2009 Keywords: aging; all-cause mortality; cardiovascular disease mortality; vitamin D, Introduction Worldwide, the population of individuals aged ≥ 65 years was 420 million in 2000, and it is expected to increase to 973 million by 2030 (Ferrucci et al, 2008). [...]

Published
2010
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8. An individual participant data analysis of prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms

Author

Wildisen, L., Giovane, C. del, Moutzouri, E., Beglinger, S., Syrogiannouli, L., Collet, T.H., Cappola, A.R., Asvold, B.O., Bakker, S.J.L., Yeap, B.B., Almeida, O.P., Ceresini, G., Dullaart, R.P.F., Ferrucci, L., Grabe, H., Jukema, J.W., Nauck, M., Trompet, S., Volzke, H., Westendorp, R., Gussekloo, J., Kloppel, S., Aujesky, D., Bauer, D., Peeters, R., Feller, M., Rodondi, N., Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC), and Internal Medicine

Subjects
Male, Quality of life, endocrine system, endocrine system diseases, Thyroid Gland, lcsh:Medicine, 610 Medicine & health, Thyroid Function Tests, Severity of Illness Index, Article, DISEASE, Endocrinology, Medical research, DESIGN, STAGE, Clinical Research, OSTEOPOROTIC FRACTURES, 360 Social problems & social services, Behavioral and Social Science, BASE-LINE CHARACTERISTICS, Humans, Psychology, lcsh:Science, METAANALYSIS, Public health, Depression, lcsh:R, MEN, Thyroid Diseases, Brain Disorders, Mental Health, HYPOTHYROIDISM, RISK-FACTORS, lcsh:Q, Female, HEALTH, Hormonal therapies
Abstract

In subclinical hypothyroidism, the presence of depressive symptoms is often a reason for starting levothyroxine treatment. However, data are conflicting on the association between subclinical thyroid dysfunction and depressive symptoms. We aimed to examine the association between subclinical thyroid dysfunction and depressive symptoms in all prospective cohorts with relevant data available. We performed a systematic review of the literature from Medline, Embase, Cumulative Index to Nursing and Allied Health Literature, and the Cochrane Library from inception to 10th May 2019. We included prospective cohorts with data on thyroid status at baseline and depressive symptoms during follow-up. The primary outcome was depressive symptoms measured at first available follow-up, expressed on the Beck's Depression Inventory (BDI) scale (range 0-63, higher values indicate more depressive symptoms, minimal clinically important difference: 5 points). We performed a two-stage individual participant data (IPD) analysis comparing participants with subclinical hypo- or hyperthyroidism versus euthyroidism, adjusting for depressive symptoms at baseline, age, sex, education, and income (PROSPERO CRD42018091627). Six cohorts met the inclusion criteria, with IPD on 23,038 participants. Their mean age was 60 years, 65% were female, 21,025 were euthyroid, 1342 had subclinical hypothyroidism and 671 subclinical hyperthyroidism. At first available follow-up [mean 8.2 (± 4.3) years], BDI scores did not differ between participants with subclinical hypothyroidism (mean difference = 0.29, 95% confidence interval = - 0.17 to 0.76, I 2 = 15.6) or subclinical hyperthyroidism (- 0.10, 95% confidence interval = - 0.67 to 0.48, I 2 = 3.2) compared to euthyroidism. This systematic review and IPD analysis of six prospective cohort studies found no clinically relevant association between subclinical thyroid dysfunction at baseline and depressive symptoms during follow-up. The results were robust in all sensitivity and subgroup analyses. Our results are in contrast with the traditional notion that subclinical thyroid dysfunction, and subclinical hypothyroidism in particular, is associated with depressive symptoms. Consequently, our results do not support the practice of prescribing levothyroxine in patients with subclinical hypothyroidism to reduce the risk of developing depressive symptoms.

Published
2020
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9. GWAS of thyroid stimulating hormone highlights pleiotropic effects and inverse association with thyroid cancer

Author

Zhou, W. (Wei), Brumpton, B. (Ben), Kabil, O. (Omer), Gudmundsson, J. (Julius), Thorleifsson, G. (Gudmar), Weinstock, J. (Josh), Zawistowski, M. (Matthew), Nielsen, J.B. (Jonas B.), Chaker, L. (Layal), Medici, M. (Marco), Teumer, A. (Alexander), Naitza, S. (Silvia), Sanna, S. (Serena), Schultheiss, U.T. (Ulla T.), Cappola, A.R. (Anne), Karjalainen, J. (Juha), Kurki, M. (Mitja), Oneka, M. (Morgan), Taylor, P.N. (Peter N.), Fritsche, L.G. (Lars), Graham, S.E. (Sarah E.), Wolford, B.N. (Brooke N.), Overton, W. (William), Rasheed, H. (Humaira), Haug, E.B. (Eirin B.), Gabrielsen, M.E. (Maiken Elvestad), Skogholt, A.H. (Anne Heidi), Surakka, I. (Ida), Davey Smith, G. (George), Pandit, A. (Anita), Roychowdhury, T. (Tanmoy), Hornsby, W.E. (Whitney E.), Jonasson, J.G. (Jon G.), Senter, L. (Leigha), Liyanarachchi, S. (Sandya), Ringel, M.D. (Matthew D.), Xu, L. (Li), Kiemeney, L.A. (Lambertus A.), He, H. (Hao), Netea-Maier, R.T. (Romana), Mayordomo, J.I. (José), Plantinga, T.S. (Theo S.), Hrafnkelsson, J. (Jon), Hjartarson, H. (Hannes), Sturgis, E.M. (Erich M.), Palotie, A. (Aarno), Daly, M.J. (Mark), Citterio, C.E. (Cintia E.), Arvan, P. (Peter), Brummett, C.M. (Chad M.), Boehnke, M. (Michael), La Chapelle, A. (Albert) de, Stefansson, K. (Kari), Hveem, K. (Kristian), Willer, C.J. (Cristen), Asvold, B.O. (Bjorn O.), Zhou, W. (Wei), Brumpton, B. (Ben), Kabil, O. (Omer), Gudmundsson, J. (Julius), Thorleifsson, G. (Gudmar), Weinstock, J. (Josh), Zawistowski, M. (Matthew), Nielsen, J.B. (Jonas B.), Chaker, L. (Layal), Medici, M. (Marco), Teumer, A. (Alexander), Naitza, S. (Silvia), Sanna, S. (Serena), Schultheiss, U.T. (Ulla T.), Cappola, A.R. (Anne), Karjalainen, J. (Juha), Kurki, M. (Mitja), Oneka, M. (Morgan), Taylor, P.N. (Peter N.), Fritsche, L.G. (Lars), Graham, S.E. (Sarah E.), Wolford, B.N. (Brooke N.), Overton, W. (William), Rasheed, H. (Humaira), Haug, E.B. (Eirin B.), Gabrielsen, M.E. (Maiken Elvestad), Skogholt, A.H. (Anne Heidi), Surakka, I. (Ida), Davey Smith, G. (George), Pandit, A. (Anita), Roychowdhury, T. (Tanmoy), Hornsby, W.E. (Whitney E.), Jonasson, J.G. (Jon G.), Senter, L. (Leigha), Liyanarachchi, S. (Sandya), Ringel, M.D. (Matthew D.), Xu, L. (Li), Kiemeney, L.A. (Lambertus A.), He, H. (Hao), Netea-Maier, R.T. (Romana), Mayordomo, J.I. (José), Plantinga, T.S. (Theo S.), Hrafnkelsson, J. (Jon), Hjartarson, H. (Hannes), Sturgis, E.M. (Erich M.), Palotie, A. (Aarno), Daly, M.J. (Mark), Citterio, C.E. (Cintia E.), Arvan, P. (Peter), Brummett, C.M. (Chad M.), Boehnke, M. (Michael), La Chapelle, A. (Albert) de, Stefansson, K. (Kari), Hveem, K. (Kristian), Willer, C.J. (Cristen), and Asvold, B.O. (Bjorn O.)

Abstract

Thyroid stimulating hormone (TSH) is critical for normal development and metabolism. To better understand the genetic contribution to TSH levels, we conduct a GWAS meta-analysis at 22.4 million genetic markers in up to 119,715 individuals and identify 74 genome-wide significant loci for TSH, of which 28 are previously unreported. Functional experiments show that the thyroglobulin protein-altering variants P118L and G67S impact thyroglobulin secretion. Phenome-wide association analysis in the UK Biobank demonstrates the pleiotropic effects of TSH-associated variants and a polygenic score for higher TSH levels is associated with a reduced risk of thyroid cancer in the UK Biobank and three other independent studies. Two-sample Mendelian randomization using TSH index variants as instrumental variables suggests a protective effect of higher TSH levels (indicating lower thyroid function) on risk of thyroid cancer and goiter. Our findings highlight the pleiotropic effects of TSH-associated variants on thyroid function and growth of malignant and benign thyroid tumors.

Published
2020
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10. Subclinical thyroid dysfunction and depressive symptoms: protocol for a systematic review and individual participant data meta-analysis of prospective cohort studies

Author

Wildisen, L. (Lea), Moutzouri, E. (Elisavet), Beglinger, S. (Shanthi), Syrogiannouli, L. (Lamprini), Cappola, A.R. (Anne), Asvold, B.O. (Bjorn O.), Bakker, S.J.L. (Stephan), Ceresini, G. (Graziano), Dullaart, R.P.F. (Robin P.F.), Ferrucci, L. (Luigi), Grabe, H.J. (Hans Jörgen), Jukema, J.W. (Jan Wouter), Nauck, M. (Matthias), Trompet, S. (Stella), Völzke, H. (Henry), Westendorp, R.G.J. (Rudi), Gussekloo, J. (Jacobijn), Peeters, R.P. (Robin), Klöppel, S. (Stefan), Aujesky, D. (Drahomir), Bauer, D.C. (Douglas), Rodondi, N. (Nicolas), Del Giovane, C. (Cinzia), Feller, M. (Martin), Wildisen, L. (Lea), Moutzouri, E. (Elisavet), Beglinger, S. (Shanthi), Syrogiannouli, L. (Lamprini), Cappola, A.R. (Anne), Asvold, B.O. (Bjorn O.), Bakker, S.J.L. (Stephan), Ceresini, G. (Graziano), Dullaart, R.P.F. (Robin P.F.), Ferrucci, L. (Luigi), Grabe, H.J. (Hans Jörgen), Jukema, J.W. (Jan Wouter), Nauck, M. (Matthias), Trompet, S. (Stella), Völzke, H. (Henry), Westendorp, R.G.J. (Rudi), Gussekloo, J. (Jacobijn), Peeters, R.P. (Robin), Klöppel, S. (Stefan), Aujesky, D. (Drahomir), Bauer, D.C. (Douglas), Rodondi, N. (Nicolas), Del Giovane, C. (Cinzia), and Feller, M. (Martin)

Abstract

INTRODUCTION: Prospective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms have yielded conflicting findings, possibly because of differences in age, sex, thyroid-stimulating hormone cut-off levels or degree of baseline depressive symptoms. Analysis of

Published
2019
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11. Association between subclinical thyroid dysfunction and change in bone mineral density in prospective cohorts

Author

Segna, D., Bauer, D.C., Feller, M., Schneider, C., Fink, H.A., Aubert, C.E., Collet, T.H., Costa, B.R. da, Fischer, K., Peeters, R.P., Cappola, A.R., Blum, M.R., Dorland, H.A. van, Robbins, J., Naylor, K., Eastell, R., Uitterlinden, A.G., Ramirez, F.R., Gogakos, A., Gussekloo, J., Williams, G.R., Schwartz, A., Cauley, J.A., Aujesky, D.A., Bischoff-Ferrari, H.A., Rodondi, N., Thyroid Studies Collaboration, Epidemiology, and Internal Medicine

Subjects
Male, Bone density, endocrine system diseases, OLDER MEN, FRACTURE RISK, Hyperthyroidism, Fractures, Bone, 0302 clinical medicine, Risk Factors, Medicine, 030212 general & internal medicine, Prospective cohort study, 610 Medicine & health, Subclinical infection, Bone mineral, Thyroid disease, Thyroid, WOMEN, bone density, medicine.anatomical_structure, Female, Life Sciences & Biomedicine, 360 Social problems & social services, medicine.medical_specialty, endocrine system, Clinical Sciences, 030209 endocrinology & metabolism, Article, 03 medical and health sciences, Rare Diseases, Medicine, General & Internal, Hypothyroidism, bone loss, OSTEOPOROTIC FRACTURES, SERUM TSH, Clinical Research, Internal medicine, General & Internal Medicine, Internal Medicine, Humans, hyperthyroidism, CORONARY-HEART-DISEASE, thyroid disease, Bone, METAANALYSIS, Femoral neck, Aged, Science & Technology, business.industry, Thyroid Studies Collaboration, HIP FRACTURE, 1103 Clinical Sciences, medicine.disease, prospective studies, Surgery, Cardiovascular System & Hematology, Musculoskeletal, Asymptomatic Diseases, Osteoporosis, hypothyroidism, business, INDIVIDUAL PARTICIPANT DATA, Fractures, Hormone
Abstract

© 2017 The Association for the Publication of the Journal of Internal Medicine Background: Subclinical hyperthyroidism (SHyper) has been associated with increased risk of hip and other fractures, but the linking mechanisms remain unclear. Objective: To investigate the association between subclinical thyroid dysfunction and bone loss. Methods: Individual participant data analysis was performed after a systematic literature search in MEDLINE/EMBASE (1946–2016). Two reviewers independently screened and selected prospective cohorts providing baseline thyroid status and serial bone mineral density (BMD) measurements. We classified thyroid status as euthyroidism (thyroid-stimulating hormone [TSH] 0.45–4.49 mIU/L), SHyper (TSH < 0.45 mIU/L) and subclinical hypothyroidism (SHypo, TSH ≥ 4.50–19.99 mIU/L) both with normal free thyroxine levels. Our primary outcome was annualized percentage BMD change (%ΔBMD) from serial dual X-ray absorptiometry scans of the femoral neck, total hip and lumbar spine, obtained from multivariable regression in a random-effects two-step approach. Results: Amongst 5458 individuals (median age 72 years, 49.1% women) from six prospective cohorts, 451 (8.3%) had SHypo and 284 (5.2%) had SHyper. During 36 569 person-years of follow-up, those with SHyper had a greater annual bone loss at the femoral neck versus euthyroidism: %ΔBMD = −0.18 (95% CI: −0.34, −0.02; I2= 0%), with a nonstatistically significant pattern at the total hip: %ΔBMD = −0.14 (95% CI: −0.38, 0.10; I2= 53%), but not at the lumbar spine: %ΔBMD = 0.03 (95% CI: −0.30, 0.36; I2= 25%); especially participants with TSH < 0.10 mIU/L showed an increased bone loss in the femoral neck (%Δ BMD = −0.59; [95% CI: −0.99, −0.19]) and total hip region (%ΔBMD = −0.46 [95% CI: −1.05, −0.13]). In contrast, SHypo was not associated with bone loss at any site. Conclusion: Amongst adults, SHyper was associated with increased femoral neck bone loss, potentially contributing to the increased fracture risk.

Published
2018
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14. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Author

Teumer, A. (Alexander), Chaker, L. (Layal), Groeneweg, S. (Stefan), Li, Y. (Yong), Di Munno, C. (Celia), Barbieri, C. (Caterina), Schultheiss, U.T. (Ulla T.), Traglia, M. (Michela), Ahluwalia, T.S. (Tarunveer Singh), Akiyama, M. (Masato), Appel, E.V.R. (Emil Vincent R.), Arking, D.E. (Dan), Arnold, A.M. (Alice), Astrup, A. (Arne), Beekman, M. (Marian), Beilby, J.P. (John), Bekaert, S. (Sofie), Boerwinkle, E. (Eric), Brown, S.J. (Stephen), Buyzere, M. (Marc) de, Campbell, P.J. (Purdey J.), Ceresini, G. (Graziano), Cerqueira, C. (Charlotte), Cucca, F. (Francesco), Deary, I.J. (Ian), Deelen, J. (Joris), Eckardt, K.-U. (Kai-Uwe), Ekici, A.B. (Arif B.), Hagen, K. (Knut), Ferrrucci, L. (Luigi), Fiers, T. (Tom), Fiorillo, E. (Edoardo), Ford, I. (Ian), Fox, C.S. (Caroline), Fuchsberger, C. (Christian), Galesloot, T.E. (Tessel), Gieger, C. (Christian), Gögele, M. (Martin), Grandi, A. (Alessandro) de, Grarup, N. (Niels), Greiser, K.H. (Karin Halina), Haljas, K. (Kadri), Hansen, T. (Torben), Harris, S.E. (Sarah), Heemst, D. (Diana) van, Heijer, M. (Martin) den, Hicks, A.A. (Andrew A.), Hollander, W. (Wouter) den, Homuth, G. (Georg), Hui, J. (Jennie), Ikram, M.A. (Arfan), Ittermann, T. (Till), Jensen, R.A. (Richard A.), Jing, J. (Jiaojiao), Jukema, J.W. (Jan Wouter), Kajantie, E. (Eero), Kamatani, Y. (Yoichiro), Kasbohm, E. (Elisa), Kaufman, J.-M. (Jean-Marc), Kiemeney, L.A. (Lambertus A.), Kloppenburg, M. (Margreet), Kronenberg, F. (Florian), Kubo, M. (Michiaki), Lahti, J. (Jari), Lapauw, B. (Bruno), Li, S. (Shuo), Liewald, D.C.M. (David C. M.), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (Marike), Franke, L. (Lude), van der Harst, P. (Pim), Navis, G. (Gerjan), Rots, M.G. (M.), Snieder, H. (Harold), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Lim, E.M. (Ee Mun), Linneberg, A. (Allan), Marina, M. (Michela), Mascalzoni, D. (Deborah), Matsuda, K. (Koichi), Medenwald, D. (Daniel), Meisinger, C. (Christa), Meulenbelt, I. (Ingrid), Meyer, T. (Thorsten), Meyer zu Schwabedissen, H.E. (Henriette E.), Mikolajczyk, R. (Rafael), Moed, H. (Heleen), Netea-Maier, R.T. (Romana), Nolte, I.M. (Ilja), Okada, Y. (Yukinori), Pala, M. (Mauro), Penninx, B.W.J.H., Pedersen, O. (Oluf), Petersmann, A. (Astrid), Porcu, E. (Eleonora), Postmus, D. (Douwe), Pramstaller, P.P. (Peter Paul), Psaty, B.M. (Bruce), Ramos, Y.F.M. (Yolande F. M.), Rawal, R. (Rajesh), Redmond, P. (Paul), Richards, J.B. (Brent), Rietzschel, E.R. (Ernst), Rivadeneira Ramirez, F. (Fernando), Roef, G.L. (Greet), Rotter, J.I. (Jerome I.), Sala, C. (Cinzia), Schlessinger, D. (David), Selvin, E. (Elizabeth), Slagboom, P.E. (Eline), Soranzo, N. (Nicole), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Starr, J.M. (John), Stott, D.J. (David. J.), Taes, Y.E. (Youri), Taliun, D. (Daniel), Tanaka, T. (Toshiko), Thuesen, L. (Leif), Tiller, D. (Daniel), Toniolo, D. (Daniela), Uitterlinden, A.G. (Andre G.), Visser, W.E. (Edward), Walsh, J.P. (John P.), Wilson, S.G. (Scott), Wolffenbuttel, B.H.R. (Bruce), Yang, Q. (Qiong Fang), Zheng, H.-F. (Hou-Feng), Cappola, A.R. (Anne), Peeters, R.P. (Robin), Naitza, S. (Silvia), Völzke, H. (Henry), Sanna, S. (Serena), Köttgen, A. (Anna), Visser, T.J. (Theo), Medici, M. (Marco), Teumer, A. (Alexander), Chaker, L. (Layal), Groeneweg, S. (Stefan), Li, Y. (Yong), Di Munno, C. (Celia), Barbieri, C. (Caterina), Schultheiss, U.T. (Ulla T.), Traglia, M. (Michela), Ahluwalia, T.S. (Tarunveer Singh), Akiyama, M. (Masato), Appel, E.V.R. (Emil Vincent R.), Arking, D.E. (Dan), Arnold, A.M. (Alice), Astrup, A. (Arne), Beekman, M. (Marian), Beilby, J.P. (John), Bekaert, S. (Sofie), Boerwinkle, E. (Eric), Brown, S.J. (Stephen), Buyzere, M. (Marc) de, Campbell, P.J. (Purdey J.), Ceresini, G. (Graziano), Cerqueira, C. (Charlotte), Cucca, F. (Francesco), Deary, I.J. (Ian), Deelen, J. (Joris), Eckardt, K.-U. (Kai-Uwe), Ekici, A.B. (Arif B.), Hagen, K. (Knut), Ferrrucci, L. (Luigi), Fiers, T. (Tom), Fiorillo, E. (Edoardo), Ford, I. (Ian), Fox, C.S. (Caroline), Fuchsberger, C. (Christian), Galesloot, T.E. (Tessel), Gieger, C. (Christian), Gögele, M. (Martin), Grandi, A. (Alessandro) de, Grarup, N. (Niels), Greiser, K.H. (Karin Halina), Haljas, K. (Kadri), Hansen, T. (Torben), Harris, S.E. (Sarah), Heemst, D. (Diana) van, Heijer, M. (Martin) den, Hicks, A.A. (Andrew A.), Hollander, W. (Wouter) den, Homuth, G. (Georg), Hui, J. (Jennie), Ikram, M.A. (Arfan), Ittermann, T. (Till), Jensen, R.A. (Richard A.), Jing, J. (Jiaojiao), Jukema, J.W. (Jan Wouter), Kajantie, E. (Eero), Kamatani, Y. (Yoichiro), Kasbohm, E. (Elisa), Kaufman, J.-M. (Jean-Marc), Kiemeney, L.A. (Lambertus A.), Kloppenburg, M. (Margreet), Kronenberg, F. (Florian), Kubo, M. (Michiaki), Lahti, J. (Jari), Lapauw, B. (Bruno), Li, S. (Shuo), Liewald, D.C.M. (David C. M.), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (Marike), Franke, L. (Lude), van der Harst, P. (Pim), Navis, G. (Gerjan), Rots, M.G. (M.), Snieder, H. (Harold), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Lim, E.M. (Ee Mun), Linneberg, A. (Allan), Marina, M. (Michela), Mascalzoni, D. (Deborah), Matsuda, K. (Koichi), Medenwald, D. (Daniel), Meisinger, C. (Christa), Meulenbelt, I. (Ingrid), Meyer, T. (Thorsten), Meyer zu Schwabedissen, H.E. (Henriette E.), Mikolajczyk, R. (Rafael), Moed, H. (Heleen), Netea-Maier, R.T. (Romana), Nolte, I.M. (Ilja), Okada, Y. (Yukinori), Pala, M. (Mauro), Penninx, B.W.J.H., Pedersen, O. (Oluf), Petersmann, A. (Astrid), Porcu, E. (Eleonora), Postmus, D. (Douwe), Pramstaller, P.P. (Peter Paul), Psaty, B.M. (Bruce), Ramos, Y.F.M. (Yolande F. M.), Rawal, R. (Rajesh), Redmond, P. (Paul), Richards, J.B. (Brent), Rietzschel, E.R. (Ernst), Rivadeneira Ramirez, F. (Fernando), Roef, G.L. (Greet), Rotter, J.I. (Jerome I.), Sala, C. (Cinzia), Schlessinger, D. (David), Selvin, E. (Elizabeth), Slagboom, P.E. (Eline), Soranzo, N. (Nicole), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Starr, J.M. (John), Stott, D.J. (David. J.), Taes, Y.E. (Youri), Taliun, D. (Daniel), Tanaka, T. (Toshiko), Thuesen, L. (Leif), Tiller, D. (Daniel), Toniolo, D. (Daniela), Uitterlinden, A.G. (Andre G.), Visser, W.E. (Edward), Walsh, J.P. (John P.), Wilson, S.G. (Scott), Wolffenbuttel, B.H.R. (Bruce), Yang, Q. (Qiong Fang), Zheng, H.-F. (Hou-Feng), Cappola, A.R. (Anne), Peeters, R.P. (Robin), Naitza, S. (Silvia), Völzke, H. (Henry), Sanna, S. (Serena), Köttgen, A. (Anna), Visser, T.J. (Theo), and Medici, M. (Marco)

Abstract

Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.

Published
2018
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15. Subclinical thyroid dysfunction and depressive symptoms: protocol for a systematic review and individual participant data meta-analysis of prospective cohort studies

Author

Wildisen, L., Moutzouri, E., Beglinger, S., Syrogiannouli, L., Cappola, A.R., Asvold, B.O., Bakker, S.J.L., Ceresini, G., Dullaart, R., Ferrucci, L., Grabe, H., Jukema, J.W., Nauck, M., Trompet, S., Volzke, H., Westendorp, R.G.J., Gussekloo, J., Peeters, R.P., Kloppel, S., Aujesky, D., Bauer, D.C., Rodondi, N., Giovane, C. del, Feller, M., Thyroid Studies Collaboration, Erasmus MC other, and Internal Medicine

Subjects
Epidemiology, Thyrotropin, Thyroid Function Tests, 030204 cardiovascular system & hematology, Logistic regression, Cohort Studies, depressive symptoms, 0302 clinical medicine, systematic review, Protocol, Medicine, 030212 general & internal medicine, 610 Medicine & health, Prospective cohort study, Depression (differential diagnoses), Subclinical infection, RISK, Depression, General Medicine, individual participant data (IPD) meta-analysis, subclinical hypothyroidism, Mental Health, Research Design, Meta-analysis, Cohort, Public Health and Health Services, subclinical hyperthyroidism, 360 Social problems & social services, Clinical psychology, Thyroid Hormones, Clinical Sciences, CINAHL, 03 medical and health sciences, Meta-Analysis as Topic, Behavioral and Social Science, Humans, Psychiatric Status Rating Scales, Other Medical and Health Sciences, subclinical thyroid dysfunction, business.industry, Prevention, Thyroid Studies Collaboration, Beck Depression Inventory, Thyroid Diseases, HYPOTHYROIDISM, business, Systematic Reviews as Topic
Abstract

IntroductionProspective cohort studies on the association between subclinical thyroid dysfunction and depressive symptoms have yielded conflicting findings, possibly because of differences in age, sex, thyroid-stimulating hormone cut-off levels or degree of baseline depressive symptoms. Analysis of individual participant data (IPD) may help clarify this association.Methods and analysis: We will conduct a systematic review and IPD meta-analysis of prospective studies on the association between subclinical thyroid dysfunction and depressive symptoms. We will identify studies through a systematic search of the literature in the Ovid Medline, Ovid Embase, Cochrane Central Register of Controlled Trials (CENTRAL) and Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases from inception to April 2019 and from the Thyroid Studies Collaboration. We will ask corresponding authors of studies that meet our inclusion criteria to collaborate by providing IPD. Our primary outcome will be depressive symptoms at the first available individual follow-up, measured on a validated scale. We will convert all the scores to the Beck Depression Inventory scale. For each cohort, we will estimate the mean difference of depressive symptoms between participants with subclinical hypothyroidism or hyperthyroidism and control adjusted for depressive symptoms at baseline. Furthermore, we will adjust our multivariable linear regression analyses for age, sex, education and income. We will pool the effect estimates of all studies in a random-effects meta-analysis. Heterogeneity will be assessed by I2. Our secondary outcomes will be depressive symptoms at a specific follow-up time, at the last available individual follow-up and incidence of depression at the first, last and at a specific follow-up time. For the binary outcome of incident depression, we will use a logistic regression model.Ethics and disseminationFormal ethical approval is not required as primary data will not be collected. Our findings will have considerable implications for patient care. We will seek to publish this systematic review and IPD meta-analysis in a high-impact clinical journal This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/

Published
2019
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16. Thyroid function tests in the reference range and fracture: Individual participant analysis of prospective cohorts

Author

Aubert, C.E. (Carole E.), Floriani, C. (Carmen), Bauer, D.C. (Douglas), B.R. da Costa (Bruno), Segna, D. (Daniel), Blum, M.R. (Manuel), Collet, T.-H. (Tinh-Hai), Fink, H.A. (Howard A.), Cappola, A.R. (Anne), Syrogiannouli, L. (Lamprini), Peeters, R.P. (Robin), Asvold, B.O. (Bjorn O.), Elzen, W.P.J. (Wendy) den, Luben, R.N. (Robert), Bremner, A. (Alexandra), Gogakos, A. (Apostolos), Eastell, R. (Richard), Kearney, P.M. (Patricia M.), Hoff, M. (Mari), Le Blanc, E. (Erin), Ceresini, G. (Graziano), Rivadeneira, F. (Fernando), Uitterlinden, A.G. (André), Khaw, K.T., Langhammer, A. (Arnulf), Stott, D.J. (David. J.), Westendorp, R.G.J. (Rudi), Ferrucci, L. (Luigi), Williams, G. (Graham), Gussekloo, J. (Jacobijn), Walsh, J.P. (John), Aujesky, D. (Drahomir), Rodondi, N. (Nicolas), Aubert, C.E. (Carole E.), Floriani, C. (Carmen), Bauer, D.C. (Douglas), B.R. da Costa (Bruno), Segna, D. (Daniel), Blum, M.R. (Manuel), Collet, T.-H. (Tinh-Hai), Fink, H.A. (Howard A.), Cappola, A.R. (Anne), Syrogiannouli, L. (Lamprini), Peeters, R.P. (Robin), Asvold, B.O. (Bjorn O.), Elzen, W.P.J. (Wendy) den, Luben, R.N. (Robert), Bremner, A. (Alexandra), Gogakos, A. (Apostolos), Eastell, R. (Richard), Kearney, P.M. (Patricia M.), Hoff, M. (Mari), Le Blanc, E. (Erin), Ceresini, G. (Graziano), Rivadeneira, F. (Fernando), Uitterlinden, A.G. (André), Khaw, K.T., Langhammer, A. (Arnulf), Stott, D.J. (David. J.), Westendorp, R.G.J. (Rudi), Ferrucci, L. (Luigi), Williams, G. (Graham), Gussekloo, J. (Jacobijn), Walsh, J.P. (John), Aujesky, D. (Drahomir), and Rodondi, N. (Nicolas)

Abstract

Context: Hyperthyroidism is associated with increased fracture risk, but it is not clear if lower thyroid-stimulating hormone (TSH) and higher free thyroxine (FT4) in euthyroid individuals are associated with fracture risk. Objective: To evaluate the association of TSH and FT4 with incident fractures in euthyroid individuals. Design: Individual participant data analysis. Setting: Thirteen prospective cohort studies with baseline examinations between 1981 and 2002. Participants: Adults with baseline TSH 0.45 to 4.49 mIU/L. Main Outcome Measures: Primary outcome was incident hip fracture. Secondary outcomes were any, nonvertebral, and vertebral fractures. Results were presented as hazard ratios (HRs) with 95% confidence interval (CI) adjusted for age and sex. For clinical relevance, we studied TSH according to five categories: 0.45 to 0.99 mIU/L; 1.00 to 1.49 mIU/L; 1.50 to 2.49 mIU/L; 2.50 to 3.49 mIU/L; and 3.50 to 4.49 mIU/L (reference). FT4 was assessed as study-specific standard deviation increase, because assays varied between cohorts. Results: During 659,059 person-years, 2,565 out of 56,835 participants had hip fracture (4.5%; 12 studies with data on hip fracture). The pooled adjusted HR (95% CI) for hip fracture was 1.25 (1.05 to 1.49) for TSH 0.45 to 0.99 mIU/L, 1.19 (1.01 to 1.41) for TSH 1.00 to 1.49 mIU/L, 1.09 (0.93 to 1.28) for TSH 1.50 to 2.49 mIU/L, and 1.12 (0.94 to 1.33) for TSH 2.50 to 3.49 mIU/L (P for trend = 0.004). Hip fracture was also associated with FT4 [HR (95% CI) 1.22 (1.11 to 1.35) per one standard deviation increase in FT4]. FT4 only was associated with any and nonvertebral fractures. Results remained similar in sensitivity analyses. Conclusions: Among euthyroid adults, lower TSH and higher FT4 are associated with an increased risk of hip fracture. These findings may help refine the definition of optimal ranges of thyroid function tests.

Published
2017
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17. Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

Author

Teumer, A. (Alexander), Qi, Q., Nethander, M. (Maria), Aschard, H. (Hugues), Bandinelli, S. (Stefania), Beekman, M. (Marian), Berndt, S.I. (Sonja), Bidlingmaier, M. (Martin), Broer, L. (Linda), Cappola, A.R. (Anne), Ceda, G.P. (Gian Paolo), Chanock, S.J. (Stephen), Chen, M.-H. (Ming-Huei), Chen, T.C. (Tai C.), Chen, Y.D. (Y.), Chung, J. (Jonathan), Del Greco Miglianico, F. (Fabiola), Eriksson, J. (Joel), Ferrucci, L. (Luigi), Friedrich, N. (Nele), Gnewuch, C. (Carsten), Goodarzi, M. (Mark), Grarup, N. (Niels), Guo, T. (Tingwei), Hammer, E. (Elke), Hayes, R.B. (Richard), Hicks, A.A. (Andrew), Hofman, A. (Albert), Houwing-Duistermaat, J.J. (Jeanine), Hu, F. (Frank), Hunter, D. (David), Husemoen, L.L.N. (Lise Lotte), Isaacs, A.J. (Aaron), Jacobs, K.B. (Kevin), Janssen, J.A.M.J.L. (Joop), Jansson, J.-O. (John-Olov), Jehmlich, N. (Nico), Johnson, S. (Simon), Juul, A. (Anders), Karlsson, M. (Magnus), Kilpeläinen, T.O. (Tuomas), Kovacs, P. (Peter), Kraft, P. (Peter), Li, C. (Chao), Linneberg, A. (Allan), Liu, Y. (YongMei), Loos, R.J.F. (Ruth), Lorentzon, M. (Mattias), Lu, Y. (Yingchang), Maggio, M. (Marcello), Mägi, R. (Reedik), Meigs, J.B. (James), Mellström, D. (Dan), Nauck, M. (Matthias), Newman, A.B. (Anne B.), Pollak, M.N. (Michael), Pramstaller, P.P. (Peter Paul), Prokopenko, I. (Inga), Psaty, B.M. (Bruce), Reincke, M. (Martin), Rimm, E.B. (Eric B.), Rotter, J.I. (Jerome I.), Saint Pierre, A. (Aude), Schurmann, C. (Claudia), Seshadri, S. (Sudha), Sjögren, K. (Klara), Slagboom, P.E. (Eline), Strickler, H.D. (Howard D.), Stumvoll, M. (Michael), Suh, Y. (Yousin), Sun, Q. (Qi), Zhang, C. (Cuilin), Svensson, J. (Johan), Tanaka, T. (Toshiko), Tare, A. (Archana), Tönjes, A. (Anke), Uh, H.-W. (Hae-Won), Duijn, C.M. (Cornelia) van, Heemst, D. (Diana) van, Vandenput, L. (Liesbeth), Vasan, R.S. (Ramachandran Srini), Völker, U. (Uwe), Willems, S.M. (Sara), Ohlsson, C. (Claes), Wallaschofski, H. (Henri), Kaplan, R.C. (Robert), Teumer, A. (Alexander), Qi, Q., Nethander, M. (Maria), Aschard, H. (Hugues), Bandinelli, S. (Stefania), Beekman, M. (Marian), Berndt, S.I. (Sonja), Bidlingmaier, M. (Martin), Broer, L. (Linda), Cappola, A.R. (Anne), Ceda, G.P. (Gian Paolo), Chanock, S.J. (Stephen), Chen, M.-H. (Ming-Huei), Chen, T.C. (Tai C.), Chen, Y.D. (Y.), Chung, J. (Jonathan), Del Greco Miglianico, F. (Fabiola), Eriksson, J. (Joel), Ferrucci, L. (Luigi), Friedrich, N. (Nele), Gnewuch, C. (Carsten), Goodarzi, M. (Mark), Grarup, N. (Niels), Guo, T. (Tingwei), Hammer, E. (Elke), Hayes, R.B. (Richard), Hicks, A.A. (Andrew), Hofman, A. (Albert), Houwing-Duistermaat, J.J. (Jeanine), Hu, F. (Frank), Hunter, D. (David), Husemoen, L.L.N. (Lise Lotte), Isaacs, A.J. (Aaron), Jacobs, K.B. (Kevin), Janssen, J.A.M.J.L. (Joop), Jansson, J.-O. (John-Olov), Jehmlich, N. (Nico), Johnson, S. (Simon), Juul, A. (Anders), Karlsson, M. (Magnus), Kilpeläinen, T.O. (Tuomas), Kovacs, P. (Peter), Kraft, P. (Peter), Li, C. (Chao), Linneberg, A. (Allan), Liu, Y. (YongMei), Loos, R.J.F. (Ruth), Lorentzon, M. (Mattias), Lu, Y. (Yingchang), Maggio, M. (Marcello), Mägi, R. (Reedik), Meigs, J.B. (James), Mellström, D. (Dan), Nauck, M. (Matthias), Newman, A.B. (Anne B.), Pollak, M.N. (Michael), Pramstaller, P.P. (Peter Paul), Prokopenko, I. (Inga), Psaty, B.M. (Bruce), Reincke, M. (Martin), Rimm, E.B. (Eric B.), Rotter, J.I. (Jerome I.), Saint Pierre, A. (Aude), Schurmann, C. (Claudia), Seshadri, S. (Sudha), Sjögren, K. (Klara), Slagboom, P.E. (Eline), Strickler, H.D. (Howard D.), Stumvoll, M. (Michael), Suh, Y. (Yousin), Sun, Q. (Qi), Zhang, C. (Cuilin), Svensson, J. (Johan), Tanaka, T. (Toshiko), Tare, A. (Archana), Tönjes, A. (Anke), Uh, H.-W. (Hae-Won), Duijn, C.M. (Cornelia) van, Heemst, D. (Diana) van, Vandenput, L. (Liesbeth), Vasan, R.S. (Ramachandran Srini), Völker, U. (Uwe), Willems, S.M. (Sara), Ohlsson, C. (Claes), Wallaschofski, H. (Henri), and Kaplan, R.C. (Robert)

Abstract

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Through

Published
2016
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18. SUBCLINICAL THYROID DYSFUNCTION AND FRACTURE RISK: AN INDIVIDUAL PARTICIPANT DATA ANALYSIS OF PROSPECTIVE COHORTS

Author

Blum, M.R., Bauer, D., Costa, B.R. da, Wirth, C.D., Cappola, A.R., Peeters, R.P., Asvold, B.O., Fink, H.A., Elzen, W.P. den, Luben, R.N., Imaizumi, M., Langhammer, A., Bremner, A.P., Gogakos, A., Eastell, R., Strotmeyer, E.S., Wallace, E., Hoff, M., Khaw, K.T., Ceresini, G., Rivadeneira, F., Ferrucci, L., Uitterlinden, A., Williams, G.R., Westendorp, R.G., Walsh, J.P., Gussekloo, J., Aujesky, D., and Rodondi, N.

Published
2014

19. Subclinical thyroid dysfunction and fracture risk a meta-analysis

Author

Blum, M.R. (Manuel), Bauer, D.C. (Douglas C.), Collet, T.-H. (Tinh-Hai), Fink, H.A. (Howard A.), Cappola, A.R. (Anne), B.R. da Costa (Bruno), Wirth, C.D. (Christina), Peeters, R.P. (Robin), Asvold, B.O. (Bjorn O.), Elzen, W.P.J. (Wendy) den, Luben, R.N. (Robert), Imaizumi, M. (Misa), Bremner, A.P. (Alexandra P.), Gogakos, A. (Apostolos), Eastell, R. (Richard), Kearney, P.M. (Patricia M.), Strotmeyer, E.S. (Elsa S.), Wallace, E.R. (Erin R.), Hoff, M. (Mari), Ceresini, G. (Graziano), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Stott, D.J. (David. J.), Westendorp, R.G.J. (Rudi), Khaw, K.T., Langhammer, A. (Arnuf), Ferrucci, L. (Luigi), Gussekloo, J. (Jacobijn), Williams, G. (Graham), Walsh, J.P. (John), Jüni, P. (Peter), Aujesky, D. (Drahomir), Rodondi, N. (Nicolas), Blum, M.R. (Manuel), Bauer, D.C. (Douglas C.), Collet, T.-H. (Tinh-Hai), Fink, H.A. (Howard A.), Cappola, A.R. (Anne), B.R. da Costa (Bruno), Wirth, C.D. (Christina), Peeters, R.P. (Robin), Asvold, B.O. (Bjorn O.), Elzen, W.P.J. (Wendy) den, Luben, R.N. (Robert), Imaizumi, M. (Misa), Bremner, A.P. (Alexandra P.), Gogakos, A. (Apostolos), Eastell, R. (Richard), Kearney, P.M. (Patricia M.), Strotmeyer, E.S. (Elsa S.), Wallace, E.R. (Erin R.), Hoff, M. (Mari), Ceresini, G. (Graziano), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Stott, D.J. (David. J.), Westendorp, R.G.J. (Rudi), Khaw, K.T., Langhammer, A. (Arnuf), Ferrucci, L. (Luigi), Gussekloo, J. (Jacobijn), Williams, G. (Graham), Walsh, J.P. (John), Jüni, P. (Peter), Aujesky, D. (Drahomir), and Rodondi, N. (Nicolas)

Abstract

IMPORTANCE Associations between subclinical thyroid dysfunction and fractures are unclear and clinical trials are lacking. OBJECTIVE To assess the association of subclinical thyroid dysfunction with hip, nonspine, spine, or any fractures. DATA SOURCES AND STUDY SELECTION The databases of MEDLINE and EMBASE (inception to March 26, 2015) were searched without language restrictions for prospective cohort studies with thyroid function data and subsequent fractures. DATA EXTRACTION Individual participant datawere obtained from 13 prospective cohorts in the United States, Europe, Australia, and Japan. Levels of thyroid functionwere defined as euthyroidism (thyroid-stimulating hormone [TSH], 0.45-4.49 mIU/L), subclinical hyperthyroidism (TSH <0.45 mIU/L), and subclinical hypothyroidism (TSH≥4.50-19.99 mIU/L) with normal thyroxine concentrations. MAIN OUTCOME AND MEASURES The primary outcomewas hip fracture. Any fractures, nonspine fractures, and clinical spine fractures were secondary outcomes. RESULTS Among 70 298 participants, 4092 (5.8%) had subclinical hypothyroidism and 2219 (3.2%) had subclinical hyperthyroidism. During 762 401 person-years of follow-up, hip fracture occurred in 2975 participants (4.6%; 12 studies), any fracture in 2528 participants (9.0%; 8 studies), nonspine fracture in 2018 participants (8.4%; 8 studies), and spine fracture in 296 participants (1.3%; 6 studies). In age-and sex-adjusted analyses, the hazard ratio (HR) for subclinical hyperthyroidism vs euthyroidismwas 1.36 for hip fracture (95%CI, 1.13-1.64; 146 events in 2082 participants vs 2534 in 56 471); for any fracture, HRwas 1.28 (95%CI, 1.06-1.53; 121 events in 888 participants vs 2203 in 25 901); for nonspine fracture, HRwas 1.16 (95%CI, 0.95-1.41; 107 events in 946 participants vs 1745 in 21 722); and for spine fracture, HRwas 1.51 (95%CI, 0.93-2.45; 17 events in 732 participants vs 255 in 20 328). Lower TSHwas associated with higher fracture rates: for TSH of less than0.10 mIU/L, HRwas

Published
2015
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20. Thyroid function within the normal range and risk of coronary heart disease an individual participant data analysis of 14 cohorts

Author

Asvold, B.O. (Bjorn O.), Vatten, L. (Lars), Bjøro, T. (Trine), Bauer, D.C. (Douglas), Bremner, A.P. (Alexandra P.), Cappola, A.R. (Anne), Ceresini, G. (Graziano), Elzen, W.P.J. (Wendy) den, Ferrucci, L. (Luigi), Franco, O.H. (Oscar), Franklyn, J.A. (Jayne), Gussekloo, J. (Jacobijn), Iervasi, G. (Giorgio), Imaizumi, M. (Misa), Kearney, P.M. (Patricia M.), Khaw, K.T., Maciel, R.M.B. (Rui M. B.), Newman, A.B. (Anne B.), Peeters, R.P. (Robin), Psaty, B.M. (Bruce), Razvi, S. (Salman), Sgarbi, J.A. (José A.), Stott, D.J. (David. J.), Trompet, S. (Stella), Vanderpump, M.P.J. (Mark P. J.), Völzke, H. (Henry), Walsh, J.P. (John), Westendorp, R.G.J. (Rudi), Rodondi, N. (Nicolas), Asvold, B.O. (Bjorn O.), Vatten, L. (Lars), Bjøro, T. (Trine), Bauer, D.C. (Douglas), Bremner, A.P. (Alexandra P.), Cappola, A.R. (Anne), Ceresini, G. (Graziano), Elzen, W.P.J. (Wendy) den, Ferrucci, L. (Luigi), Franco, O.H. (Oscar), Franklyn, J.A. (Jayne), Gussekloo, J. (Jacobijn), Iervasi, G. (Giorgio), Imaizumi, M. (Misa), Kearney, P.M. (Patricia M.), Khaw, K.T., Maciel, R.M.B. (Rui M. B.), Newman, A.B. (Anne B.), Peeters, R.P. (Robin), Psaty, B.M. (Bruce), Razvi, S. (Salman), Sgarbi, J.A. (José A.), Stott, D.J. (David. J.), Trompet, S. (Stella), Vanderpump, M.P.J. (Mark P. J.), Völzke, H. (Henry), Walsh, J.P. (John), Westendorp, R.G.J. (Rudi), and Rodondi, N. (Nicolas)

Abstract

IMPORTANCE Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD). OBJECTIVE To assess the association between differences in thyroid function within the reference range and CHD risk. DESIGN, SETTING, AND P

Published
2015
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21. Subclinical hypothyroidism and the risk of stroke events and fatal stroke: An individual participant data analysis

Author

Chaker, L. (Layal), Baumgartner, C. (Christine), Elzen, W.P.J. (Wendy) den, Ikram, M.A. (Arfan), Blum, M.R. (Manuel), Collet, T.-H. (Tinh-Hai), Bakker, S.J.L. (Stephan), Dehghan, A. (Abbas), Drechsler, C. (Christiane), Luben, R.N. (Robert), Hofman, A. (Albert), Portegies, M.L.P. (Marileen), Medici, M. (Marco), Iervasi, G. (Giorgio), Stott, D.J. (David. J.), Ford, I. (Ian), Bremner, A.P. (Alexandra P.), Wanner, C. (Christoph), Ferrucci, L. (Luigi), Newman, A.B. (Anne B.), Dullaart, R.P.F. (Robin), Sgarbi, J.A. (José A.), Ceresini, G. (Graziano), Maciel, R.M.B. (Rui M. B.), Westendorp, R.G.J. (Rudi), Jukema, J.W. (Jan Wouter), Imaizumi, M. (Misa), Franklyn, J.A. (Jayne), Bauer, D.C. (Douglas C.), Walsh, J.P. (John), Razvi, S. (Salman), Khaw, K.T., Cappola, A.R. (Anne), Völzke, H. (Henry), Franco, O.H. (Oscar), Gussekloo, J. (Jacobijn), Rodondi, N. (Nicolas), Peeters, R.P. (Robin), Chaker, L. (Layal), Baumgartner, C. (Christine), Elzen, W.P.J. (Wendy) den, Ikram, M.A. (Arfan), Blum, M.R. (Manuel), Collet, T.-H. (Tinh-Hai), Bakker, S.J.L. (Stephan), Dehghan, A. (Abbas), Drechsler, C. (Christiane), Luben, R.N. (Robert), Hofman, A. (Albert), Portegies, M.L.P. (Marileen), Medici, M. (Marco), Iervasi, G. (Giorgio), Stott, D.J. (David. J.), Ford, I. (Ian), Bremner, A.P. (Alexandra P.), Wanner, C. (Christoph), Ferrucci, L. (Luigi), Newman, A.B. (Anne B.), Dullaart, R.P.F. (Robin), Sgarbi, J.A. (José A.), Ceresini, G. (Graziano), Maciel, R.M.B. (Rui M. B.), Westendorp, R.G.J. (Rudi), Jukema, J.W. (Jan Wouter), Imaizumi, M. (Misa), Franklyn, J.A. (Jayne), Bauer, D.C. (Douglas C.), Walsh, J.P. (John), Razvi, S. (Salman), Khaw, K.T., Cappola, A.R. (Anne), Völzke, H. (Henry), Franco, O.H. (Oscar), Gussekloo, J. (Jacobijn), Rodondi, N. (Nicolas), and Peeters, R.P. (Robin)

Abstract

Copyright

Published
2015
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22. A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function

Author

McCarthy, M.I., Porcu, E., Medici, M., Pistis, G., Volpato, C.B., Wilson, S.G., Cappola, A.R., Bos, S.D., Deelen, J., den Heijer, M., Freathy, R.M., Lahti, J., Liu, C., Lopez, L.M., Nolte, I.M., O'Connell, J.R., Tanaka, T., Trompet, S., Arnold, A., Bandinelli, S., Beekman, M., Böhringer, S., Brown, S.J., Buckley, B.M., Camaschella, C., de Craen, A.J.M., Davies, G., de Visser, M.C.H., Ford, I., Forsen, T., Frayling, T.M., Fugazzola, L., Gögele, M., Hattersley, A.T., Hermus, A.R., Hofman, A., Houwing-Duistermaat, J.J., Jensen, R.A., Kajantie, E., Kloppenburg, M., Lim, E.M., Masciullo, C., Mariotti, S., Minelli, C., Mitchell, B.D., Nagaraja, R., Netea-Maier, R.T., Palotie, A., Persani, L., Piras, M.G., Psaty, B.M., Räikkönen, K., Richards, J.B., Rivadeneira, F., Sala, C., Sabra, M.M., Sattar, N., Shields, B.M., Soranzo, N., Starr, J.M., Stott, D.J., Sweep, F.C.G.J., Usala, G., van der Klauw, M.M., van Heemst, D., van Mullem, A., H.Vermeulen, S., Visser, W.E., Walsh, J.P., Westendorp, R.G.J., Widen, E., Zhai, G., Cucca, F., Deary, I.J., Eriksson, J.G., Ferrucci, L., Fox, C.S., Jukema, J.W., Kiemeney, L.A., Pramstaller, P.P., Schlessinger, D., Shuldiner, A.R., Slagboom, E.P., Uitterlinden, A.G., Vaidya, B., Visser, T.J., Wolffenbuttel, B.H.R., Meulenbelt, I., Rotter, J.I., Spector, T.D., Hicks, A.A., Toniolo, D., Sanna, S., Peeters, R.P., Naitza, S., Internal Medicine, Clinical Genetics, Public Health, Epidemiology, Internal medicine, ICaR - Circulation and metabolism, Behavioural Sciences, Clinicum, Department of General Practice and Primary Health Care, Children's Hospital, Lastentautien yksikkö, Institute for Molecular Medicine Finland, Haartman Institute (-2014), Department of Medical and Clinical Genetics, Diabetes and Obesity Research Program, Developmental Psychology Research Group, Genomics of Neurological and Neuropsychiatric Disorders, Genomic Discoveries and Clinical Translation, Life Course Epidemiology (LCE), Lifestyle Medicine (LM), Center for Liver, Digestive and Metabolic Diseases (CLDM), Porcu, E, Medici, M, Pistis, G, Volpato, Cb, Wilson, Sg, Cappola, Ar, Bos, Sd, Deelen, J, DEN HEIJER, M, Freathy, Rm, Lahti, J, Liu, C, Lopez, Lm, Nolte, Im, O'Connell, Jr, Tanaka, T, Trompet, S, Arnold, A, Bandinelli, S, Beekman, M, Böhringer, S, Brown, Sj, Buckley, Bm, Camaschella, Clara, DE CRAEN, Aj, Davies, G, DE VISSER, Mc, Ford, I, Forsen, T, Frayling, Tm, Fugazzola, L, Gögele, M, Hattersley, At, Hermus, Ar, Hofman, A, HOUWING DUISTERMAAT, Jj, Jensen, Ra, Kajantie, E, Kloppenburg, M, Lim, Em, Masciullo, C, Mariotti, S, Minelli, C, Mitchell, Bd, Nagaraja, R, NETEA MAIER, Rt, Palotie, A, Persani, L, Piras, Mg, Psaty, Bm, Räikkönen, K, Richards, Jb, Rivadeneira, F, Sala, C, Sabra, Mm, Sattar, N, Shields, Bm, Soranzo, N, Starr, Jm, Stott, Dj, Sweep, Fc, Usala, G, VAN DER KLAUW, Mm, VAN HEEMST, D, VAN MULLEM, A, Vermeulen, Sh, Visser, We, Walsh, Jp, Westendorp, Rg, Widen, E, Zhai, G, Cucca, F, Deary, Ij, Eriksson, Jg, Ferrucci, L, Fox, C, Jukema, Jw, Kiemeney, La, Pramstaller, Pp, Schlessinger, D, Shuldiner, Ar, Slagboom, Ep, Uitterlinden, Ag, Vaidya, B, Visser, Tj, Wolffenbuttel, Bh, Meulenbelt, I, Rotter, Ji, Spector, Td, Hicks, Aa, Toniolo, D, Sanna, S, Peeters, Rp, and Naitza, S.

Subjects
Male, Cancer Research, endocrine system diseases, Factor binding protein 5, Thyroid Gland, FACTOR BINDING PROTEIN-5, Thyrotropin, Genome-wide association study, Expression, Aetiology, screening and detection [ONCOL 5], Growth, Hyperthyroidism, CLEFT-PALATE, Serum TSH, 0302 clinical medicine, Euthyroid, Genetics (clinical), 0303 health sciences, Sex Characteristics, factor binding protein-S, Thyroid, 3. Good health, medicine.anatomical_structure, Phenotype, NFIA, Cleft palate, GROWTH, Genome wide Association, Female, Thyroid function, hormones, hormone substitutes, and hormone antagonists, Research Article, Signal Transduction, EXPRESSION, medicine.medical_specialty, endocrine system, lcsh:QH426-470, cleft-palate, 515 Psychology, education, 030209 endocrinology & metabolism, Biology, Polymorphism, Single Nucleotide, Molecular epidemiology [NCEBP 1], 03 medical and health sciences, Thyroid-stimulating hormone, Hypothyroidism, SERUM TSH, Internal medicine, medicine, Genetics, Humans, Hormonal regulation Translational research [IGMD 6], GENOME-WIDE ASSOCIATION, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Health aging / healthy living Cardiovascular diseases [IGMD 5], 030304 developmental biology, Molecular epidemiology Aetiology, screening and detection [NCEBP 1], Polymorphism, Genetic, THYROTROPIN, HORMONE PATHWAY GENES, Hormonal regulation [IGMD 6], R1, Thyroxine, Common variation, lcsh:Genetics, Endocrinology, HYPOTHYROIDISM, Hormone pathway genes, genome-wide association, Hormonal regulation Aetiology, screening and detection [IGMD 6], 3111 Biomedicine, COMMON VARIATION, Hormone, FOXE1, Genome-Wide Association Study, Developmental Biology
Abstract

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism., Author Summary Levels of thyroid hormones are tightly regulated by TSH produced in the pituitary, and even mild alterations in their concentrations are strong indicators of thyroid pathologies, which are very common worldwide. To identify common genetic variants associated with the highly heritable markers of thyroid function, TSH and FT4, we conducted a meta-analysis of genome-wide association studies in 26,420 and 17,520 individuals, respectively, of European ancestry with normal thyroid function. Our analysis identified 26 independent genetic variants regulating these traits, several of which are new, and confirmed previously detected polymorphisms affecting TSH (within the PDE8B gene and near CAPZB, MAF/LOC440389, and NR3C2) and FT4 (within DIO1) levels. Gender-specific differences in the genetic effects of several variants for TSH and FT4 levels were identified at several loci, which offer clues to understand the known sexual dimorphism in thyroid function and pathology. Of particular clinical interest, we show that TSH-associated loci contribute not only to normal variation, but also to TSH values outside reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings add to the developing landscape of the regulation of thyroid homeostasis and the consequences of genetic variation for thyroid related diseases.

Published
2013
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24. Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts

Author

Gencer, B., Collet, T.H., Virgini, V., Bauer, D.C., Gussekloo, J., Cappola, A.R., Nanchen, D., Elzen, W.P.J. den, Balmer, P., Luben, R.N., Iacoviello, M., Triggiani, V., Cornuz, J., Newman, A.B., Khaw, K.T., Jukema, J.W., Westendorp, R.G.J., Vittinghoff, E., Aujesky, D., Rodondi, N., Thyroid Studies Collaboration, and Thyroid Studies Collaboration

Subjects
Male, endocrine system diseases, Thyrotropin, heart failure, Comorbidity, 030204 cardiovascular system & hematology, Cardiorespiratory Medicine and Haematology, Cardiovascular, thyroid, 0302 clinical medicine, cohort studies, Risk Factors, 80 and over, Prospective Studies, Prospective cohort study, Subclinical infection, Aged, 80 and over, medicine.diagnostic_test, Thyroid, Middle Aged, medicine.anatomical_structure, Heart Disease, Public Health and Health Services, Female, epidemiology, Cardiology and Cardiovascular Medicine, hormones, hormone substitutes, and hormone antagonists, Cohort study, Risk, Adult, endocrine system, medicine.medical_specialty, Management of heart failure, Clinical Sciences, 030209 endocrinology & metabolism, Aged, Follow-Up Studies, Heart Failure/epidemiology, Humans, Hypothyroidism/blood, Hypothyroidism/epidemiology, Sensitivity and Specificity, Thyrotropin/blood, Thyroxine/blood, Thyroid function tests, Article, 03 medical and health sciences, Hypothyroidism, Clinical Research, Physiology (medical), Internal medicine, medicine, Metabolic and endocrine, business.industry, Thyroid Studies Collaboration, medicine.disease, meta-analysis, Thyroxine, Endocrinology, Cardiovascular System & Hematology, Heart failure, business
Abstract

Background— American College of Cardiology/American Heart Association guidelines for the diagnosis and management of heart failure recommend investigating exacerbating conditions such as thyroid dysfunction, but without specifying the impact of different thyroid-stimulation hormone (TSH) levels. Limited prospective data exist on the association between subclinical thyroid dysfunction and heart failure events. Methods and Results— We performed a pooled analysis of individual participant data using all available prospective cohorts with thyroid function tests and subsequent follow-up of heart failure events. Individual data on 25 390 participants with 216 248 person-years of follow-up were supplied from 6 prospective cohorts in the United States and Europe. Euthyroidism was defined as TSH of 0.45 to 4.49 mIU/L, subclinical hypothyroidism as TSH of 4.5 to 19.9 mIU/L, and subclinical hyperthyroidism as TSH P for quadratic pattern P for trend P for trend=0.047). Risks remained similar after adjustment for cardiovascular risk factors. Conclusion— Risks of heart failure events were increased with both higher and lower TSH levels, particularly for TSH ≥10 and

Published
2012

27. Identification of Novel Genetic Loci Associated with Thyroid Peroxidase Antibodies and Clinical Thyroid Disease

Author

Medici, M. (Marco), Porcu, E. (Eleonora), Pistis, G. (Giorgio), Teumer, A. (Alexander), Brown, S.J. (Stephen), Jensen, R.A. (Richard), Rawal, R. (Rajesh), Roef, G.L. (Greet), Plantinga, T.S. (Theo S.), Vermeulen, S.H.H.M. (Sita), Lahti, J. (Jari), Simmonds, M.C. (Mark), Husemoen, L.L.N. (Lise Lotte), Freathy, R.M. (Rachel), Shields, B.M. (Beverley), Pietzner, D. (Diana), Nagy, R. (Rebecca), Broer, L. (Linda), Chaker, L. (Layal), Korevaar, T.I.M. (Tim), Plia, M.G. (Maria Grazia), Sala, C. (Cinzia), Völker, U. (Uwe), Richards, J.B. (Brent), Sweep, F.C. (Fred), Gieger, C. (Christian), Corre, T. (Tanguy), Kajantie, E. (Eero), Thuesen, L. (Leif), Taes, Y.E. (Youri), Visser, W.E. (Edward), Hattersley, A.T. (Andrew), Kratzsch, J. (Jürgen), Hamilton, A. (Amy), Li, W. (Wei), Homuth, G. (Georg), Lobina, M. (Monia), Mariotti, S. (Stefano), Soranzo, N. (Nicole), Cocca, M. (Massimiliano), Nauck, M. (Matthias), Spielhagen, C. (Christin), Ross, H.A. (Alec), Arnold, A.M. (Alice), Bunt, M. (Martijn) van de, Liyanarachchi, S. (Sandya), Heier, M. (Margit), Grabe, H.J. (Hans Jörgen), Masciullo, C. (Corrado), Galesloot, T.E. (Tessel), Lim, E.M. (Ee Mun), Reischl, G. (Gunilla), Leedman, P.J. (Peter), Lai, S. (Sandra), Delitala, A. (Alessandro), Bremner, A. (Alexandra), Philips, D.I.W. (David I.), Beilby, J.P. (John), Mulas, A. (Antonella), Vocale, M. (Matteo), Abecasis, G.R. (Gonçalo), Forsen, T. (Tom), James, A. (Alan), Widen, E. (Elisabeth), Hui, J. (Jennie), Prokisch, H. (Holger), Rietzschel, E.E. (Ernst), Palotie, A. (Aarno), Feddema, W. (Wouter), Fletcher, S.J. (Stephen), Schramm, K. (Katharina), Rotter, J.I. (Jerome), Kluttig, A. (Alexander), Radke, D. (Dörte), Traglia, M. (Michela), Surdulescu, G. (Gabriela), He, H. (Hao), Franklyn, J.A. (Jayne), Tiller, D. (Daniel), Vaidya, B. (Bijay), Meyer, T. (Thorsten), Jorgensen, T. (Torben), Hagen, K. (Knut), O'Leary, P.C. (Peter), Wichmann, E. (Eric), Hermus, A.R.M.M. (Ad), Psaty, B.M. (Bruce), Ittermann, T. (Till), Hofman, A. (Albert), Bosi, E. (Emanuele), Schlessinger, D. (David), Wallaschofski, H. (Henri), Pirastu, N. (Nicola), Aulchenko, Y.S. (Yurii), de la Chapelle, A. (Albert), Netea-Maier, R.T. (Romana), Gough, J.E. (Julie), Meyer zu Schwabedissen, H. (Henriette), Frayling, T.M. (Timothy), Kaufman, J.-M. (Jean-Marc), Linneberg, A. (Allan), Räikkönen, K. (Katri), Smit, J.W.A. (Jan), Kiemeney, L.A.L.M. (Bart), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Walsh, J.P. (John), Meisinger, C. (Christa), Heijer, M. (Martin) den, Visser, T.J. (Theo), Spector, T.D. (Timothy), Wilson, S.G. (Scott), Völzke, H. (Henry), Cappola, A.R. (Anne), Toniolo, D. (Daniela), Sanna, S. (Serena), Naitza, S. (Silvia), Peeters, R.P. (Robin), Medici, M. (Marco), Porcu, E. (Eleonora), Pistis, G. (Giorgio), Teumer, A. (Alexander), Brown, S.J. (Stephen), Jensen, R.A. (Richard), Rawal, R. (Rajesh), Roef, G.L. (Greet), Plantinga, T.S. (Theo S.), Vermeulen, S.H.H.M. (Sita), Lahti, J. (Jari), Simmonds, M.C. (Mark), Husemoen, L.L.N. (Lise Lotte), Freathy, R.M. (Rachel), Shields, B.M. (Beverley), Pietzner, D. (Diana), Nagy, R. (Rebecca), Broer, L. (Linda), Chaker, L. (Layal), Korevaar, T.I.M. (Tim), Plia, M.G. (Maria Grazia), Sala, C. (Cinzia), Völker, U. (Uwe), Richards, J.B. (Brent), Sweep, F.C. (Fred), Gieger, C. (Christian), Corre, T. (Tanguy), Kajantie, E. (Eero), Thuesen, L. (Leif), Taes, Y.E. (Youri), Visser, W.E. (Edward), Hattersley, A.T. (Andrew), Kratzsch, J. (Jürgen), Hamilton, A. (Amy), Li, W. (Wei), Homuth, G. (Georg), Lobina, M. (Monia), Mariotti, S. (Stefano), Soranzo, N. (Nicole), Cocca, M. (Massimiliano), Nauck, M. (Matthias), Spielhagen, C. (Christin), Ross, H.A. (Alec), Arnold, A.M. (Alice), Bunt, M. (Martijn) van de, Liyanarachchi, S. (Sandya), Heier, M. (Margit), Grabe, H.J. (Hans Jörgen), Masciullo, C. (Corrado), Galesloot, T.E. (Tessel), Lim, E.M. (Ee Mun), Reischl, G. (Gunilla), Leedman, P.J. (Peter), Lai, S. (Sandra), Delitala, A. (Alessandro), Bremner, A. (Alexandra), Philips, D.I.W. (David I.), Beilby, J.P. (John), Mulas, A. (Antonella), Vocale, M. (Matteo), Abecasis, G.R. (Gonçalo), Forsen, T. (Tom), James, A. (Alan), Widen, E. (Elisabeth), Hui, J. (Jennie), Prokisch, H. (Holger), Rietzschel, E.E. (Ernst), Palotie, A. (Aarno), Feddema, W. (Wouter), Fletcher, S.J. (Stephen), Schramm, K. (Katharina), Rotter, J.I. (Jerome), Kluttig, A. (Alexander), Radke, D. (Dörte), Traglia, M. (Michela), Surdulescu, G. (Gabriela), He, H. (Hao), Franklyn, J.A. (Jayne), Tiller, D. (Daniel), Vaidya, B. (Bijay), Meyer, T. (Thorsten), Jorgensen, T. (Torben), Hagen, K. (Knut), O'Leary, P.C. (Peter), Wichmann, E. (Eric), Hermus, A.R.M.M. (Ad), Psaty, B.M. (Bruce), Ittermann, T. (Till), Hofman, A. (Albert), Bosi, E. (Emanuele), Schlessinger, D. (David), Wallaschofski, H. (Henri), Pirastu, N. (Nicola), Aulchenko, Y.S. (Yurii), de la Chapelle, A. (Albert), Netea-Maier, R.T. (Romana), Gough, J.E. (Julie), Meyer zu Schwabedissen, H. (Henriette), Frayling, T.M. (Timothy), Kaufman, J.-M. (Jean-Marc), Linneberg, A. (Allan), Räikkönen, K. (Katri), Smit, J.W.A. (Jan), Kiemeney, L.A.L.M. (Bart), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Walsh, J.P. (John), Meisinger, C. (Christa), Heijer, M. (Martin) den, Visser, T.J. (Theo), Spector, T.D. (Timothy), Wilson, S.G. (Scott), Völzke, H. (Henry), Cappola, A.R. (Anne), Toniolo, D. (Daniela), Sanna, S. (Serena), Naitza, S. (Silvia), and Peeters, R.P. (Robin)

Abstract

Autoimmune thyroid diseases (AITD) are common, affecting 2-5% of the general population. Individuals with positive thyroid peroxidase antibodies (TPOAbs) have an increased risk of autoimmune hypothyroidism (Hashimoto's thyroiditis), as well as autoimmune hyperthyroidism (Graves' disease). As the possible causative genes of TPOAbs and AITD remain largely unknown, we performed GWAS meta-analyses in 18,297 individuals for TPOAb-positivity (1769 TPOAb-positives and 16,528 TPOAb-negatives) and in 12,353 individuals for TPOAb serum levels, with replication in 8,990 individuals. Significant associations (P<5×10-8) were detected at T

Published
2014
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28. Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study

Author

Rodondi, N., Bauer, D.C., Cappola, A.R., Cornuz, J., Robbins, J., Fried, L.P., Ladenson, P.W., Vittinghoff, E., Gottdiener, J.S., and Newman, A.B.

Subjects
Aged, 80 and over, Heart Failure, Male, endocrine system, Time Factors, endocrine system diseases, Heart, Hyperthyroidism, Article, Cohort Studies, Hypothyroidism, Echocardiography, Risk Factors, Heart Function Tests, Humans, Female, Hypertrophy, Left Ventricular, Aged, hormones, hormone substitutes, and hormone antagonists
Abstract

OBJECTIVES: The goal of this study was to determine whether subclinical thyroid dysfunction was associated with incident heart failure (HF) and echocardiogram abnormalities. BACKGROUND: Subclinical hypothyroidism and hyperthyroidism have been associated with cardiac dysfunction. However, long-term data on the risk of HF are limited. METHODS: We studied 3,044 adults>or=65 years of age who initially were free of HF in the Cardiovascular Health Study. We compared adjudicated HF events over a mean 12-year follow-up and changes in cardiac function over the course of 5 years among euthyroid participants, those with subclinical hypothyroidism (subdivided by thyroid-stimulating hormone [TSH] levels: 4.5 to 9.9, >or=10.0 mU/l), and those with subclinical hyperthyroidism. RESULTS: Over the course of 12 years, 736 participants developed HF events. Participants with TSH>or=10.0 mU/l had a greater incidence of HF compared with euthyroid participants (41.7 vs. 22.9 per 1,000 person years, p=0.01; adjusted hazard ratio: 1.88; 95% confidence interval: 1.05 to 3.34). Baseline peak E velocity, which is an echocardiographic measurement of diastolic function associated with incident HF in the CHS cohort, was greater in those patients with TSH>or=10.0 mU/l compared with euthyroid participants (0.80 m/s vs. 0.72 m/s, p=0.002). Over the course of 5 years, left ventricular mass increased among those with TSH>or=10.0 mU/l, but other echocardiographic measurements were unchanged. Those patients with TSH 4.5 to 9.9 mU/l or with subclinical hyperthyroidism had no increase in risk of HF. CONCLUSIONS: Compared with euthyroid older adults, those adults with TSH>or=10.0 mU/l have a moderately increased risk of HF and alterations in cardiac function but not older adults with TSHor=10.0 mU/l.

Published
2008

29. A meta-analysis of thyroid-related traits reveals novel loci and gender-specific differences in the regulation of thyroid function

Author

Porcu, E., Medici, M., Pistis, G., Volpato, C.B., Wilson, S.G., Cappola, A.R., Bos, S.D., Deelen, J., Heijer, M. den, Freathy, R.M., Lahti, J., Liu, C., Lopez, L.M., Nolte, I.M., O'Connell, J.R., Tanaka, T., Trompet, S., Arnold, A., Bandinelli, S., Beekman, M., Bohringer, S., Brown, S.J., Buckley, B.M., Camaschella, C., Craen, A.J. de, Davies, G., Visser, M.C.H. de, Ford, I., Forsen, T., Frayling, T.M., Fugazzola, L., Gogele, M., Hattersley, A.T., Hermus, A.R.M.M., Hofman, A., Houwing-Duistermaat, J.J., Jensen, R.A., Kajantie, E., Kloppenburg, M., Lim, E.M., Masciullo, C., Mariotti, S., Minelli, C., Mitchell, B.D., Nagaraja, R., Netea-Maier, R.T., Palotie, A., Persani, L., Piras, M.G., Psaty, B.M., Raikkonen, K., Richards, J.B., Rivadeneira, F., Sala, C., Sabra, M.M., Sattar, N., Shields, B.M., Soranzo, N., Starr, J.M., Stott, D.J., Sweep, C.G.J., Usala, G., Klauw, M.M. van der, Heemst, D. van, Mullem, A. van, Vermeulen, S., Visser, W.E., Walsh, J.P., Westendorp, R.G.J., Widen, E., Zhai, G., Cucca, F., Deary, I.J., Eriksson, J.G., Ferrucci, L., Fox, C.S., Jukema, J.W., Kiemeney, L.A.L.M., Pramstaller, P.P., Schlessinger, D., Shuldiner, A.R., Slagboom, E.P., Uitterlinden, A.G., Vaidya, B., Visser, T.J., Wolffenbuttel, B.H.R., Meulenbelt, I., Rotter, J.I., Spector, T.D., Hicks, A.A., Toniolo, D., Sanna, S., Peeters, R.P., Naitza, S., Porcu, E., Medici, M., Pistis, G., Volpato, C.B., Wilson, S.G., Cappola, A.R., Bos, S.D., Deelen, J., Heijer, M. den, Freathy, R.M., Lahti, J., Liu, C., Lopez, L.M., Nolte, I.M., O'Connell, J.R., Tanaka, T., Trompet, S., Arnold, A., Bandinelli, S., Beekman, M., Bohringer, S., Brown, S.J., Buckley, B.M., Camaschella, C., Craen, A.J. de, Davies, G., Visser, M.C.H. de, Ford, I., Forsen, T., Frayling, T.M., Fugazzola, L., Gogele, M., Hattersley, A.T., Hermus, A.R.M.M., Hofman, A., Houwing-Duistermaat, J.J., Jensen, R.A., Kajantie, E., Kloppenburg, M., Lim, E.M., Masciullo, C., Mariotti, S., Minelli, C., Mitchell, B.D., Nagaraja, R., Netea-Maier, R.T., Palotie, A., Persani, L., Piras, M.G., Psaty, B.M., Raikkonen, K., Richards, J.B., Rivadeneira, F., Sala, C., Sabra, M.M., Sattar, N., Shields, B.M., Soranzo, N., Starr, J.M., Stott, D.J., Sweep, C.G.J., Usala, G., Klauw, M.M. van der, Heemst, D. van, Mullem, A. van, Vermeulen, S., Visser, W.E., Walsh, J.P., Westendorp, R.G.J., Widen, E., Zhai, G., Cucca, F., Deary, I.J., Eriksson, J.G., Ferrucci, L., Fox, C.S., Jukema, J.W., Kiemeney, L.A.L.M., Pramstaller, P.P., Schlessinger, D., Shuldiner, A.R., Slagboom, E.P., Uitterlinden, A.G., Vaidya, B., Visser, T.J., Wolffenbuttel, B.H.R., Meulenbelt, I., Rotter, J.I., Spector, T.D., Hicks, A.A., Toniolo, D., Sanna, S., Peeters, R.P., and Naitza, S.

Abstract

Contains fulltext : 118203.pdf (publisher's version ) (Open Access), Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

Published
2013

30. A Meta-Analysis of Thyroid-Related Traits Reveals Novel Loci and Gender-Specific Differences in the Regulation of Thyroid Function

Author

Porcu, E. (Eleonora), Medici, M. (Marco), Pistis, G. (Giorgio), Volpato, C.B., Wilson, S.G. (Scott), Cappola, A.R. (Anne), Bos, S.D. (Steffan), Deelen, J. (Joris), Heijer, M. (Martin) den, Freathy, R.M. (Rachel), Lahti, J. (Jari), Liu, C. (Chunyu), Lopez, L.M. (Lorna), Nolte, I.M. (Ilja), O´Connell, J.R., Tanaka, T. (Toshiko), Trompet, S. (Stella), Arnold, A.M. (Alice), Bandinelli, S. (Stefania), Beekman, M. (Marian), Böhringer, S. (Stefan), Brown, S.J. (Stephen), Buckley, B.M. (Brendan M.), Camaschella, C. (Clara), Craen, A.J. (Anton) de, Davies, G. (Gail), Visser, M.C.H. (Marieke) de, Ford, I. (Ian), Forsen, T. (Tom), Frayling, T.M. (Timothy), Fugazzola, L. (Laura), Gögele, M. (Martin), Hattersley, A.T. (Andrew), Hermus, A.R.M.M. (Ad), Hofman, A. (Albert), Houwing-Duistermaat, J.J. (Jeanine), Jensen, R.A. (Richard), Kajantie, E. (Eero), Kloppenburg, M. (Margreet), Lim, E.M. (Ee Mun), Masciullo, C. (Corrado), Mariotti, S. (Stefano), Minelli, C. (Cosetta), Mitchell, B.D. (Braxton), Nagaraja, R. (Ramaiah), Netea-Maier, R.T. (Romana), Palotie, A. (Aarno), Persani, L. (Luca), Piras, M.G. (Maria Grazia), Psaty, B.M. (Bruce), Räikkönen, K. (Katri), Richards, J.B. (Brent), Rivadeneira Ramirez, F. (Fernando), Sala, C. (Cinzia), Sabra, M.M. (Mona), Sattar, N. (Naveed), Shields, B.M. (Beverley), Soranzo, N. (Nicole), Starr, J.M. (John), Stott, D.J. (David. J.), Sweep, F.C. (Fred), Usala, G., Klauw, M.M. (Melanie) van der, Heemst, D. (Diana) van, Mol-van Mullem, A.A.A. (Alies) van, Vermeulen, S.H. (Sita), Walsh, J.P. (John), Westendorp, R.G.J. (Rudi), Widen, E. (Elisabeth), Zhai, G. (Guangju), Cucca, F. (Francesco), Deary, I.J. (Ian), Visser, W.E. (Edward), Eriksson, J.G. (Johan), Ferrucci, L. (Luigi), Fox, C. (Craig), Jukema, J.W. (Jan Wouter), Kiemeney, L.A.L.M. (Bart), Pramstaller, P.P. (Peter Paul), Schlessinger, D., Shuldiner, A.R. (Alan), Slagboom, P.E. (Eline), Uitterlinden, A.G. (André), Vaidya, B. (Bijay), Visser, T.J. (Theo), Wolffenbuttel, B.H.R. (Bruce), Meulenbelt, I. (Ingrid), Rotter, J.I. (Jerome), Spector, T.D. (Timothy), Hicks, A.A. (Andrew), Toniolo, D. (Daniela), Sanna, S. (Serena), Peeters, R.P. (Robin), Naitza, S. (Silvia), Porcu, E. (Eleonora), Medici, M. (Marco), Pistis, G. (Giorgio), Volpato, C.B., Wilson, S.G. (Scott), Cappola, A.R. (Anne), Bos, S.D. (Steffan), Deelen, J. (Joris), Heijer, M. (Martin) den, Freathy, R.M. (Rachel), Lahti, J. (Jari), Liu, C. (Chunyu), Lopez, L.M. (Lorna), Nolte, I.M. (Ilja), O´Connell, J.R., Tanaka, T. (Toshiko), Trompet, S. (Stella), Arnold, A.M. (Alice), Bandinelli, S. (Stefania), Beekman, M. (Marian), Böhringer, S. (Stefan), Brown, S.J. (Stephen), Buckley, B.M. (Brendan M.), Camaschella, C. (Clara), Craen, A.J. (Anton) de, Davies, G. (Gail), Visser, M.C.H. (Marieke) de, Ford, I. (Ian), Forsen, T. (Tom), Frayling, T.M. (Timothy), Fugazzola, L. (Laura), Gögele, M. (Martin), Hattersley, A.T. (Andrew), Hermus, A.R.M.M. (Ad), Hofman, A. (Albert), Houwing-Duistermaat, J.J. (Jeanine), Jensen, R.A. (Richard), Kajantie, E. (Eero), Kloppenburg, M. (Margreet), Lim, E.M. (Ee Mun), Masciullo, C. (Corrado), Mariotti, S. (Stefano), Minelli, C. (Cosetta), Mitchell, B.D. (Braxton), Nagaraja, R. (Ramaiah), Netea-Maier, R.T. (Romana), Palotie, A. (Aarno), Persani, L. (Luca), Piras, M.G. (Maria Grazia), Psaty, B.M. (Bruce), Räikkönen, K. (Katri), Richards, J.B. (Brent), Rivadeneira Ramirez, F. (Fernando), Sala, C. (Cinzia), Sabra, M.M. (Mona), Sattar, N. (Naveed), Shields, B.M. (Beverley), Soranzo, N. (Nicole), Starr, J.M. (John), Stott, D.J. (David. J.), Sweep, F.C. (Fred), Usala, G., Klauw, M.M. (Melanie) van der, Heemst, D. (Diana) van, Mol-van Mullem, A.A.A. (Alies) van, Vermeulen, S.H. (Sita), Walsh, J.P. (John), Westendorp, R.G.J. (Rudi), Widen, E. (Elisabeth), Zhai, G. (Guangju), Cucca, F. (Francesco), Deary, I.J. (Ian), Visser, W.E. (Edward), Eriksson, J.G. (Johan), Ferrucci, L. (Luigi), Fox, C. (Craig), Jukema, J.W. (Jan Wouter), Kiemeney, L.A.L.M. (Bart), Pramstaller, P.P. (Peter Paul), Schlessinger, D., Shuldiner, A.R. (Alan), Slagboom, P.E. (Eline), Uitterlinden, A.G. (André), Vaidya, B. (Bijay), Visser, T.J. (Theo), Wolffenbuttel, B.H.R. (Bruce), Meulenbelt, I. (Ingrid), Rotter, J.I. (Jerome), Spector, T.D. (Timothy), Hicks, A.A. (Andrew), Toniolo, D. (Daniela), Sanna, S. (Serena), Peeters, R.P. (Robin), and Naitza, S. (Silvia)

Published
2013
Full Text
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31. Subclinical hypothyroidism in community-dwelling older people: consequences and treatment outcomes

Author

Du Puy, R.S., Gussekloo, J., Mooijaart, S.P., Poortvliet, R.K.E., Achterberg, W.P., Cappola, A.R., Olde Rikkert, M.G.M., Verheij, T.J.M., and Leiden University

Subjects
Thyroid, endocrine system, endocrine system diseases, Subclinical hypothyroidism, Older patients, Levothyroxine, Primary care
Abstract

The thyroid gland plays a crucial role in regulating nearly all bodily processes. A particular state of thyroid function, dubbed subclinical hypothyroidism (with high thyroid-stimulating hormone [TSH] and normal free thyroid hormone [fT4] in blood tests), becomes more prevalent with advancing age and it is unclear how this condition should be interpreted in community-dwelling older people (arbitrarily 65 years and older). Whether or not the condition is associated with negative health consequences, and whether treatment with levothyroxine (artificial thyroid hormone) is warranted, are subjects of decades-long debate. This thesis aims to identify whether subclinical hypothyroidism is associated with a range of relevant outcomes, and whether levothyroxine treatment leads to benefits, in community-dwelling older persons. The results in this thesis demonstrate that subclinical hypothyroidism is not associated with clinically (e.g. physical and cognitive function, mood or mortality risk) or biologically (e.g. thyroid antibodies or anaemia) relevant outcomes. Levothyroxine treatment does not provide benefits. These results suggest that subclinical hypothyroidism in older people is a strictly biochemical diagnosis, they support more conservative diagnostic approaches and do not support routine treatment with levothyroxine. More research is needed before extrapolating to more specific subgroups and to assess whether international guidelines should be updated.

Published
2021

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