{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T16:03:17Z","timestamp":1791475397906,"version":"4.3.4"},"reference-count":50,"publisher":"Oxford University Press (OUP)","issue":"15","license":[{"start":{"date-parts":[[2022,2,28]],"date-time":"2022-02-28T00:00:00Z","timestamp":1646006400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,8,17]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Autoimmune thyroid disease (AITD) and pernicious anemia (PA) often coexist, but the directionality is unknown. In a two-sample Mendelian randomization (MR) analysis, using summary statistics from large genome-wide association studies (GWASs) in Europeans (N\u00a0=\u200949\u2009269\u2013755\u2009406), we examined the genetic associations between thyroid function, PA and markers of erythropoiesis. We performed inverse variance weighted random-effects MR, several sensitivity MR analyses, and bidirectional MR and MR Steiger for directionality. AITD and PA were associated bidirectionally (P\u00a0\u2264\u20098\u2009\u00d7\u200910\u22126). Neither euthyroid thyroid stimulating hormone (TSH) nor free thyroxine (FT4) were causally associated with PA. One standard deviation (SD) increase in euthyroid FT4 regulated by genetic variants in deiodinases 1 and 2 genes (DIO1\/DIO2), corresponding to low-normal free triiodothyronine (FT3) levels, was causally associated with a pernicious\/macrocytic anemia pattern, i.e. decreased erythrocyte counts (rank-based inverse normal transformed \u03b2\u2009=\u2009\u22120,064 [95% confidence interval: \u22120,085, \u22120,044], P\u00a0=\u20098\u2009\u00d7\u200910\u221210) and hemoglobin (\u22120.028 [\u22120.051, \u22120.005], P\u00a0=\u20090.02) and increased mean corpuscular hemoglobin (0.058 [0.025, 0.091], P\u00a0=\u20095\u2009\u00d7\u200910\u22124) and mean corpuscular volume levels (0.075 [0.052, 0.098], P\u00a0=\u20091\u2009\u00d7\u200910\u22128). Meanwhile, subclinical hyperthyroidism mirrored that pattern. AITD was causally associated with increased erythrocyte distribution width (P\u00a0=\u20090.007) and decreased reticulocyte counts (P\u00a0\u2264\u20090.02), whereas high-normal FT4 regulated by DIO1\/DIO2 variants was causally associated with decreased bilirubin (\u22120.039 (\u22120.064, \u22120.013), P\u00a0=\u20090.003). In conclusion, the bidirectional association between AITD and PA suggests a shared heritability for these two autoimmune diseases. AITD was causally associated with impaired erythropoiesis and not autoimmune hemolysis. Additionally, in euthyroid individuals, local regulation of thyroid hormones by deiodinases likely plays a role in erythropoiesis.<\/jats:p>","DOI":"10.1093\/hmg\/ddac052","type":"journal-article","created":{"date-parts":[[2022,2,25]],"date-time":"2022-02-25T20:11:26Z","timestamp":1645819886000},"page":"2548-2559","source":"Crossref","is-referenced-by-count":20,"title":["Thyroid function, pernicious anemia and erythropoiesis: a two-sample Mendelian randomization study"],"prefix":"10.1093","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3899-1324","authenticated-orcid":false,"given":"Alisa D","family":"Kjaergaard","sequence":"first","affiliation":[{"name":"Steno Diabetes Center Aarhus, Aarhus University Hospital , Aarhus , Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8309-094X","authenticated-orcid":false,"given":"Alexander","family":"Teumer","sequence":"additional","affiliation":[{"name":"Institute for Community Medicine, University Medicine Greifswald , Greifswald , Germany"},{"name":"German Center for Cardiovascular Research, Partner Site Greifswald , Greifswald , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirini","family":"Marouli","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute , Barts and The London School of Medicine and Dentistry, , London , UK"},{"name":"Queen Mary University of London , Barts and The London School of Medicine and Dentistry, , London , UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9251-070X","authenticated-orcid":false,"given":"Panos","family":"Deloukas","sequence":"additional","affiliation":[{"name":"William Harvey Research Institute , Barts and The London School of Medicine and Dentistry, , London , UK"},{"name":"Queen Mary University of London , Barts and The London School of Medicine and Dentistry, , London , UK"},{"name":"Princess Al-Jawhara Al-Brahim Centre of Excellence in Research of Hereditary Disorders (PACER-HD), King Abdulaziz University , Jeddah , Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aleksander","family":"Ku\u015b","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Endocrinology, Medical University of Warsaw , Warsaw , Poland"},{"name":"Academic Center for Thyroid Diseases , Department of Internal Medicine, , Rotterdam , The Netherlands"},{"name":"Erasmus Medical Center , Department of Internal Medicine, , Rotterdam , The Netherlands"},{"name":"Department of Epidemiology, Erasmus Medical Center , Rotterdam , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosalie","family":"Sterenborg","sequence":"additional","affiliation":[{"name":"Academic Center for Thyroid Diseases , Department of Internal Medicine, , Rotterdam , The Netherlands"},{"name":"Erasmus Medical Center , Department of Internal Medicine, , Rotterdam , The Netherlands"},{"name":"Department of Epidemiology, Erasmus Medical Center , Rotterdam , The Netherlands"},{"name":"Department of Internal Medicine , Radboud University Medical Center, , Nijmegen , The Netherlands"},{"name":"Radboud Institute for Health Sciences , Radboud University Medical Center, , Nijmegen , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bj\u00f8rn O","family":"\u00c5svold","sequence":"additional","affiliation":[{"name":"K.G. Jebsen Center for Genetic Epidemiology , Department of Public Health and Nursing, NTNU, , Trondheim , Norway"},{"name":"Norwegian University of Science and Technology , Department of Public Health and Nursing, NTNU, , Trondheim , Norway"},{"name":"HUNT Research Center , Department of Public Health and Nursing, NTNU, , Trondheim , Norway"},{"name":"Norwegian University of Science and Technology , Department of Public Health and Nursing, NTNU, , Trondheim , Norway"},{"name":"Department of Endocrinology , St. Olavs Hospital, , Trondheim , Norway"},{"name":"Trondheim University Hospital , St. Olavs Hospital, , Trondheim , Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Medici","sequence":"additional","affiliation":[{"name":"Academic Center for Thyroid Diseases , Department of Internal Medicine, , Rotterdam , The Netherlands"},{"name":"Erasmus Medical Center , Department of Internal Medicine, , Rotterdam , The Netherlands"},{"name":"Department of Epidemiology, Erasmus Medical Center , Rotterdam , The Netherlands"},{"name":"Department of Internal Medicine , Radboud University Medical Center, , Nijmegen , The Netherlands"},{"name":"Radboud Institute for Health Sciences , Radboud University Medical Center, , Nijmegen , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Ellervik","sequence":"additional","affiliation":[{"name":"Department of Clinical Medicine , Faculty of Health and Medical Sciences, , Copenhagen , Denmark"},{"name":"University of Copenhagen , Faculty of Health and Medical Sciences, , Copenhagen , Denmark"},{"name":"Department of Pathology, Harvard Medical School , Boston 02215, MA , USA"},{"name":"Department of Laboratory Medicine, Boston Children\u2019s Hospital , Boston 02215, MA , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,28]]},"reference":[{"key":"2022082311423630300_ref1","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1056\/NEJMra1713301","article-title":"Autoimmune polyendocrine syndromes","volume":"378","author":"Husebye","year":"2018","journal-title":"New Engl. 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