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Endocrine Abstracts (2024) 101 OP10-02 | DOI: 10.1530/endoabs.101.OP-10-02

1Medical University of Warsaw, Department of Internal Medicine and Endocrinology, Warsaw, Poland; 2Radboud University Medical Center, Nijmegen, Erasmus Medical Center, Rotterdam, Department of Internal Medicine - Division of Endocrinology, Nijmegen, Netherlands; 3Ntnu, Norwegian University of Science and Technology (Ntnu), Hunt Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, Trondheim, Norway; 4Department for Health Evidence, Radboud Institute for Health Sciences (T.E.G.), Radboud University Medical Center, Nijmegen, the Netherlands, Radboud University Medical Center, Department for Health Evidence, Nijmegen, Netherlands; 5Erasmus Medical Center, Academic Center for Thyroid Diseases, Department of Internal Medicine, Academic Center for Thyroid Diseases, Rotterdam, Netherlands; 6Radboud University Nijmegen Medical Centre, Radboud University Medical Center, Department of Internal Medicine, 463 Internal Medicine, Nijmegen, Netherlands; 7Medical University of Warsaw, Department of Internal Medicine and Endocrinology, Department of Internal Medicine and Endocrinology, Warsaw, Poland; 8Academic Center for Thyroid Diseases, Department of Endocrinology, Erasmus, Department of Internal Medicine,, Rotterdam, Netherlands; 9Norwegian University of Science and Technology, Department of Public Health and Nursing, Trondheim, Norway; 10University Medicine Greifswald, Department of Psychiatry and Psychotherapy, Department of Psychiatry and Psychotherapy, Greifswald, Germany; 11Radboud University Medical Center, Nijmegen, Erasmus Medical Center, Rotterdam, Department of Internal Medicine, Radboud University Medical Center, Nijmegen, Netherlands


Background: Serum thyroid-stimulating hormone (TSH) measurement is the diagnostic cornerstone for primary thyroid dysfunction. There is high inter-individual, but limited intra-individual variation in TSH concentrations, largely due to genetic factors. The currently used wide population-based reference intervals may lead to inappropriate management decisions.

Methods: A polygenic score (PGS) including 59 genetic variants was used to calculate genetically-determined TSH reference ranges in a thyroid disease-free cohort (n= 6,834). Its effect on reclassification of diagnoses was investigated when compared to using population-based reference ranges. Next, results were validated in a second independent population-based thyroid disease-free cohort (n = 3,800). Potential clinical implications were assessed in a third independent population-based cohort including individuals without thyroid disease (n = 26,321) as well as individuals on levothyroxine (LT4) treatment (n = 1,132).

Results: PGS was a much stronger predictor of individual TSH concentrations than FT4 (total variance in TSH concentrations explained 9.2-11.1% vs. 2.4-2.7%, respectively) or any other non-genetic factor (total variance in TSH concentrations explained 0.2-1.8%). Genetically-determined TSH reference ranges differed significantly between PGS quartiles in all cohorts, while the differences in FT4 concentrations were absent or only minor. Up to 24.7-30.1% of individuals, previously classified as having subclinical hypo- and hyperthyroidism when using population-based TSH reference ranges, were reclassified as euthyroid when genetically-determined TSH reference ranges were applied. Individuals in the higher PGS quartiles had a higher probability of being prescribed LT4 treatment compared to individuals from the lower PGS quartiles (3.3% in Q1 vs. 5.2% in Q4, Pfor trend =1.7 × 10-8).

Conclusions: Individual genetic profiles have potential to personalize TSH reference ranges, with large effects on reclassification of diagnosis and LT4 prescriptions.

Volume 101

46th Annual Meeting of the European Thyroid Association (ETA) 2024

European Thyroid Association 

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