ETA2024 Oral Presentations Oral Session 10: Thyroid dysfunction-2 (5 abstracts)
Towards personalized TSH reference ranges: a genetic and population-based approach in three independent cohorts
Aleksander Kuś 1 , Rosalie Sterenborg 2 , Eirin Haug 3 , Tessel Galesloot 4 , W. Edward Visser 5 , Johannes W.A. Smit 6 , Tomasz Bednarczuk 7 , Robin Peeters 8 , Bjørn Olav Æsvold 9 , Alexander Teumer 10 & Marco Medici 11
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.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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