학술논문
Towards personalized TSH reference ranges: A genetic and population-based approach in three independent cohorts.
Document Type
Academic Journal
Author
Kuś A; Medical University of Warsaw, Department of Internal Medicine and Endocrinology, Warsaw, Poland.; Erasmus Medical Center, Academic Center for Thyroid Diseases, Department of Internal Medicine, Rotterdam, Netherlands.; Erasmus Medical Center, Department of Epidemiology, Rotterdam, Netherlands; akus@wum.edu.pl.; Sterenborg RBTM; Erasmus Medical Center, Academic Center for Thyroid Diseases, Department of Internal Medicine, Rotterdam, Netherlands.; Erasmus Medical Center, Department of Epidemiology, Rotterdam, Netherlands.; Radboud University Medical Center, Department of Internal Medicine, Nijmegen, Netherlands; rosalie.sterenborg@radboudumc.nl.; Haug EB; Norwegian University of Science and Technology, HUNT Center for Molecular and Clinical Epidemiology, Department of Public Health and Nursing, Trondheim, Trøndelag, Norway; eirin.haug@ntnu.no.; Galesloot TE; Radboud University Medical Center, Department for Health Evidence, Nijmegen, Netherlands; tessel.galesloot@radboudumc.nl.; Visser WE; Erasmus Medical Center, Academic Center for Thyroid Diseases, Department of Internal Medicine, Rotterdam, Netherlands; w.e.visser@erasmusmc.nl.; Smit J; Radboud University Medical Center, Department of Internal Medicine, Nijmegen, Netherlands; jan.smit@radboudumc.nl.; Bednarczuk T; Medical University of Warsaw, Department of Internal Medicine and Endocrinology, Warsaw, Poland; tbednarczuk@wum.edu.pl.; Peeters RP; Erasmus Medical Center, Academic Center for Thyroid Diseases, Department of Internal Medicine, Rotterdam, Netherlands; r.peeters@erasmusmc.nl.; Åsvold BO; Norwegian University of Science and Technology, Postboks 8905 MTFS, Trondheim, Norway, 7491; bjorn.o.asvold@ntnu.no.; Teumer A; University Medicine Greifswald, Institute for Community Medicine, W.-Rathenau-Str. 48, Greifswald, Germany, 17475; ateumer@uni-greifswald.de.; Medici M; Erasmus Medical Center, Academic Center for Thyroid Diseases, Department of Internal Medicine, Rotterdam, Zuid-Holland, Netherlands.; Erasmus Medical Center, Department of Epidemiology, Rotterdam, Zuid-Holland, Netherlands.; Radboud University Medical Center, Department of Internal Medicine, Nijmegen, Netherlands; m.medici@erasmusmc.nl.
Source
Publisher: Mary Ann Liebert Publishers Country of Publication: United States NLM ID: 9104317 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1557-9077 (Electronic) Linking ISSN: 10507256 NLM ISO Abbreviation: Thyroid Subsets: MEDLINE
Subject
Language
English
Abstract
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 =1.7x10 -8 ).
Conclusions: Individual genetic profiles have potential to personalize TSH reference ranges, with large effects on reclassification of diagnosis and LT4 prescriptions. As the currently used PGS can only predict approximately 10% of inter-individual variation in TSH concentrations, it should be further improved when more genetic variants determining TSH concentrations are identified in future studies.
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, P
Conclusions: Individual genetic profiles have potential to personalize TSH reference ranges, with large effects on reclassification of diagnosis and LT4 prescriptions. As the currently used PGS can only predict approximately 10% of inter-individual variation in TSH concentrations, it should be further improved when more genetic variants determining TSH concentrations are identified in future studies.