Polygenic score could provide individualized TSH reference ranges for disease-free adults
Click Here to Manage Email Alerts
Key takeaways:
- Polygenic score was a stronger predictor of TSH levels than free T4 in two study cohorts.
- Using polygenic score-specific TSH ranges reclassified some adults with subclinical thyroid disease as euthyroid.
Polygenic score is a stronger predictor for thyroid-stimulating hormone levels than free thyroxine and other factors, and could be used to develop individual TSH reference ranges for adults, according to findings published in Thyroid.
In an analysis of data from three study cohorts, polygenic score was a stronger predictor of TSH levels than nongenetic factors, and reference ranges created for different polygenic score profiles differed from population-based reference ranges.
“Up to 30% of individuals, previously classified as having subclinical hypothyroidism and hyperthyroidism when using population-based TSH reference ranges, were reclassified as euthyroid when these genetically determined TSH reference ranges were applied,” Marco Medici, MD, PhD, a researcher in the department of internal medicine at the Academic Center for Thyroid Diseases, Erasmus Medical Center in Rotterdam, the Netherlands, told Healio. “These results show that individual genetic profiles have the potential to personalize TSH reference ranges.”
In the first part of a two-part study, researchers collected data from 6,834 adults in the Rotterdam Study and 3,800 adults in the Nijmegen Biomedical Study. Thyroid function tests, genotyping data and clinical characteristics were obtained. Researchers created a polygenic score using 59 single nucleotide polymorphisms associated with reference range TSH levels. Participants were divided into four quartiles based on polygenic score. TSH reference ranges tied to polygenic scores were created.
“TSH reference ranges have always been based on the 2.5 percentile and 97.5 percentile of observed values in a reference population of presumably healthy individuals, leading to wide ranges,” Medici said. “Applying these wide population-based reference ranges to an individual patient may lead to incorrect diagnoses and related overtreatment and undertreatment.”
Population-based TSH reference ranges were 0.43 mU/L to 5.11 mU/L in the Rotterdam Study and 0.35 mU/L to 3.82 mU/L in the Nijmegen Biomedical Study. Polygenic score-specific TSH reference ranges differed from both population-based reference ranges. In multiple linear regression models, polygenic score was a stronger predictor of TSH concentrations than free T4 and nongenetic factors. Polygenic score was not associated with thyroid peroxidase autoantibodies in either study group.
If polygenic score-specific TSH ranges were used, 24.7% of adults with subclinical hypothyroidism and 30.1% with subclinical hyperthyroidism in the Rotterdam Study would be reclassified as euthyroid. Similarly, 24.5% of adults with subclinical hypothyroidism and 30.1% of those with subclinical hyperthyroidism would be reclassified as euthyroid in the Nijmegen Biomedical Study according to polygenic score-specific TSH ranges.
In part two of the study, researchers obtained data from adults who participated in the Trøndelag Health Study. Levothyroxine use was self-reported.
There were 1,132 adults in the Trøndelag Health Study using levothyroxine and 26,321 adults without thyroid disease included in the study. Findings on the reclassification of thyroid status among participants in the Trøndelag Health Study without thyroid disease were similar to what was observed in the other two cohorts. In an assessment of adults receiving levothyroxine, those in the highest polygenic score quartile were more likely to be prescribed levothyroxine than those in the lowest quartile (5.2% vs. 3.3%).
Medici said improvements to the polygenic score can be made in the future by adding more genetic and nongenetic-factors. He added that only people of European ancestries were included in the study and more research should be conducted in other populations.
For more information:
Marco Medici, MD, PhD, can be reached at m.medici@erasmusmc.nl.
Perspective
Back to Top
Anupam Kotwal, MD, MSc, FACE, FRCP (Edin)
A recent study evaluated large databases to determine genetic prediction on the predominant marker of thyroid function, that is, thyroid-stimulating hormone. The researchers were able to demonstrate an effect of the genetic makeup or polygenic score of an individual on their TSH.
A key finding of this study was approximately 25% of individuals initially classified with thyroid dysfunction were reclassified as having normal thyroid function or euthyroid. This has important clinical implications in terms of reducing unnecessary treatment, which can come with its own harms for a substantial proportion of individuals who in fact have a TSH that is normal for them based on their genetic makeup. In addition, this information can then help determine if a TSH within or close to the reference range is normal for that individual or not.
However, before genetic determination of thyroid function makes it into widespread clinical practice, the limited availability of genetic testing in routine practice will have to be addressed worldwide. Additionally, validation of the study’s findings in cohorts of ancestries besides European is essential to determine genetic determinants of thyroid function in those respective populations. Nonetheless, this study adds to the next direction for personalized care of thyroid dysfunction considering the genetic makeup of individuals.
Collapse
Click Here to Manage Email Alerts