Public Cohort Analysis Identifies Thyroglobulin Variants as Hypothyroidism Risk Factors

Area of Science:

• Endocrinology
• Genetics
• Molecular Biology

Background:

• Hypothyroidism is a common endocrine disorder caused by insufficient thyroid hormone production.
• Thyroglobulin (Tg) gene variants are numerous, but many have uncertain clinical significance.
• Understanding Tg genotype-phenotype relationships is crucial for advancing thyroid disease management.

Purpose of the Study:

• To investigate the clinical associations of undercharacterized thyroglobulin (Tg) gene variants using a large biobank.
• To elucidate the molecular mechanisms underlying the pathophysiology of identified Tg variants.
• To explore potential precision medicine strategies for hypothyroidism based on genetic profiles.

Main Methods:

• Leveraged the All of Us biobank to associate Tg variants with thyroid function proxies (TSH, LT4 usage).
• Conducted molecular characterization in rat thyroid cells to assess variant secretion efficiency.
• Employed affinity purification-mass spectrometry to identify protein interaction networks for secretion-deficient variants.

Main Results:

• Identified Tg variants (R152H, Q870H, A993T, P1012L, P1494L, R320C) associated with altered thyroid function and LT4 usage.
• Demonstrated that R152H, Q870H, and R320C variants exhibit impaired secretion due to protein quality control defects.
• Showed that A993T and P1494L variants are linked to elevated anti-TPO antibodies, suggesting a role in autoimmune thyroid disease.

Conclusions:

• Specific Tg variants have distinct pathophysiological mechanisms impacting thyroid function.
• The Q870H variant is a potential target for molecular therapies to restore Tg secretion.
• Combining biobank data with molecular studies enables precise understanding of Tg genotype-to-phenotype relationships for personalized hypothyroidism treatment.