PXD069688

PXD069688 is an original dataset announced via ProteomeXchange.

Title	Public Cohort Analysis Identifies Thyroglobulin Variants as Hypothyroidism Risk Factors
Description	Hypothyroidism is a prevalent endocrine disorder that is characterized by the insufficient production of thyroid hormones (T3/T4), with etiologies related to environmental, autoimmune factors, or genetic variants. Thyroglobulin (Tg) serves as the prohormone to T3/T4 production and due to a large genetic diversity there are many variants of clinical uncertainty. Here, we leveraged the large-scale “All of Us” biobank to investigate disease association of Tg variants that are more prevalent in the general population compared to previously characterized variants. We compared these variants to thyroid stimulating hormone levels and levothyroxine (LT4) usage to estimate thyroid function. This identified R152H, Q870H, A993T, P1012L and P1494L variants linked to an increased susceptibility to levothyroxine usage and decreased thyroid function while the R320C variant was associated with a decrease in thyroid function. Molecular characterization and secretion of these variants in Fisher rat thyroid cells showed decreased secretion efficiency and/or correlates with higher anti-TPO antibody levels in participants for disease associated variants while benign variants showed minimal effect. Using previously determined structures of Tg, variants found with a decrease in thyroid efficiency are in structural positions that disrupt stabilizing bonds, but variants with minimal effect are in more flexible regions with fewer interactions. Affinity purification mass spectrometry demonstrated that secretion deficient variants show higher engagement with the protein homeostasis network. We estimate that around 150,000 individuals in the US could benefit from precision medicine with the variants highlighted in this study currently take levothyroxine, with ~100,000 of those individuals carrying the Q870H variant. Our findings highlight the power of combining data from large public biobanks with molecular characterization to better understand the genotype to phenotype relationships of Tg. Our analysis suggests that Q870H serves as a possible candidate to be targeted by molecular therapies to restore secretion and T3/T4 production offering a precision medicine approach beyond LT4 replacement therapy.
HostingRepository	PRIDE
AnnounceDate	2026-08-07
AnnouncementXML	Submission_2026-08-06_20:27:37.957.xml
DigitalObjectIdentifier	https://doi.org/10.6019/PXD069688
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Jake Hermanson
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606; scientific name: Rattus norvegicus (Rat); NCBI TaxID: NEWT:10116;
ModificationList	No PTMs are included in the dataset
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2025-10-20 17:55:05	ID requested
⏵ 1	2026-08-06 20:27:38	announced

Hermanson JN, Hudson AD, Plate L, Public cohort analysis identifies thyroglobulin variants as hypothyroidism risk factors. J Biol Chem, 302(9):113344(2026) [pubmed]

10.6019/PXD069688;

10.1016/j.jbc.2026.113344;

submitter keyword: AP-MS, TMT,Hypothyroidisim, LC-MS/MS

Lars Plate
contact affiliation	Department of Chemistry, Biological Sciences, Microbiolgy and Immunology at Vanderbilt University
contact email	lars.plate@vanderbilt.edu
lab head
Jake Hermanson
contact affiliation	Vanderbilt University
contact email	jake.hermanson@vanderbilt.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD069688
     1. Label: PRIDE project
     2. Name: Public Cohort Analysis Identifies Thyroglobulin Variants as Hypothyroidism Risk Factors