Sensorineural hearing loss can be caused by lesions to the inner ear during development. Understanding the events and signaling pathways that drive inner ear formation is crucial for determining the possible causes of congenital hearing loss. We have analyzed the innervation and expression of SOX2, JAGGED1, β-catenin (CTNNB1), and vitamin D receptor (VDR) in the inner ears of human conceptuses aged 5 to 10 weeks after fertilization (W) using immunohistochemistry. The prosensory domains of the human inner ear displayed SOX2 and JAGGED1 expression throughout the analyzed period, with SOX2 expression being more extensive in all the analyzed timepoints. Innervation of vestibular prosensory domains was present at 6 W and extensive at 10 W, while nerve fibers reached the base of the cochlear prosensory domain at 7–8 W. CTNNB1 and VDR expression was mostly membranous and present during all analyzed timepoints in the inner ear, being the strongest in the non-sensory epithelium. Their expression was stronger in the vestibular region compared to the cochlear duct. CTNNB1 and VDR expression displayed opposite expression trends during the analyzed period, but additional studies are needed to elucidate whether they interact during inner ear development.

In this cross-sectional observational study, we investigated whether recreational exercise (RE) influences systemic inflammation in Hashimoto’s thyroiditis (HT) across different disease severity groups. We analyzed 403 participants from the Croatian Biobank of Patients with HT (CRO-HT), including 173 controls and 230 HT patients (euthyroid, levothyroxine [LT4]-treated, and hypothyroid). Serum levels of 92 inflammatory proteins were measured using the Olink^® Target 96 Inflammation panel, and exercise status was assessed via structured questionnaires. Linear regression revealed distinct protein associations depending on thyroid status. In controls, RE was associated with reduced MMP-10 and FGF-5, reflecting cardiovascular and muscle benefits. In euthyroid patients, RE was associated with decreased CXCL9 and TRAIL, implicating reduced type 1 inflammation and vascular risk. LT4-treated patients showed increases in IL-15RA and IL-24 with RE, suggesting improved muscle metabolism and anti-inflammatory effects. In hypothyroid patients, RE was associated with reduced CCL20 and increased HGF, while changes in TRANCE and TWEAK indicated mixed effects on bone and immune regulation. Notably, RE was associated with reduced CXCL9 and CCL20, two proteins previously linked to HT risk. Overall, RE is associated with distinct changes in inflammatory profiles across HT disease severity groups, with the most favourable responses observed in LT4-treated patients, suggesting synergy with hormone therapy.

We investigated whether recreational exercise (RE) influences systemic inflammation in Hashimoto’s thyroiditis (HT) across different disease severity groups. We analyzed 403 participants from the Croatian Biobank of Patients with HT (CROHT), including 173 controls and 230 HT patients (euthyroid, levothyroxine [LT4]-treated, and hypothyroid). Serum levels of 92 inflammatory proteins were measured using the Olink® Target 96 Inflammation panel, and exercise status was assessed via structured questionnaires. Linear regression revealed distinct protein associations depending on thyroid status. In controls, RE was associated with reduced MMP-10 and FGF-5, reflecting cardiovascular and muscle benefits. In euthyroid patients, RE was associated with decreased CXCL9 and TRAIL, implicating reduced type 1 inflammation and vascular risk. LT4-treated patients showed increases in IL-15RA and IL-24 with RE, suggesting improved muscle metabolism and anti-inflammatory effects. In hypothyroid patients, RE was associated with reduced CCL20 and increased HGF, while changes in TRANCE and TWEAK indicated mixed effects on bone and immune regulation. Notably, RE was associated with reduced CXCL9 and CCL20, two proteins previously linked to HT risk. Overall, RE is associated with distinct changes in inflammatory profiles across HT disease severity groups, with the most favourable responses observed in LT4-treated patients, suggesting synergy with hormone therapy.

Background/Objectives: Multigenerational families with unusually early disease onset provide a unique opportunity to investigate the genetic architecture underlying the missing heritability of complex diseases. Here, we investigated the genetic basis of apparent autosomal dominant early-onset Hashimoto’s thyroiditis (HT) in a multigenerational pedigree using whole-exome sequencing (WES) in 9 individuals and PacBio HiFi long-read whole-genome sequencing (LR-WGS) in four family members spanning three generations. Methods: WES identified a rare disease-segregating TPH2 missense variant, while LR-WGS identified approximately 2000 structural variants (SVs) shared by the three sequenced affected relatives and absent from the unaffected father. Results: Affected-lineage-shared SVs were significantly enriched within established hypothyroidism GWAS loci (447 observed vs. 292.6 expected overlaps; p = 6.99 × 10⁻⁴), with prominent clusters at the NFATC1-ATP9B and PDCD6-AHRR loci. Integrative analyses incorporating regulatory annotation, GWAS overlap, and exploratory proteomic profiling highlighted candidate regulatory SVs affecting enhancers and long non-coding RNAs within the TPH2/TRHDE, TPO/LALTOP, and TSHR loci. Exploratory proteomic profiling was consistent with involvement of the NFATC1-ATP9B and PDCD6-AHRR loci and identified AXIN1 as an additional candidate locus. Parallel polygenic risk score (PRS) analysis showed that the three affected sequenced family members ranked above the 95th percentile of the HT PRS distribution. Conclusions: Together, these findings are consistent with a multi-hit genetic model in which elevated polygenic burden and multiple regulatory structural variants may jointly contribute to early-onset familial HT. The observed enrichment of affected-lineage-shared SVs within established hypothyroidism GWAS loci further suggests that regulatory structural variation may contribute to previously unexplained non-coding genetic susceptibility.