LDLR and APOB pathogenic variants predict discordant TSH effect on LDL-C

Kafol, Jan (author), Šikonja, Jaka (author), Mlinarič, Matej (author), Čugalj Kern, Barbara (author), Pricop-Jeckstadt, Mihaela (author), Drole Torkar, Ana (author), Gorjanc, Tevž (author), Petek, Andraž (author), Lakner, Andreja (author), Kovač, Jernej (author), Battelino, Tadej (author), Grošelj, Urh (author)

Background and aims Thyroid hormones regulate lipoprotein metabolism—primarily by up-regulating the LDL receptor. Whether TSH relates to LDL-C in hypercholesterolemic children, and whether this depends on familial hypercholesterolemia (FH) status or the underlying defective gene, is uncertain. We evaluated TSH–lipid associations in prepubertal children and tested effect modification by FH status and, within FH, by gene with a pathogenic variant (LDLR vs APOB). Methods We performed a cross-sectional study of prepubertal children referred to the Slovenian national tertiary center through the universal FH screening program or cascade screening. Eligibility required concurrent TSH and fasting lipid measurement and completed genetic testing (pathogenic/likely pathogenic variants in LDLR/APOB/PCSK9 vs polygenic hypercholesterolemia). Results Among 738 children, 182 (24.7%) were FH-positive (LDLR 132; APOB 50). In the pooled cohort, TSH did not correlate with age or lipids (all p≥0.050). After sex stratification, TSH correlated with triglycerides only in males (ρ=0.156; p=0.012). In FH-positive children, TSH correlated with total cholesterol, LDL-cholesterol, and ApoB (ρ≈0.184–0.207; all p<0.050), with no associations in FH-negative children. Interaction testing confirmed effect modification by FH (TSH×FH β=0.141 mmol/L per mIU/L, p=0.023). Within FH-positive children, a positive TSH–LDL-C slope was seen in LDLR carriers (β=0.237, p=0.004) but not in APOB carriers (β=−0.065, p=0.655). Conclusions TSH was positively associated with LDL-C only in FH due to LDLR variants, not in APOB carriers. These findings suggest that genetic background may shape hormonal sensitivity, and that attention to thyroid status could be particularly relevant in LDLR-FH.

• Language: English
• Keywords: TSH, low-density lipoprotein cholesterol, familial hypercholesterolemia, LDLR, APOB, subclinical hypothyroidism
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2026
• Number of pages: 7 str.
• Numbering: Vol. 415, art. 120672
• PID: 20.500.12556/RUL-183385
• UDC: 616.1:616-053.2
• ISSN on article: 1879-1484
• DOI: 10.1016/j.atherosclerosis.2026.120672
• COBISS.SI-ID: 268549379
• Publication date in RUL: 12.06.2026

Record is a part of a journal

• Title: Atherosclerosis
• Shortened title: Atherosclerosis
• Publisher: Elsevier
• ISSN: 1879-1484
• COBISS.SI-ID: 23193093

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Projects

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: P3-0343
• Name: Etiologija, zgodnje odkrivanje in zdravljenje bolezni pri otrocih in mladostnikih

• Funder: ARIS - Slovenian Research and Innovation Agency
• Project number: J3-2536
• Name: UGOTAVLJANJE GENETSKIH VZROKOV DISLIPIDEMIJ PRI OTROCIH IN MLADOSTNIKIH TER NJIHOVO ZGODNJE ODKRIVANJE S POPULACIJSKIM PRESEJANJEM