Lipids & metabolic liver disease
Pleiotropic Effects of an eQTL in the CELSR2/PSRC1/SORT1 Cluster That Associates With Low-density Lipoprotein Cholesterol (LDL-C) and Resting Metabolic Rate
Authors' conclusion
Variants in the CELSR2/PSRC1/SORT1 locus exhibit tissue-specific effects on metabolic traits, with an independent role in muscle metabolism through glucocorticoid signaling.
Study context
- Population
- Clinically characterized American Indians; 5205 with fasting lipid levels, 509 with resting metabolic rate (RMR) and substrate oxidation by indirect calorimetry, 207 with skeletal muscle biopsiesgenotyped
- Participants
- 7,000 participants
- Outcome
- LDL-C levels (GWAS)
Methodological detailslongitudinally studied American Indian population, custom-designed array, skeletal muscle transcriptome analysis, functional validation in mouse myoblasts (luciferase assay)
- Longitudinally studied American Indian population
- Custom-designed array
- Skeletal muscle transcriptome analysis
- Functional validation in mouse myoblasts (luciferase assay)
Main finding
As reported in the abstract
- rs12740374 in CELSR2: top signal for LDL-C levels
- P = 1 × 10-22
- rs12740374: reduced RMR
- −44.3 kcal/day/minor-allele
- rs12740374: reduced carbohydrate oxidation rate
- −5.21 mg/hour/kg-EMBS
Further findings
Potential functional variant rs6670347
- rs6670347 minor-allele frequency
- 0.20
- Positioned in glucocorticoid receptor's core binding motif; part of a skeletal muscle-specific enhancer
Human skeletal muscle transcriptome
- CELSR2 most differentially expressed gene; RMR-lowering minor allele elevated expression
- P = 1.9 × 10-7
- rs6670347 associated with increased oxidative phosphorylation gene expression
Mouse myoblast experiments
- Enhancer-based regulation of CELSR2 expression confirmed, dependent on glucocorticoids
Original publication
Pleiotropic Effects of an eQTL in the CELSR2/PSRC1/SORT1 Cluster That Associates With LDL-C and Resting Metabolic Rate. J Clin Endocrinol Metab. Published 17 July 2024. doi:10.
Composed by AI from the published abstract and checked against it. How Briefs are made →