Bandesh Khushdeep, Freeland Kendrick, Traurig Michael, Hanson Robert L, Bogardus Clifton, Piaggi Paolo, Baier Leslie J
Phoenix Epidemiology and Clinical Research Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, AZ 85004, USA.
J Clin Endocrinol Metab. 2025 Jan 21;110(2):480-488. doi: 10.1210/clinem/dgae498.
The locus CELSR2-PSRC1-SORT1, a primary genetic signal for lipids, has recently been implicated in different metabolic processes. Our investigation identified its association with energy metabolism.
This work aimed to determine biological mechanisms that govern diverse functions of this locus.
Genotypes for 491 265 variants in 7000 clinically characterized American Indians were previously determined using a custom-designed array specific for this longitudinally studied American Indian population. Among the genotyped individuals, 5205 had measures of fasting lipid levels and 509 had measures of resting metabolic rate (RMR) and substrate oxidation rate assessed through indirect calorimetry. A genome-wide association study (GWAS) for low-density lipoprotein cholesterol (LDL-C) levels identified a variant in CELSR2, and the molecular effect of this variant on gene expression was assessed in skeletal muscle biopsies from 207 participants, followed by functional validation in mouse myoblasts using a luciferase assay.
A GWAS in American Indians identified rs12740374 in CELSR2 as the top signal for LDL-C levels (P = 1 × 10-22); further analysis of this variant identified an unexpected correlation with reduced RMR (effect = -44.3 kcal/day/minor-allele) and carbohydrate oxidation rate (effect = -5.21 mg/hour/kg-EMBS). Tagged variants showed a distinct linkage disequilibrium architecture in American Indians, highlighting a potential functional variant, rs6670347 (minor-allele frequency = 0.20). Positioned in the glucocorticoid receptor's core binding motif, rs6670347 is part of a skeletal muscle-specific enhancer. Human skeletal muscle transcriptome analysis showed CELSR2 as the most differentially expressed gene (P = 1.9 × 10-7), with the RMR-lowering minor allele elevating gene expression. Experiments in mouse myoblasts confirmed enhancer-based regulation of CELSR2 expression, dependent on glucocorticoids. Rs6670347 was also associated with increased oxidative phosphorylation gene expression; CELSR2, as a regulator of these genes, suggests a potential influence on energy metabolism through muscle oxidative capacity.
Variants in the CELSR2/PSRC1/SORT1 locus exhibit tissue-specific effects on metabolic traits, with an independent role in muscle metabolism through glucocorticoid signaling.
CELSR2 - PSRC1 - SORT1基因座是脂质的主要遗传信号，最近已被证明与不同的代谢过程有关。我们的研究确定了它与能量代谢的关联。
这项工作旨在确定控制该基因座多种功能的生物学机制。
此前，我们使用专门为这个经过长期研究的美洲印第安人群定制设计的芯片，确定了7000名具有临床特征的美洲印第安人身上491265个变体的基因型。在这些基因分型个体中，5205人有空腹血脂水平测量数据，509人有通过间接量热法评估的静息代谢率（RMR）和底物氧化率测量数据。一项针对低密度脂蛋白胆固醇（LDL - C）水平的全基因组关联研究（GWAS）确定了CELSR2中的一个变体，并在207名参与者的骨骼肌活检样本中评估了该变体对基因表达的分子效应，随后在小鼠成肌细胞中使用荧光素酶测定法进行功能验证。
美洲印第安人的GWAS确定CELSR2中的rs12740374是LDL - C水平的最强信号（P = 1×10⁻²²）；对该变体的进一步分析发现它与RMR降低（效应 = - 44.3千卡/天/次要等位基因）和碳水化合物氧化率降低（效应 = - 5.21毫克/小时/千克 - EMBS）存在意外的相关性。标记变体在美洲印第安人中显示出独特的连锁不平衡结构，突出了一个潜在的功能变体rs6670347（次要等位基因频率 = 0.20）。rs6670347位于糖皮质激素受体的核心结合基序中，是骨骼肌特异性增强子的一部分。人类骨骼肌转录组分析显示CELSR2是差异表达最显著的基因（P = 1.9×10⁻⁷），降低RMR的次要等位基因会提高基因表达。小鼠成肌细胞实验证实了基于增强子对CELSR2表达的调控，该调控依赖于糖皮质激素。rs6670347也与氧化磷酸化基因表达增加有关；CELSR2作为这些基因的调节因子，表明它可能通过肌肉氧化能力对能量代谢产生影响。
CELSR2/PSRC1/SORT1基因座中的变体对代谢性状表现出组织特异性影响，通过糖皮质激素信号在肌肉代谢中发挥独立作用。
