| Title: | CEBPB binding at rs2643219 modulates insulin sensitivity via RASGRP1-GLUT4 axis |
| Journal: | Genes & Diseases |
| Published: | 1 Jan 2026 |
| DOI: | https://doi.org/10.1016/j.gendis.2026.102042 |
Publication 18735
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Abstract
Genome-wide association studies (GWAS) face critical limitations in resolving noncoding variants with functional impacts. Here, we introduce a function-first prioritization strategy that integrates SNP-SELEX-derived transcription factor binding profiles with genetic epidemiology. Applied to type 2 diabetes in the UK Biobank (n = 480,000), this approach identified 305 risk SNPs - 162 novel - with significantly enhanced heritability contribution, with 91 risk SNPs co-localizing at islet enhancers. CEBPB emerged as a master regulator. Focusing on a previously uncharacterized locus (rs2643219), we demonstrated allele-specific CEBPB binding at an intestinal enhancer regulating RASGRP1 - a key effector for insulin-stimulated glucose uptake. CRISPR-mediated knockout of RASGRP1 in intestinal cells ablated GLUT4 translocation and impaired glucose homeostasis in mice. Trans-ethnic validation in a Chinese cohort (n = 1718) confirmed rs2643219's clinical relevance (OR = 1.30; P = 0.023). Our strategy bridges functional genomics with pathophysiological mechanisms, establishing a blueprint for complex disease variant prioritization.</p>
20 Authors
- Yongqiang Ning
- Linbu Liao
- Lijun Zhang
- Xiao Yang
- Jie Wang
- Qianwen Xie
- Yihui Zhang
- Rui Li
- Qian Liu
- Xiling Zhao
- Nan Wu
- Shancheng Zhao
- Jiguang He
- Erfei Chen
- Ping Gao
- Gonghong Wei
- Ke Dong
- Wenju Sun
- Jing Ye
- Jian Yan
1 Application
| Application ID | Title |
|---|---|
| 52238 | Identification of novel risk variants associated with metabolism and type 2 diabetes |
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