| Title: | Investigation of the impact of gynoid fat on steatotic and advanced liver diseases-Genomic and clinical perspectives from a large-scale population cohort |
| Journal: | Clinical Nutrition |
| Published: | 21 Nov 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41314110/ |
| DOI: | https://doi.org/10.1016/j.clnu.2025.11.012 |
Publication 18851
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Abstract
BACKGROUND AND AIMS: Gynoid fat (hip-thigh subcutaneous adiposity) is metabolically favorable, yet its genetic architecture and impact on liver diseases are unknown. We aimed to identify genetic determinants of gynoid tissue fat percentage (GTFP) and explore their clinical implications to liver disease.</p>
METHODS: We conducted a genome-wide association study (GWAS) in 37,385 European individuals from the UK Biobank to identify genetic variants associated with GTFP. A polygenic risk score (PRS) was then derived for GTFP. Post-GWAS analyses, including colocalization, transcriptome-wide association studies (TWAS), logistic regression models, and interaction analyses, were employed to assess the impact of GTFP indicated by PRS on alcoholic and non-alcoholic fatty liver disease (NAFLD), metabolic dysfunction associated steatotic liver disease (MASLD), liver fibrosis and liver cancer.</p>
RESULTS: Our GWAS identified 18 significant genetic variants that were associated with GTFP. Colocalization and TWAS highlighted shared signals with adipose gene expression at RSPO3, CCND1, and MYEOV et al. Integrative single-cell analysis revealed that candidate genes were mostly enriched in adipogenic progenitors, macrophages, myeloid cells and mature adipocytes. GTFP PRS showed negative correlation with metabolic traits that are crucial for steatotic liver disease development. GTFP PRS was associated with a reduced risk of NAFLD (OR = 0.97 [95 % CI 0.95-0.99], p = 0.017), liver fibrosis (OR = 0.97 [95 % CI 0.94-1.00], p = 0.029) and MASLD defined by either fatty liver index (OR = 0.94 [95 % CI 0.91-0.97], p < 0.001) or liver proton density fat fraction (OR = 0.95 [95 % CI 0.947-0.953], p < 0.001) and the decline of indices reflecting hepatic steatosis in MASLD population. No significant associations were observed for alcoholic liver disease and liver cancer. The restricted cubic spline regression suggested a linear relationship between GTFP PRS and MASLD risk, but not for other liver diseases. GTFP PRS plays stronger effects among individuals with healthier metabolic status and higher physical activity, but were independent of PNPLA3-rs738409 and TM6SF2-rs58542926.</p>
CONCLUSIONS: We delineate the genetic landscape of gynoid fat and provide evidence that higher GTFP, proxied by PRS, protects against NAFLD, MASLD and liver fibrosis, supporting adipose-targeted strategies for prevention and risk stratification.</p>
13 Authors
- Zhengye Liu
- Haotian Chen
- Hanze Du
- Guang Lin
- Tian Tu
- Ziqi Wan
- Nan Zhao
- Guanqiao Li
- Bowen Tang
- Huilin Wu
- Xiaoyin Bai
- Qiao-Li Wang
- Jiarui Mi
3 Applications
| Application ID | Title |
|---|---|
| 42066 | Development and validation of a risk prediction model for oesophageal squamous cell carcinoma using cohort studies |
| 100787 | New integrated approaches based on phenotype and genetic data to explore the potential pathogenesis and novel biomarkers for the digestive diseases |
| 157997 | Decoding the pathogenesis of digestive disorders and developing predictive tools using phenotypic and genomic data from the UK Biobank |
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