脂质和面部衰老的因果和中介作用：整合 GWAS、eQTL、mQTL 和 pQTL 数据的关联研究。

Causal and mediating effects of lipid and facial aging: association study integrating GWAS, eQTL, mQTL, and pQTL data.

机构信息

Department of Plastic Surgery, The First Affiliated Hospital of Dalian Medical University, 222 Zhongshan Road, Dalian, 116011, China.

Stem Cell Clinical Research Center, The First Affiliated Hospital of Dalian Medical University, Dalian, 116011, China.

出版信息

Lipids Health Dis. 2024 Oct 21;23(1):342. doi: 10.1186/s12944-024-02328-1.

DOI:10.1186/s12944-024-02328-1

PMID:39434152

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11492622/

Abstract

BACKGROUND

Increasing evidence suggests a potential causal association between lipid levels and facial aging. The aim of this study was to investigate the relationship between levels of specific lipids and facial aging via Mendelian randomization methods. Additionally, this study aimed to identify mediators and explore relevant genes and drug targets.

METHODS

In this study, genome-wide association data on plasma lipids from 7,174 Finnish individuals in the UK Biobank were used. Two-sample Mendelian randomization was applied to assess the causal effects of specific lipids on facial aging. Sensitivity and pleiotropy analyses were conducted to ensure the robustness and reliability of the results. Multivariate Mendelian randomization was conducted to account for the potential impact of confounding factors. Furthermore, summary-data-based Mendelian randomization was used to identify relevant genes, which were validated through multiomics data. Finally, drug‒gene interactions were explored via molecular docking techniques.

RESULTS

Two-sample Mendelian randomization analysis revealed a causal relationship between lipid levels and facial aging. According to the multivariate Mendelian randomization results, smoking was found to mediate this association, and these lipids remained significantly associated with facial aging, even after accounting for environmental confounders. Using summary-data-based Mendelian randomization, CYP21A2, CCND1, PSMA4, and MED1 were identified as potential gene targets, with MED1 further validated through pQTL and mQTL data. Additionally, the MED1 protein was found to bind spontaneously with astragalin, fenofibrate, and ginsenoside.

CONCLUSIONS

The results revealed a causal relationship between lipid levels and facial aging, revealing key gene targets that were still significantly associated with facial aging after controlling for environmental confounders. Additionally, the interactions between MED1 and certain drugs may indicate potential pathways for therapeutic interventions related to facial aging.

摘要

背景

越来越多的证据表明，血脂水平与面部衰老之间可能存在因果关系。本研究旨在通过孟德尔随机化方法探讨特定脂质水平与面部衰老之间的关系。此外，本研究旨在确定中介物，并探索相关基因和药物靶点。

方法

本研究使用英国生物库中 7174 名芬兰个体的血浆脂质全基因组关联数据。采用两样本孟德尔随机化方法评估特定脂质对面部衰老的因果效应。进行敏感性和多效性分析以确保结果的稳健性和可靠性。进行多变量孟德尔随机化以考虑潜在混杂因素的影响。此外，使用基于汇总数据的孟德尔随机化来识别相关基因，并通过多组学数据进行验证。最后，通过分子对接技术探讨药物-基因相互作用。

结果

两样本孟德尔随机化分析显示脂质水平与面部衰老之间存在因果关系。根据多变量孟德尔随机化结果，发现吸烟是这种关联的中介物，这些脂质与面部衰老仍然存在显著关联，即使考虑了环境混杂因素。使用基于汇总数据的孟德尔随机化，鉴定出 CYP21A2、CCND1、PSMA4 和 MED1 作为潜在的基因靶点，并且通过 pQTL 和 mQTL 数据进一步验证了 MED1。此外，发现 MED1 蛋白与黄芩素、非诺贝特和人参皂苷自发结合。