A comprehensive multi-layered analysis reveals genetic pleiotropy underlying coronary artery calcification and bone mineral density

IF 3.9 2区医学 Q2 ENDOCRINOLOGY & METABOLISM

Bone Pub Date : 2026-02-01 Epub Date: 2025-11-06 DOI:10.1016/j.bone.2025.117719

Tao Han , Yang Qu , Jiangbo Zhu , Linna Sha , Bowen Lei , Rong Xiang , Xunying Zhao , Jiaojiao Hou , Qin Deng , Sirui Zheng , Jinyu Zhou , Ting Yu , Xin Song , Bin Yang , Yangdan Zhong , Maoyao Xia , Douglas P. Kiel , Xia Jiang

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引用次数: 0

Abstract

Objectives

Subclinical atherosclerosis and osteoporosis are often present together in the same individual, but their common mechanisms remain unclear. This study aims to investigate the pleiotropic relationship underlying coronary artery calcification (CAC) and estimated calcaneal bone mineral density (eBMD), providing molecular insights into their observed phenotypic associations.

Methods

Genetic correlation between CAC and eBMD was estimated based on genome-wide summary statistics. Shared loci were examined at the levels of single-nucleotide polymorphism (SNP), multi-SNP, and gene expressions to provide insights into genetic pleiotropy. Sensitivity analyses using data of DXA-derived BMD at femoral neck and lumbar spine were performed to validate key findings. Pathway enrichment analyses were conducted on significant shared loci to explore potential biological mechanisms.

Results

Despite an absence of a global genetic correlation, partitioning the genome into independent regions revealed five significant signals. Through subsequent multi-layered analysis, we identified 211 non-overlapping significant shared genes, including 190 from single-SNP-level, 27 from multi-SNP-level, and 3 from gene expression level, underscoring the widespread pleiotropy across CAC and eBMD. Notably, the shared signals were predominantly concentrated on chromosome 17, with SMG6 and PAFAH1B1 highlighted as crucial pleiotropic genes, and both were further confirmed by sensitivity analyses. Pathway enrichment analyses revealed oxidative stress regulation and the ubiquitin-proteasome system as critical biological mechanisms potentially linking the two traits.

Conclusion

Our study demonstrates that the observed association between CAC and eBMD is mainly driven by pleiotropic associations.

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一项全面的多层分析揭示了冠状动脉钙化和骨密度的遗传多效性。

目的：亚临床动脉粥样硬化和骨质疏松常伴有，但其共同机制尚不清楚。本研究旨在探讨冠状动脉钙化（CAC）和跟骨骨密度（eBMD）之间的多效性关系，为观察到的表型关联提供分子见解。方法：基于全基因组汇总统计估计CAC与eBMD的遗传相关性。在单核苷酸多态性（SNP），多SNP和基因表达水平上检查共享位点，以提供遗传多效性的见解。利用dxa衍生的股骨颈和腰椎骨密度数据进行敏感性分析，以验证关键发现。对重要的共享位点进行通路富集分析，探索潜在的生物学机制。结果：尽管缺乏全局遗传相关性，但将基因组划分为独立区域揭示了五个重要信号。通过随后的多层分析，我们确定了211个非重叠的重要共享基因，其中190个来自单snp水平，27个来自多snp水平，3个来自基因表达水平，强调了CAC和eBMD中广泛存在的多效性。值得注意的是，共享信号主要集中在17号染色体上，SMG6和PAFAH1B1被强调为关键的多效性基因，这两个基因都被敏感性分析进一步证实。途径富集分析显示，氧化应激调节和泛素-蛋白酶体系统可能是连接这两个性状的关键生物学机制。结论：我们的研究表明，CAC与eBMD之间的关联主要是由多效性关联驱动的。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Bone 医学-内分泌学与代谢

CiteScore

8.90

自引率

4.90%

发文量

264

审稿时长

30 days

期刊介绍： BONE is an interdisciplinary forum for the rapid publication of original articles and reviews on basic, translational, and clinical aspects of bone and mineral metabolism. The Journal also encourages submissions related to interactions of bone with other organ systems, including cartilage, endocrine, muscle, fat, neural, vascular, gastrointestinal, hematopoietic, and immune systems. Particular attention is placed on the application of experimental studies to clinical practice.