2型糖尿病改变CAD基因组风险变异与亚临床动脉粥样硬化的关系

IF 6 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

Circulation: Genomic and Precision Medicine Pub Date : 2023-12-01 Epub Date: 2023-11-28 DOI:10.1161/CIRCGEN.123.004176

Natalie R Hasbani, Kenneth E Westerman, Soo Heon Kwak, Han Chen, Xihao Li, Daniel Di Corpo, Jennifer Wessel, Joshua C Bis, Chloè Sarnowski, Peitao Wu, Lawrence F Bielak, Xiuqing Guo, Nancy Heard-Costa, Gregory L Kinney, Michael C Mahaney, May E Montasser, Nicholette D Palmer, Laura M Raffield, James G Terry, Lisa R Yanek, Jessica Bon, Donald W Bowden, Jennifer A Brody, Ravindranath Duggirala, David R Jacobs, Rita R Kalyani, Leslie A Lange, Braxton D Mitchell, Jennifer A Smith, Kent D Taylor, April P Carson, Joanne E Curran, Myriam Fornage, Barry I Freedman, Stacey Gabriel, Richard A Gibbs, Namrata Gupta, Sharon L R Kardia, Brian G Kral, Zeineen Momin, Anne B Newman, Wendy S Post, Karine A Viaud-Martinez, Kendra A Young, Lewis C Becker, Alain G Bertoni, John Blangero, John J Carr, Katherine Pratte, Bruce M Psaty, Stephen S Rich, Joseph C Wu, Rajeev Malhotra, Patricia A Peyser, Alanna C Morrison, Ramachandran S Vasan, Xihong Lin, Jerome I Rotter, James B Meigs, Alisa K Manning, Paul S de Vries

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引用次数: 0

摘要

背景:2型糖尿病(T2D)患者发生冠状动脉疾病(CAD)的风险增加，但其潜在病理仍存在疑问。确定哪些CAD位点在亚临床动脉粥样硬化(冠状动脉钙化[CAC]、颈动脉内膜-中膜厚度或颈动脉斑块)的发展过程中被T2D修饰，可以提高我们对导致T2D中CAD增加的机制的理解。方法:我们利用来自Trans-Omics for Precision Medicine项目的全基因组测序数据，在29670名参与者中比较了CAC、颈动脉内膜-中膜厚度和颈动脉斑块等文献中已知CAD基因座的常见和罕见变异关联，其中包括24157名血糖控制正常的患者和5513名T2D患者。我们在每个模型中加入一阶T2D相互作用项，以确定CAD基因座是否被T2D修改。使用联合测试评估遗传主效应和相互作用效应，以确定CAD变体或基于基因的罕见变体集是否与各自的亚临床动脉粥样硬化措施相关，然后进一步确定这些位点是否具有显著的相互作用测试。结果:采用bonferroni校正的P-4显著性阈值，通过基于基因的罕见变异集分析，我们分别鉴定出与CAC相关的3个基因(ATP1B1、ARVCF和LIPG)和与颈动脉内膜-中膜厚度和颈动脉斑块相关的2个基因(ABCG8和EIF2B2)。T2D患者与对照组相比，ATP1B1和ARVCF与CAC的相关性也有显著差异。通过候选单变量分析未发现显著的相互作用试验。结论:这些结果强调T2D是CAD基因座与CAC罕见变异关联的重要修饰因子。

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Type 2 Diabetes Modifies the Association of CAD Genomic Risk Variants With Subclinical Atherosclerosis.

Background: Individuals with type 2 diabetes (T2D) have an increased risk of coronary artery disease (CAD), but questions remain about the underlying pathology. Identifying which CAD loci are modified by T2D in the development of subclinical atherosclerosis (coronary artery calcification [CAC], carotid intima-media thickness, or carotid plaque) may improve our understanding of the mechanisms leading to the increased CAD in T2D.

Methods: We compared the common and rare variant associations of known CAD loci from the literature on CAC, carotid intima-media thickness, and carotid plaque in up to 29 670 participants, including up to 24 157 normoglycemic controls and 5513 T2D cases leveraging whole-genome sequencing data from the Trans-Omics for Precision Medicine program. We included first-order T2D interaction terms in each model to determine whether CAD loci were modified by T2D. The genetic main and interaction effects were assessed using a joint test to determine whether a CAD variant, or gene-based rare variant set, was associated with the respective subclinical atherosclerosis measures and then further determined whether these loci had a significant interaction test.

Results: Using a Bonferroni-corrected significance threshold of P<1.6×10^-4, we identified 3 genes (ATP1B1, ARVCF, and LIPG) associated with CAC and 2 genes (ABCG8 and EIF2B2) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both ATP1B1 and ARVCF also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis.

Conclusions: These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.

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来源期刊

Circulation: Genomic and Precision Medicine Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

9.20

自引率

5.40%

发文量

144

期刊介绍： Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations. Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.