Department of Epidemiology Human Genetics and Environmental Sciences, Human Genetics Center, The University of Texas Health Science Center at Houston School of Public Health (N.R.H., H.C., C.S., A.C.M., P.S.d.V.).
Department of Medicine, Clinical and Translation Epidemiology Unit (K.E.W., A.K.M.), Massachusetts General Hospital, Boston.
Circ Genom Precis Med. 2023 Dec;16(6):e004176. doi: 10.1161/CIRCGEN.123.004176. Epub 2023 Nov 28.
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.
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.
Using a Bonferroni-corrected significance threshold of <1.6×10, we identified 3 genes (, , and ) associated with CAC and 2 genes ( and ) associated with carotid intima-media thickness and carotid plaque, respectively, through gene-based rare variant set analysis. Both and also had significantly different associations for CAC in T2D cases versus controls. No significant interaction tests were identified through the candidate single-variant analysis.
These results highlight T2D as an important modifier of rare variant associations in CAD loci with CAC.
2 型糖尿病（T2D）患者发生冠状动脉疾病（CAD）的风险增加，但CAD 的潜在病理学仍存在疑问。确定 CAD 基因座中哪些受 T2D 影响而在亚临床动脉粥样硬化（冠状动脉钙化[CAC]、颈动脉内膜中层厚度或颈动脉斑块）的发展中发生改变，可能有助于我们理解导致 T2D 中 CAD 增加的机制。
我们比较了文献中 CAC、颈动脉内膜中层厚度和颈动脉斑块方面的已知 CAD 基因座的常见和罕见变异关联，研究对象包括多达 29670 名参与者，包括多达 24157 名血糖正常对照者和 5513 例 T2D 患者，这些数据来自 Trans-Omics for Precision Medicine 计划的全基因组测序数据。我们在每个模型中纳入了一级 T2D 相互作用项，以确定 CAD 基因座是否受 T2D 影响。使用联合检验评估遗传主效应和相互作用效应，以确定 CAD 变异体或基于基因的罕见变异体集是否与各自的亚临床动脉粥样硬化测量值相关，然后进一步确定这些基因座是否存在显著的相互作用检验。
使用 Bonferroni 校正后的显著阈值<1.6×10，我们通过基于基因的罕见变异体集分析，鉴定出 3 个与 CAC 相关的基因（、和）和 2 个与颈动脉内膜中层厚度和颈动脉斑块分别相关的基因（和）。和在 T2D 患者与对照组之间的 CAC 也有显著不同的相关性。候选单变异体分析未发现显著的相互作用检验。
这些结果强调了 T2D 是 CAC 中 CAD 基因座罕见变异体关联的重要修饰因子。
