Department of Cardiology, Lihuili Hospital Affiliated to Ningbo University, Ningbo University, Ningbo, Zhejiang, China.
School of Medicine, Ningbo University, Ningbo, Zhejiang, China.
Front Immunol. 2024 Aug 29;15:1408347. doi: 10.3389/fimmu.2024.1408347. eCollection 2024.
Coronary artery disease (CAD) imposes a significant global health burden, necessitating a deeper comprehension of its genetic foundations to uncover innovative therapeutic targets. Employing a comprehensive Mendelian randomization (MR) approach, we aimed to explore the genetic associations between lipid profiles, immune cell phenotypes, and CAD risk.
Utilizing data from recent large-scale genome-wide association studies (GWAS), we scrutinized 179 lipid and 731 immune cell phenotypes to delineate their genetic contributions to CAD pathogenesis, including coronary artery calcification (CAC). Moreover, specific immune cell phenotypes were examined as potential mediators of the lipid-CAD/CAC causal pathway.
Among the 162 lipid species with qualified instrumental variables (IVs) included in the analysis, we identified 36 lipids that exhibit a genetic causal relationship with CAD, with 29 being risk factors and 7 serving as protective factors. Phosphatidylethanolamine (18:0_20:4) with 8 IVs (OR, 95% CI, P-value: 1.04, 1.02-1.06, 1.50E-04) met the Bonferroni-corrected significance threshold (0.05/162 = 3.09E-04). Notably, all 18 shared lipids were determined to be risk factors for both CAD and CAC, including 16 triacylglycerol traits (15 of which had ≥ 3 IVs), with (50:1) exhibiting the highest risk [OR (95% CI) in CAC: 1.428 (1.129-1.807); OR (95% CI) in CAD: 1.119 (1.046-1.198)], and 2 diacylglycerol traits. Furthermore, we identified HLA DR+ natural killer cells (IVs = 3) as nominally significant with lipids and as potential mediators in the causal pathway between diacylglycerol (16:1_18:1) or various triacylglycerols and CAD (mediated effect: 0.007 to 0.013).
This study provides preliminary insights into the genetic correlations between lipid metabolism, immune cell dynamics, and CAD susceptibility, highlighting the potential involvement of natural killer cells in the lipid-CAD/CAC causal pathway and suggesting new targets for therapy. Further evidence is necessary to substantiate our findings.
冠心病（CAD）在全球范围内造成了重大的健康负担，因此需要深入了解其遗传基础，以发现新的治疗靶点。我们采用全面的孟德尔随机化（MR）方法，旨在探讨脂质谱、免疫细胞表型与 CAD 风险之间的遗传关联。
利用最近的大型全基因组关联研究（GWAS）数据，我们研究了 179 种脂质和 731 种免疫细胞表型，以阐明它们在 CAD 发病机制中的遗传贡献，包括冠状动脉钙化（CAC）。此外，我们还研究了特定的免疫细胞表型是否可以作为脂质与 CAD/CAC 因果关系的潜在中介。
在纳入分析的 162 种具有合格工具变量（IVs）的脂质中，我们鉴定出 36 种脂质与 CAD 具有遗传因果关系，其中 29 种是危险因素，7 种是保护因素。具有 8 个 IVs 的磷脂酰乙醇胺（18:0_20:4）（OR，95%CI，P 值：1.04，1.02-1.06，1.50E-04）达到了 Bonferroni 校正的显著性阈值（0.05/162=3.09E-04）。值得注意的是，所有 18 种共享脂质均被确定为 CAD 和 CAC 的危险因素，包括 16 种三酰甘油特征（其中 15 种具有≥3 个 IVs），其中（50:1）的风险最高[OR（95%CI）在 CAC 中：1.428（1.129-1.807）；OR（95%CI）在 CAD 中：1.119（1.046-1.198）]，还有 2 种二酰甘油特征。此外，我们还发现 HLA-DR+自然杀伤细胞（IVs=3）与脂质呈名义相关，并且可能是二酰甘油（16:1_18:1）或各种三酰甘油与 CAD 之间因果关系的潜在中介（中介效应：0.007 至 0.013）。
本研究初步探讨了脂质代谢、免疫细胞动态与 CAD 易感性之间的遗传相关性，强调了自然杀伤细胞在脂质与 CAD/CAC 因果关系中的潜在作用，并为治疗提供了新的靶点。需要进一步的证据来证实我们的发现。
