Circulating inflammatory proteins and myocardial hypertrophy: large sample analysis of European populations from GWAS Catalog and FinnGen databases

doi:10.12307/2025.944

Abstract

Abstract: BACKGROUND: Myocardial hypertrophy often leads to severe cardiovascular diseases and is difficult to diagnose due to its early stages being hard to detect. Circulating inflammatory proteins have been found to be significantly associated with cardiovascular diseases, yet the specific mechanisms linking them to myocardial hypertrophy remain unclear.
OBJECTIVE: To investigate the relationship between circulating proteins and myocardial hypertrophy using multiple Mendelian randomization approaches.
METHODS: Utilizing data from 91 circulating inflammatory proteins in the GWAS Catalog database and the latest myocardial hypertrophy data from the R11 FinnGen database, we employed bidirectional two-sample Mendelian randomization, multivariate Mendelian randomization, and Genome-Wide Association Studies co-localization to investigate the causal relationship between circulating inflammatory proteins and myocardial hypertrophy. The accuracy of the results was verified through sensitivity tests including MR-PRESSO, Cochran’s Q test, MR-Egger intercept assessment, leave-one-out analysis, and funnel plot analysis.
RESULTS AND CONCLUSION: In the results of two-sample Mendelian randomization, the primary method used for evaluation was the Inverse Variance Weighting (IVW) approach. It was found that the level of T-cell surface glycoprotein CD6 isoform (IVW: P=0.046, OR=0.74, 95% CI: 0.66-1.00), level of slit chemokine (IVW: P=2.1×10-2, OR=0.74, 95%CI: 0.556-0.95), level of Delta and Notch-like epidermal growth factor-related receptor (IVW: P=3.7×10-4, OR=0.66, 95% CI: 0.49-0.87), level of interleukin-2 (IVW: P=3.8×10-3, OR=0.667, 95%CI: 0.50-0.88), and sulfotransferase 1A1 (IVW: P=1.42×10-2, OR=0.80, 95% CI: 0.67-0.96) had a unidirectional causal effect on cardiac hypertrophy. (2) Among the findings in multivariate Mendelian randomization, the levels of the CD6 isoform of T-cell surface glycoprotein (IVW: P=1.39×10-2, OR=0.81, 95%CI: 0.69-0.96) and the levels of Delta and Notch-like epidermal growth factor-related receptor (IVW: P=3.7×10-2, OR=0.73, 95%CI: 0.55-0.98) were positive, indicating that the results remained significant after excluding the effects of other circulating inflammatory proteins that had an impact on myocardial hypertrophy. (3) In colocalization, T-cell surface glycoprotein CD6 isoform levels had H3+H4=0.96, with the most significant single nucleotide polymorphism being rs59570070, suggesting an intrinsic link between T-cell surface glycoprotein CD6 isoform levels and myocardial hypertrophy. (4) Sensitivity results showed no abnormalities, indicating no heterogeneity or pleiotropic effects influencing the results. (5) These results verified that T cell surface glycoprotein CD6 isoforms, Slit chemokine, Delta and Notch-like epidermal growth factor-related receptors, interleukin-2, and sulfotransferase 1A1 had a unidirectional causal effect on myocardial hypertrophy. T cell surface glycoprotein CD6 isoforms and Delta and Notch-like epidermal growth factor-related receptors had the deepest impact, suggesting that there may be related pathways between T cell surface glycoprotein CD6 isoforms and myocardial hypertrophy. Mendelian randomization studies require large amounts of clinical data and therefore often use European samples from international databases for analysis. Since this analytical method has significant advantages in causal inference, precision medicine, and cross-population validation, its research results still hold great significance for the medical development in China. As Mendelian randomization research deepens, it also promotes the collection and analysis of clinical data in China to some extent. In the future, we can further analyze key protein mechanisms, combine multiomics and clinical validation, develop an inflammatory marker monitoring system and novel anti-inflammatory therapies, thereby promoting the prevention and control of cardiovascular diseases and the development of personalized medicine.

Key words: myocardial hypertrophy, circulating protein, cardiovascular disease, mendelian randomization, causal relationship, observational study, co-localization, multivariate Mendelian randomization

CLC Number:

Ding Yu, Chen Jingwen, Chen Xiuyan, Shi Huimin, Yang Yudie, Zhou Meiqi, Cui Shuai, . Circulating inflammatory proteins and myocardial hypertrophy: large sample analysis of European populations from GWAS Catalog and FinnGen databases[J]. Chinese Journal of Tissue Engineering Research, 2026, 30(4): 1047-1057.

Figures/Tables 6

2.1 研究流程此研究的暴露——循环炎症蛋白来自欧洲生物信息研究所 GWAS 目录数据库，研究人员采取用Olink Target平台对 14 824 名参与者中的 91 种血浆蛋白进行了全基因组蛋白质数量性状位点 (pQTL) 研究，并采用精准蛋白质组学技术对样本进行扫描，排除了脑源性神经营养性因子。同时用当下最新的第11版芬兰数据库中的心肌肥厚作为结局，共涵盖了453 733名参与者。该心肌肥厚数据库按照国际疾病分类(ICD-10)I42.1型，I42.2为条件，筛选出了具有显著指标的1 245例患者，并将他们的SNP作为结局变量。通过选择合适的条件筛选出SNP后，再将他们进行孟德尔随机化分析，最后通过留一法和MR-PRESSO方法进行筛选，此次未筛选出异常值。随后进行了敏感性和随机性分析，保证了所有结果的稳健性。最后还针对孟德尔随机化的结果进行了反向孟德尔随机化和多变量孟德尔随机化以及共定位分析，见图1。 2.2 工具变量的筛选结果文章对此研究的工具变量进行严格的筛选，以P显著性为1×10-2为标准纳入与之相关的工具变量，其中在阳性的结果中，分别纳入了8个SNP作为T细胞表面糖蛋白CD6异构体水平的工具变量，31个SNP作为裂隙趋化因子的工具变量，28个SNP作为Delta和Notch样表皮生长因子相关受体水平的工具变量，21个SNP作为白细胞介素2水平的工具变量，33个SNP作为白细胞介素2的工具变量。查阅PhenoScanner网站后，发现并没有与心肌肥厚显著相关的SNP。同时，所有以上SNP的F值统计量均大于10 (F > 10)，表明以上工具变量具有强烈相关性，文章中出现弱工具变量导致研究结果偏差的可能性极小。 2.3 孟德尔随机化分析结果通过孟德尔随机化法对91种循环炎症蛋白和心肌肥厚疾病进行分析。有以下5种蛋白表明在遗传学上可能与心肌肥厚存在关系，其中 T细胞表面糖蛋白CD6异构体水平(IVW：P=0.046，OR=0.74，95%CI：0.55-1.00)，裂隙趋化因子(又称为趋化因子裂隙趋化因子1)水平(IVW：P=2.1×10-2，OR=0.73，95%CI：0.556-0.95)，Delta和Notch样表皮生长因子相关受体水平(IVW：P=3.7×10-4，OR=0.66，95%CI：0.49-0.87)，白细胞介素2水平(IVW：P= 3.8×10-3，OR=0.667，95%CI：0.50-0.88)，硫酸转移酶1A1(IVW：P= 1.42×10-2，OR=0.80，95%CI：0.67-0.96)。文章还利用其他几种孟德尔随机化方法如MR Egger回归、加权中位数法和加权众数对结果进行了验证，他们的Beta值为同一指向，同一暴露的不同仿佛均显示该暴露与心肌肥厚呈正相关或负相关，这意味这结果稳健可靠，可作为遗传学上判断二者相关性的依据，见图2。在反向孟德尔随机化中，并未发现任何心肌肥厚作为暴露的情况下，为阳性结局的循环炎症蛋白。 2.4 敏感性分析结果为加强结果的稳定性，使研究成果更有说服力，在此研究中还对结果进行了敏感性分析。MR-Egger截距检验表明文章不存在异质性和水平多效性(P > 0.05)。经Cochran’s Q检验，除Delta和Notch样表皮生长因子相关受体水平外其他结果P值均大于0.05，说明无异质性。而Delta和Notch样表皮生长因子相关受体存在异质性可能是因为个别样本量相互作用导致，但对结果并无影响。通过MR-PRESSO方法未检测到异常值(P > 0.05)，更加肯定本结果在MR-PRESSO方法层面上无多效性和异质性，表明结果可靠，无其他混杂因素影响。Steiger 检验的结果P均小于0.05为TRUE，说明阳性暴露对结果均为单向阳性作用，这一点和双向孟德尔随机化结果相辅相成。留一分析和漏斗图未显示异常，说明不存在偏移的SNP，见图3，4。敏感性分析肯定了结果的稳定性和可靠性，见表2。 2.5 多变量孟德尔随机化分析结果因为此研究采用的是批量两样本孟德尔随机化分析，为了排除其他阳性暴露的影响更准确地评估每个暴露因子对某一结局的独立因果效应，文章还做了多变量孟德尔随机化分析，见图5。基于两样本孟德尔随机化分析，对5个阳性暴露进行了分析，结果如下：T细胞表面糖蛋白CD6异构体水平(IVW：P=1.39×10-2，OR=0.81，95%CI：0.69-0.96)，裂隙趋化因子水平(IVW：P=5.28×10-2，OR=0.90，95%CI：0.64-1.26)，Delta和Notch样表皮生长因子相关受体水平(IVW：P=3.7×10-2， OR=0.73，95%CI：0.55-0.98)，白细胞介素2水平(IVW：P=0.30，OR=0.83，95%CI：0.59-1.17)，硫酸转移酶1A1 (IVW：P=0.18，OR=0.85，95%CI：0.68-1.07)。从以上结果可知，T细胞表面糖蛋白CD6异构体水平和Delta和Notch样表皮生长因子相关受体水平在多变量孟德尔随机化中为阳性结果，说明在其他的阳性暴露影响下，这二者对心肌肥厚依然有相当大的影响。而Delta和Notch样表皮生长因子相关受体水平、白细胞介素2水平和硫酸转移酶1A1在多变量结果中呈阴性，说明这三者对心肌肥厚具有影响，但在其他阳性暴露的共同影响下，三者的影响没那么显著。 2.6 共定位分析结果为了找出在阳性结果中最显著的SNP基因和二者在基因范围上的关系，还进行了全基因组关联研究共定位分析，其中共定位的结果如下：T细胞表面糖蛋白CD6异构体水平H3+H4=0.96，其中H3=0.89， H4=0.07，裂隙趋化因子水平H3+H4=0.11，Delta和Notch样表皮生长因子相关受体水平H3+H4=0.04，白细胞介素2水平H3+H4=0.01，硫酸转移酶1A1 H3+H4=0.03。从以上结果可知，几个阳性结果在共定位中有显著意义的为T细胞表面糖蛋白CD6异构体水平。 T细胞表面糖蛋白CD6异构体水平和心肌肥厚的共定位结果中，H3=0.89意味着T细胞表面糖蛋白CD6异构体水平与心肌肥厚在该区域内的SNP位点显著相关，但是是不同的因果变异位点。并且文章测得它的最显著的SNP为rs59570070，见图6，最显著的SNP是指与表型关联最强的SNP，通常是指可能和表型相关的关键位点。因此rs59570070可用于识别T细胞表面糖蛋白CD6异构体和心肌肥厚相关基因区域的潜在基因位点，帮助探寻二者在机制上的联系[44]。 2.7 假设验证结果遗传变异通过影响循环炎症蛋白水平，与心肌肥厚的风险相关。文章的研究结果充分印证了这一假设，得出了循环炎症蛋白在遗传学上与心肌肥厚存在一定的关联，并且筛选出了5种具有显著意义的循环炎症蛋白，分别是T细胞表面糖蛋白CD6异构体水平、裂隙趋化因子、Delta和Notch样表皮生长因子相关受体水平、白细胞介素2水平和磺基转移酶。这也证实了先前的假设，即在基于遗传学工具变量，推断炎症蛋白的升高是会增加心肌肥厚的风险，验证了炎症蛋白是心肌肥厚的因果因素。这一假设的验证将为炎症蛋白在心肌疾病中的作用提供新的见解，并可能为预防和治疗心肌肥厚提供潜在的生物学靶点。药物或生活方式干预措施可以针对炎症反应进行管理，从而降低心肌肥厚的风险，该发现可能进一步拓展心血管疾病的治疗策略。"

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