Abstract
Background
Coronary heart disease (CHD) is a chronic inflammatory disease carrying high morbidity and mortality. Interleukin (IL)-29 may be used as a biomarker for autoimmune diseases. This paper investigates the diagnostic value of serum IL-29 in CHD patients.
Methods
A total of 90 CHD patients (39 mild and 51 severe patients) and 90 controls were included. Serum IL-29 levels were detected by ELISA, and the diagnostic value of IL-29 in CHD was analyzed by ROC curve. According to the median value of serum IL-29 level, CHD patients were categorized into IL-29 low-level group and high-level group. The correlation between IL-29 and pathological indexes of CHD patients was analyzed by chi-square test. SYNTAX score was used to classify CHD patients into mild CHD and moderate/severe CHD. Pearson coefficient analyzed the correlation between IL-29 and CHD severity. Multivariate logistic regression analyzed the risk factors for CHD exacerbation.
Results
IL-29 serum levels were elevated in CHD patients. The AUC for CHD diagnosis by serum IL-29 was 0.789 (65.6% sensitivity and 76.7% specificity). IL-29 was correlated with BMI, PHASE score, and CRP. IL-29 serum level was positively correlated with CHD severity. The AUC for differentiating mild and moderate/severe CHD patients by IL-29 level was 0.739 (70.6% sensitivity and 66.7% specificity). IL-29 was an independent risk factor for CHD exacerbation, and each one-unit increase in IL-29 increased the risk of exacerbation in CHD patients by 1.065-fold.
Conclusion
IL-29 is highly expressed in CHD patients and has auxiliary diagnostic value for CHD.
Keywords: Coronary heart disease, IL-29, Diagnosis, ROC, Logistic regression, SYNTAX score
Introduction
Coronary heart disease (CHD) is a common cardiovascular disease with substantial morbidity and mortality [1]. The pathogenesis of CHD is a highly complex process that involves an imbalanced lipid metabolism and a maladaptive immune response entailing a chronic inflammation of the arterial wall [2, 3]. The main risk factors for CHD consist of dyslipidemia, diabetes, arterial hypertension, obesity, smoking, and a sedentary lifestyle [4]. Despite the continuous innovation of diagnostic methods for CHD, CHD in the early stage is still missed diagnosis due to the absence of any symptoms [5]. Hence, the identification of effective diagnostic targets is crucial for the management of CHD [6]. On the account of the strong inflammation nature of CHD, various inflammatory factors are considered potent biomarkers for the early prediction of CHD [7].
The interleukin (IL)-10 family of cytokines, including IL-10, IL-19, IL-20, IL-22, IL-24, IL-26, and the more distantly related IL-28 A, IL-28B, and IL-29, plays important roles in the development of atherosclerosis, cardiac fibrosis, hypertension, and cardiac hypertrophy [8]. IL-29 belongs to the type III interferon (IFN) family, which can mediate signal transduction via binding to its receptor complex and induces the generation of inflammatory components via activation of downstream signaling pathways such as JAK-STAT, AKT, and MAPK [9]. Compelling evidence has revealed the significant diagnostic value of IL-29 in inflammatory autoimmune diseases. For example, serum IL-29 level can be used as a biological diagnostic marker in rheumatoid arthritis [10], and serum IL-29 level is also closely associated with the severity of psoriasis vulgaris [11]. IL-29 can activate the production of IL-10, IL-8 and IL-6 by monocytes and macrophages [12], which are inflammatory factors indicating systemic inflammation in CHD. The mRNA expression of IL-29 is significantly increased in calcified carotid arteries from patients with CHD [13]. However, the clinical significance of IL-29 in CHD is rarely reported. Based on the above background, the current study was performed to determine the serum expression levels of IL-29 in CHD patients and its clinical diagnostic values in CHD patients.
Methods
Study subjects
This study was approved by the Ethics Committee of The Third People’s Hospital of Kunshan, and all subjects were fully informed of the study purpose before inclusion and signed an informed consent form before sampling. Ninety CHD patients hospitalized in The Third People’s Hospital of Kunshan from January 2022 to January 2024 were enrolled. In addition, 90 volunteers who received health examinations during the same period were selected as the controls.
Inclusion criteria: (1) All patients met the World Health Organization (WHO) diagnostic criteria for CHD based on medical history, physical examination, electrocardiogram, and cardiac ultrasound, and the diagnosis was confirmed by coronary arteriography; (2) Clinical examination and medical record data were complete.
Exclusion criteria: Patients who suffered from chronic heart failure, myocarditis, cardiomyopathy, pericardial disease, moderate-to-severe valvular disease, severe liver or renal disease, thyroid disease, severe infections, systemic autoimmune diseases, and malignant tumors.
The severity of 90 CHD patients was assessed by SYNTAX score, a precise angiographic tool for assessing the complexity of CHD. Coronary angiographic images of each patient were independently evaluated by 2 experienced cardiologists without knowledge of the patient’s clinical features and outcomes, and the SYNTAX score was calculated. Patients were categorized into 2 subgroups based on the SYNTAX score: (1) mild CHD (0 ~ 22 points) (N = 39) and (2) moderate/severe CHD (≥ 23 points) (N = 51).
Baseline information collection
The baseline information of all subjects was collected on admission, including age, gender, body mass index (BMI), history of hypertension, smoking, alcohol consumption, and diabetes. About 8 mL of venous blood was collected from each subject and centrifuged (2000 g, 10 min) within 3 h. The C-reactive protein (CRP) level was detected by a fully automatic analyzer (BC-5390, Mindray, Shenzhen, China), and the lipid levels, including total cholesterol (TC), triglyceride (TG), low-density lipoprotein-cholesterol (LDL-c), and high-density lipoprotein-cholesterol (HDL-c) were detected by a fully automatic biochemical analyzer (Chemray 240, Rayto, Shenzhen, China).
Measurement of IL-29 levels
Human IL-29 ELISA kit (ab236715, Abcam, Cambridge, MA, USA) was used to detect serum IL-29 levels in all subjects according to the manufacturer’s instructions.
Data analysis
SPSS 21.0 (SPSS, Inc, Chicago, IL, USA) and GraphPad Prism 8 (GraphPad Software, San Diego, CA, USA) were used for data analyses and graphing. Data were categorized into counts and measures, with counting data expressed as the number of cases and percentages, and measurement data expressed as mean ± standard deviation. The chi-square test was utilized to compare the counting data between two groups. Kolmogorov-Smirnov test and D’Agostino test were used for normality tests. Independent samples t-test was used for comparisons between two groups of measurement data when continuous variables conformed to normal distribution. The diagnostic value of IL-29 in CHD was analyzed using the receiver operation characteristic (ROC) curve. Binary logistic regression equations were used to assess the risk factors of CHD patients. P value was obtained from two-sided tests, and P < 0.05 implied statistically significant differences.
Results
Clinical baseline characteristics of the enrolled population
There were no statistical differences in age, gender, BMI, hypertension, TG, HDL-c, LDL-c, history of smoking, history of alcohol consumption, and history of diabetes between CHD patients and controls (all P > 0.05). Compared with those in the control group, the TC and CRP levels were elevated in the CHD group (all P < 0.05) (Table 1).
Table 1.
Comparison of clinical baseline characteristics
| Information | Control (N = 90) |
CHD (N = 90) |
P |
|---|---|---|---|
| Age (years) | 62.69 ± 7.16 | 61.36 ± 7.88 | 0.236a |
| Gender (male) | 48 (53.3%) | 53 (58.9%) | 0.453b |
| BMI (kg/m2) | 23.69 ± 1.41 | 23.41 ± 1.38 | 0.171a |
| Hypertension | 38 (42.2%) | 41 (45.6%) | 0.652b |
| TC (mmol/L) | 4.32 ± 0.84 | 4.62 ± 0.75 | 0.011a |
| TG (mmol/L) | 1.31 ± 0.42 | 1.36 ± 0.48 | 0.503a |
| HDL-c (mmol/L) | 1.23 ± 0.30 | 1.23 ± 0.26 | 0.892a |
| LDL-c (mmol/L) | 2.51 ± 0.33 | 2.54 ± 0.40 | 0.561a |
| Smoking, Current | 54 (60.0%) | 49 (54.4%) | 0.451b |
| Drinking, Current | 44 (48.9%) | 51 (56.7%) | 0.296b |
| Diabetes | 25 (27.8%) | 32 (35.6%) | 0.262b |
| SNYTAX score | - | 23.66 ± 7.41 | - |
| CRP (mg/L) | 6.24 ± 1.86 | 9.37 ± 2.84 | < 0.001a |
Note: CHD, coronary heart disease; BMI, body mass index; TC, total cholesterol; TG, triglyceride; HDL-c, high-density lipoprotein-cholesterol; LDL-c, low-density lipoprotein-cholesterol; CRP, C-reactive protein
IL-29 is highly expressed in CHD patients
ELISA results revealed that IL-29 levels were significantly higher in the CHD group than those in the Control group (P < 0.05, Fig. 1A). We further plotted the ROC curves of CHD patients by IL-29 levels. The results uncovered that the area under the ROC curve (AUC) for differentiating controls from CHD patients by IL-29 levels was 0.789, with a cutoff value of 64.12, a sensitivity of 65.6%, and a specificity of 76.7% (P < 0.001, Fig. 1B). Briefly, serum IL-29 levels have potential value in aiding CHD diagnosis.
Fig. 1.
IL-29 is highly expressed in the serum of CHD patients and has high diagnostic value
A: ELISA to detect the level of IL-29 in the serum of controls and CHD groups; B: ROC curve to analyze the diagnostic efficacy of IL-29 in CHD patients. Figure A was analyzed using independent samples t-test and Figure B was analyzed using ROC. *P < 0.05
Correlation between IL-29 levels and clinical characteristics of CHD patients
The median value of serum IL-29 levels in CHD patients was used to classify CHD patients into IL-29 high-level and low-level groups to further analyze the correlation between serum IL-29 levels and clinicopathological characteristics of CHD patients. The results noted no significant correlation of serum IL-29 levels with age, gender, BMI, hypertension, TC, TG, HDL-c, LDL-c, smoking, alcohol consumption, and diabetes in CHD patients (all P > 0.05), whereas there were significant correlations with SNYTAX scores and CRP levels in CHD patients (all P < 0.05) (Table 2).
Table 2.
IL-29 expression and clinical baseline characteristics of CHD patients
| Clinical pathological features |
IL-29 | P | |
|---|---|---|---|
| Low level (N = 45) |
High level (N = 45) |
||
| Age (years) | 62.27 ± 8.18 | 60.44 ± 7.56 | 0.275a |
| Gender (male) | 29 (64.4%) | 24 (53.3%) | 0.284b |
| BMI (kg/m 2 ) | 23.38 ± 1.44 | 23.43 ± 1.32 | 0.888a |
| Hypertension | 21 (46.7%) | 20 (44.4%) | 0.832b |
| TC (mmol/L) | 4.62 ± 0.75 | 4.63 ± 0.76 | 0.963a |
| TG (mmol/L) | 1.44 ± 0.51 | 1.28 ± 0.44 | 0.106a |
| HDL-c (mmol/L) | 1.24 ± 0.27 | 1.21 ± 0.25 | 0.525a |
| LDL-c (mmol/L) | 2.56 ± 0.39 | 2.52 ± 0.40 | 0.599a |
| Smoking, Current | 28 (62.2%) | 21 (46.7%) | 0.138b |
| Drinking, Current | 24 (53.3%) | 27 (60.0%) | 0.523b |
| Diabetes | 15 (33.3%) | 17 (37.8%) | 0.660b |
| SNYTAX score | 20.89 ± 6.61 | 26.42 ± 7.18 | < 0.001a |
| CRP (mg/L) | 8.77 ± 2.44 | 9.97 ± 3.10 | 0.043a |
Note: CHD, coronary heart disease; BMI, body mass index; TC, total cholesterol; TG, triglyceride; HDL-c, high-density lipoprotein-cholesterol; LDL-c, low-density lipoprotein-cholesterol; CRP, C-reactive protein
Elevated IL-29 level predicts severe CHD
CHD severity was scored by SYNTAX score, and the correlation between SNYTAX score and IL-29 level was analyzed. The results manifested that the serum IL-29 levels in CHD patients were positively correlated with SNYTAX scores (Fig. 2A) (r = 0.454, P < 0.001). Next, CHD patients were categorized into the mild CHD group (SYNTAX score ≤ 22) (n = 39) and moderate/severe CHD group (SYNTAX score > 23) (n = 51) based on the SYNTAX score. The serum levels of IL-29 were notably higher in the moderate/severe group than those in the mild CHD group (P < 0.05, Fig. 2B). The ROC curve distinguishing mild and moderate/severe CHD by IL-29 levels was further plotted. The AUC for differentiating mild and moderate/severe CHD by IL-29 levels was 0.739, with a cutoff value of 66.8,, a sensitivity of 70.6%, and a specificity of 66.7% (Fig. 2C). Altogether, elevated serum levels of IL-29 in CHD patients may predict increased severity.
Fig. 2.
High IL-29 expression predicts increased severity of CHD
A: Scatter plot to detect the correlation between IL-29 levels and SYNTAX scores. B: ELISA to detect IL-29 levels in serum of patients with mild CHD and moderate/serve CHD; C: ROC curve to analyze the diagnostic efficacy of IL-29 in differentiating between mild CHD and moderate/serve CHD. Figure A was analyzed using Pearson’s coefficient analysis, Figure B was analyzed using independent samples t-test, and Figure C was analyzed using ROC. *P < 0.05
Elevated serum IL-29 level is an independent risk factor for CHD exacerbation
To further analyze whether IL-29 was independently correlated with CHD exacerbation, we classified CHD patients into mild CHD and moderate/severe CHD according to the SNYTAX score. We analyzed the correlation between each clinical index and CHD severity by univariate logistic analysis and then included CRP level and IL-29 level (P < 0.1) as independent variables in the multivariate analysis. CRP and IL-29 could be independent risk factors for CHD exacerbation (P < 0.05), and the risk of exacerbation in CHD was increased by 1.065-fold for each unit increase in IL-29 level (P = 0.008, 95%CI: 1.017–1.116) (Table 3).
Table 3.
IL-29 levels are independently associated with CHD exacerbation
| Logistic univariate analysis | Logistic multivariate analysis | |||||
|---|---|---|---|---|---|---|
| P | OR | 95% CI | P | OR | 95% CI | |
| Age (years) | 0.810 | 1.007 | 0.954 ~ 1.062 | - | - | - |
| Gender (male) | 0.655 | 0.824 | 0.352 ~ 1.928 | - | - | - |
| BMI (kg/m2) | 0.650 | 0.932 | 0.686 ~ 1.265 | - | - | - |
| Hypertension | 0.110 | 2.009 | 0.855 ~ 4.722 | - | - | - |
| TC (mmol/L) | 0.420 | 1.263 | 0.716 ~ 2.226 | - | - | - |
| TG (mmol/L) | 0.264 | 0.602 | 0.248 ~ 1.465 | - | - | - |
| HDL-c (mmol/L) | 0.967 | 0.967 | 0.195 ~ 4.805 | - | - | - |
| LDL-c (mmol/L) | 0.949 | 0.966 | 0.335 ~ 2.788 | - | - | - |
| Smoking, Current | 0.451 | 0.723 | 0.312 ~ 1.679 | - | - | - |
| Drinking, Current | 0.966 | 1.019 | 0.439 ~ 2.362 | - | - | - |
| Diabetes | 0.953 | 0.974 | 0.408 ~ 2.326 | - | - | - |
| CRP (mg/L) | < 0.001 | 2.551 | 1.760 ~ 3.699 | < 0.001 | 2.512 | 1.685 ~ 3.745 |
| IL-29 (pg/mL) | < 0.001 | 1.063 | 1.030 ~ 1.098 | 0.008 | 1.065 | 1.017 ~ 1.116 |
Note: CHD, coronary heart disease; BMI, body mass index; TC, total cholesterol; TG, triglyceride; HDL-c, high-density lipoprotein-cholesterol; LDL-c, low-density lipoprotein-cholesterol; CRP, C-reactive protein
Discussion
CHD is the leading cause of mortality and disability in adults [14]. However, conventional diagnostic approaches for CHD are limited by low sensitivity, high cost, and side effects [15]. These challenges necessitate the identification of new diagnostic biomakers.
Emerging evidence suggests that CHD risk may also be associated with novel biomarkers related to lipoprotein subfractions, inflammation, and metabolic pathways [16]. The severity and prognosis of CHD can be assessed by the levels of inflammatory biomarkers such as IL-6 and CRP [17]. IL-29 is designated as a type III interferon within the IL-10-interferon family. Due to antiviral and immunoregulatory characteristics of IL-29, IL-29 performs significantly in the pathogenesis of inflammatory autoimmune diseases [9]. For instance, IL-29 aggravates LPS/TLR4-mediated inflammation in RA depending on NF-κB signaling activation [18]. Since CHD is a chronic inflammatory diseases, we speculate that IL-29 can also be used as an important inflammatory indicator in CHD. Importantly, the mRNA expression of IL-29 has been found significantly increased and positively associated with an increase in the mRNA level of bone morphogenetic protein 2 in calcified carotid arteries from patients with CHD [13]. Consistently, we found that serum IL-29 in CHD patients was increased relative to that in healthy volunteers. In our study, the AUC of IL-29 level in distinguishing CHD patients and healthy volunteers was 0.789 at the cut-off value of 64.12 (sensitivity: 65.6%, specificity: 76.7%). These findings suggest that serum IL-29 levels may have certain assisting values in CHD diagnosis.
In observational epidemiologic studies, a lower TC is associated with a reduced risk from CHD [19]. Men with early-onset CHD had higher serum TC levels than men with late-onset CHD [20]. Higher TC levels were also observed in CHD patients compared with healthy controls in our study. However, serum IL-29 showed no significant correlation with TC in CHD patients. CRP is a sensitive and dynamic systemic marker of inflammation [21]. CRP concentration has continuous associations with the risk of CHD [22]. Our study results indicated that CHD patients had higher levels of CRP than healthy volunteers. SYNTAX score is a clinical evaluation method for patients with multi-vessel coronary artery disease, which reflects the severity and complexity of CHD and can guide further revascularization strategies [23]. Patients with higher SYNTAX scores generally had more severe coronary artery stenosis [24]. Our study results illustrated that serum IL-29 levels were significantly correlated with SYNTAX scores and CRP levels in CHD patients.
Further analysis revealed that serum IL-29 levels were positively correlated with SYNTAX scores in CHD patients. Given that patients with higher SYNTAX scores may have more serious adverse cardiac events [25], we categorized CHD patients as mild and medium/severe severity based on their SYNTAX scores. In these CHD patients, serum IL-29 levels were increased gradually. ROC analysis unraveled that the AUC of serum IL-29 levels in distinguishing mild and medium/severe CHD was 0.739 at the cut-off value of 66.8 (sensitivity: 70.6%; specificity: 66.7%). These results suggested that an increase in serum IL-29 levels might indicate an exacerbation of CHD. Elevated high-sensitive CRP is an independent biomarker for cardiovascular risk [26]. We thus deduced that CRP and IL-29 could also act as independent risk factors for CHD progression. The condition of CHD mighty worsen with the increase of IL-29 levels.
In summary, this prospective study for the first time measured serum IL-29 levels in CHD patients and investigated its function on CHD diagnosis using ROC analysis. The study also adopted Pearson analysis for the correlation between IL-29 level and CHD severity and the Logistic regression analysis for the effect of IL-29 level on CHD severity. At present, there is limited research on the correlation between IL-29 and CHD, therefore, this study is of great significance for the clinical diagnosis of CHD.
Limitations of study
However, this study has several limitations. Firstly, the subjects enrolled and events observed were relatively insufficient. The small sample size causes no significant difference in the risk factors such as hypertension, hyperlipidemia, and smoking between the CHD group and the control group, which may indicate a bias in the selection of the health control group. Secondly, SYNTAX-based CHD grading has limitations because SYNTAX scoring only involves the anatomical characteristics of coronary arteries, whereas clinical characteristics such as age, underlying diseases, and life habits are not considered. One of the possible consequences would be that patients were graded the same severity despite different clinical features. Moreover, this study only observed the phenomenon of IL-29 and the incidence and severity of CHD, without further exploring the reasons. Hence, multi-center prospective studies with larger sample sizes are necessary to increase the reliability of the results. Additionally, the upstream and downstream pathways of IL-29 can be further investigated in vivo and in vitro, to delve into their effects and mechanisms of action in CHD.
Author contributions
XLL, PN, and LMD conceived the study and experiments. PN, HL, JS and YCZ performed experiments. PN and LMD wrote the main manuscript. XLL reviewed the manuscript.
Funding
No funding.
Data availability
No datasets were generated or analysed during the current study.
Declarations
Ethics approval and consent to participate
This study was approved by the Ethics Committee of The Third People’s Hospital of Kunshan.
Consent for publication
Written informed consent was obtained from all participants.
Competing interests
The authors declare no competing interests.
Footnotes
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
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Data Availability Statement
No datasets were generated or analysed during the current study.