Association of Interleukin-18 Gene Polymorphisms with Takayasu Arteritis in a Chinese Han Population
Takayasu arteritis (TA) is a chronic, non-specific granulomatous vasculitis that primarily affects the aorta and its main branches, including the coronary and pulmonary arteries. This disease is characterized by its heterogeneity in terms of ethnic population, regional distribution, age, and sex. The pathogenesis of TA is multifactorial, involving autoimmunity, inflammation, genetic predisposition, and environmental factors. Among these, genetic abnormalities have been shown to play a significant role in the occurrence, progression, treatment response, and prognosis of TA. Specifically, the human leukocyte antigen (HLA) gene has been closely associated with TA.
Interleukin-18 (IL18) is a pro-inflammatory cytokine with multiple biological functions, including the regulation of inflammatory and immune responses. IL18 induces monocytes, macrophages, and natural killer cells to produce interferon-gamma, which enhances the activity of natural killer cells and contributes to immune dysregulation. This cytokine is implicated in the pathogenesis of various diseases, including chronic hepatitis B, asthma, coronary heart disease, rheumatoid arthritis, systemic lupus erythematosus, Crohn’s disease, multiple sclerosis, and graft-versus-host disease.
The IL18 gene is located on chromosome 11q22.2-22.3 and consists of six exons. Single-nucleotide polymorphisms (SNPs) in the promoter region of the IL18 gene, specifically at positions -607C/A and -137G/C, have been shown to significantly affect the transcription and expression levels of IL18. These SNPs have been associated with altered plasma concentrations of IL18, which are notably elevated in patients with TA, particularly during the active phase of the disease.
Despite the established role of IL18 in inflammation and its elevated levels in TA, there has been a lack of studies investigating the correlation between IL18 gene polymorphisms and TA. This study aimed to address this gap by examining the association between IL18 -607C/A and -137G/C polymorphisms and TA in a Chinese Han population.
The study enrolled 200 patients with TA as the case group and 334 region-, age-, and sex-matched healthy subjects as the control group. The diagnosis of TA was based on the commonly used diagnostic criteria proposed by the American College of Rheumatology in 1990, which include age of onset ≤40 years, limb claudication, decreased brachial artery pulse, a difference in bilateral limb systolic blood pressure >10 mmHg, subclavian or abdominal aortic murmur, and abnormal arteriography indicating narrowing or occlusion of the aorta and its main branches. Disease activity was assessed using the National Institutes of Health (NIH) criteria, which consider systemic features, elevated erythrocyte sedimentation rate, vascular ischemia or inflammation, and angiographic features.
Genotyping of the IL18 -607C/A and -137G/C polymorphisms was performed using TaqMan probes. The probes were labeled with fluorescent dyes VIC and FAM, and polymerase chain reaction (PCR) was conducted under standard conditions. The genotype frequencies were tested for Hardy-Weinberg equilibrium (HWE), and statistical analyses were performed using the Mann-Whitney U test, t-test, Chi-squared test, and logistic regression.
The clinical baseline data showed no significant differences between the TA patients and healthy controls, except for a higher prevalence of hypertension in the TA group. The genotype frequencies of the IL18 -607C/A and -137G/C polymorphisms conformed to HWE in both groups.
For the IL18 -607C/A polymorphism, the C and A alleles and the CC, CA, and AA genotypes were identified. Before adjusting for risk factors, the crude odds ratios (ORs) and 95% confidence intervals (CIs) under the dominant, additive, and recessive models were 0.532 (0.406–0.851, P = 0.005), 0.320 (0.568–0.928, P = 0.011), and 0.294 (0.481–1.154, P = 0.188), respectively. After adjusting for risk factors, the adjusted ORs and 95% CIs were 0.533 (0.391–0.880, P = 0.010), 0.266 (0.586–1.002, P = 0.051), and 0.122 (0.552–1.420, P = 0.613), respectively. These results suggest that the -607C/A polymorphism may decrease the risk of TA, acting as a protective factor.
For the IL18 -137G/C polymorphism, the G and C alleles and the GG, GC, and CC genotypes were identified. Before adjusting for risk factors, the crude ORs and 95% CIs under the dominant, additive, and recessive models were 1.658 (1.164–2.361, P = 0.005), 1.554 (1.185–2.039, P = 0.001), and 2.141 (1.150–3.986, P = 0.016), respectively. After adjusting for risk factors, the adjusted ORs and 95% CIs were 1.571 (1.068–2.311, P = 0.022), 1.467 (1.086–1.980, P = 0.012), and 1.815 (0.901–3.656, P = 0.095), respectively. These findings indicate that the -137G/C polymorphism may increase the risk of TA, acting as a risk factor.
The study also examined the distribution of genotype frequencies between the active and quiescent phases of TA. For the IL18 -607C/A polymorphism, no significant differences were observed under the dominant, additive, or recessive models. Similarly, for the IL18 -137G/C polymorphism, no significant differences were found between the active and quiescent phases under any of the genetic models. These results suggest that neither polymorphism is associated with the activity of TA.
In conclusion, this study provides evidence that the IL18 -607C/A polymorphism may decrease the risk of TA, acting as a protective factor, while the -137G/C polymorphism may increase the risk of TA, acting as a risk factor. However, neither polymorphism is related to the activity of TA. These findings contribute to the understanding of the genetic basis of TA and highlight the potential role of IL18 gene polymorphisms in the pathogenesis of this disease.
Further research is needed to explore the functional mechanisms of these polymorphisms and their interactions with other genetic and environmental factors. Additionally, larger studies involving diverse populations are necessary to validate these findings and to investigate the potential implications for the diagnosis, treatment, and prognosis of TA.
doi.org/10.1097/CM9.0000000000001047
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