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Association of IL-1RAcP rs16865597 gene polymorphism with susceptibility to essential hypertension: a case-control study in the Chinese Han population

BMC Cardiovascular Disorders volume 25, Article number: 172 (2025) Cite this article

Abstract

Background

The IL-33/ST2 pathway plays a crucial role in the development of essential hypertension (EH). This study aimed to investigate the relationship between EH and genetic variations in this pathway in the Chinese Han population.

Methods

A total of 1,151 EH patients and 1,135 healthy controls were included in the study. Sixteen single nucleotide polymorphisms (SNPs) in the interleukin-33 (IL-33) and interleukin-1receptor associated protein (IL-1RAcP) genes were genotyped using the Sequenom MassArray and TaqMan assays. Genotype and allele frequencies were compared between the EH patients and controls using logistic regression analysis.

Results

The rs16865597 SNP in the IL-1RAcP gene was found to be associated with the risk of EH. Specifically, the presence of the C allele of rs16865597 was negatively correlated with EH susceptibility in both the additive model (P = 0.014, OR = 0.75, 95% CI = 0.59–0.94) and the recessive model (P = 0.011, OR = 0.72, 95% CI = 0.56–0.93). Additionally, rs16865597 was linked to a reduced risk of EH in specific subgroups, including males (OR add = 0.73, 95% CI = 0.56–0.94, P = 0.015), nonsmokers (OR add = 0.72, 95% CI = 0.54–0.96, P = 0.023), nondrinkers (OR add = 0.70, 95% CI = 0.53–0.93, P = 0.013), and individuals with low BMI (OR add = 0.69, 95% CI = 0.51–0.92, P = 0.013). Moreover, the C genotype of rs16865597 was strongly associated with higher interleukin-10 levels in vivo.

Conclusion

The rs16865597 SNP is significantly associated with a reduced risk of EH in the Chinese Han population, potentially due to its role in immune regulation.

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Introduction

Hypertension is a crucial risk factor for cardiovascular disease morbidity and mortality. In China, hypertension affects about 23.2% of the adult population, with more than 244.5 million people suffering from this disease [1]. Essential hypertension (EH) is defined as high blood pressure in which secondary causes such as renovascular disease, renal failure, pheochromocytoma, aldosteronism, or other causes of secondary hypertension or mendelian forms (monogenic) are not present. EH accounts for 95% of all cases of hypertension. The interactions between genetic and environmental factors contribute greatly to the pathophysiology of EH. Besides traditional risk factors including high-salt diet, smoking, drinking, obesity, and metal stresses, approximately 30–50% of the variation in EH is due to genetics [2]. Thus, the mining of susceptibility genes is an important tool for exploring the etiology of EH.

Increasing evidence has suggested the pathophysiological role of systemic and local inflammation in the development of EH, which might induce the change of cardiac function, vascular resistance, and renal damage [3, 4]. interleukin-33(IL-33) belongs to the IL-1 family, which drives T helper 2(Th2) responses in vivo. This cytokine interacts with its receptor interleukin 1 receptor-like 1(ST2), which consists of four isoforms (sST2, ST2L, ST2V, and ST2LV), to trigger the secretion of proinflammatory factors, such as leukotrienes, IL-6, and TNF-α. The binding affinity of IL-33 and ST2 is determined by the presence of interleukin-1receptor associated protein (IL-1RAcP) [5,6,7]. Many studies have reported the role of the IL-33/ST2 pathway in the pathologies of several cardiovascular diseases, including atherosclerosis, myocardial fibrosis, and EH [8,9,10]. In 2013, Ho and coworkers indicated that high sST2 concentrations were associated with incident hypertension and the plasma level of sST2 predicted changes in blood pressure physiology in a 3-year follow-up study [11]. Among Framingham Heart Study participants, elevated sST2 was associated with EH and diabetes mellitus (DM) [12]. Moreover, our previous study also suggested that the genetic variant rs3821204 in the ST2 gene may influence the development of EH by controlling sST2 expression, and miR-202-3p was involved in the development of EH partially by suppressing sST2 expression in a feedback manner [13, 14]. Yin and coworkers detected an obvious elevation of sST2 protein levels in serum and peripheral blood mononuclear cells (PBMC) in EH patients, meanwhile the levels of IL-33 in serum and PBMCs and ST2L in PBMCs did not change [15]. Given the essential role of IL-33/ST2 pathway in EH development, we hypothesized that genetic variations within IL-33 and IL1RAcP might also influence the susceptibility to EH.

In the present study, we conducted a case-control study to investigate the associations of IL-33 and IL1RAcP genetic variants and EH risk in the Chinese Han population. Furthermore, a correlation analysis was performed to determine the association between genetic polymorphisms and plasma levels of Th2 cytokines. The results might provide new insights into hypertension etiology.

Materials and methods

Study population

The sample population included 1151 EH patients and 1135 sex-matched controls. Patients were recruited from three hospitals (Union Hospital, Tongji Hospital, and Wugang Hospital) in Wuhan, China [16, 17]. Healthy Controls were from the same community as the patients. Hypertension was diagnosed as average systolic blood pressure(SBP)≥140 mmHg, and/or average diastolic pressure (DBP) ≥ 90 mmHg, and/or self-reported current treatment for hypertension with antihypertensive drugs. Control subjects were from the same community as the patients. Control subjects had SBP < 140 mmHg, DBP < 90 mmHg, and had never been treated for hypertension [18]. The 35 EH patients for IL-10 detection were consecutively recruited from the Second Affiliated Hospital of Nanchang University in China. All subjects completed an Inter-Heart questionnaire and were interviewed about their demographic data, medical history, history of disease, family history of cardiovascular disease, and lifestyle habits (including smoking and alcohol consumption) by trained interviewers.

Ethics statement

All participants signed the approved consent forms prior to the initiation of this study. This study was approved by the Ethics Committee of Tongji Medical College (project identification code: S073; 21 February, 2011) and the ethics committee of the Second Affiliated Hospital of Nanchang University (5 March, 2017).

Selection of SNPs

TagSNPs were selected based on the HapMap phase I & II database (available online:http://www.hapmap.org, accessed on 15 October 2012,CHB and JPT as the reference set). According to the criteria of r2 ≥ 0.8 and minor allele frequency (MAF) ≥ 0.05, we extended 2000 bp into the 5′ and 3′ ends of IL-33 and IL-1RAcP. Eventually, 16 tagSNPs within IL-33 and IL-1RAcP genes were selected (Table 1).

Table 1 SNP locations and allele frequencies
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DNA extraction and genotyping

Genomic DNA was extracted from fasting venous blood with a Puregene kit (Gentra Systems Inc., Minneapolis, MN, USA). The genotype distributions of 15 SNPs were assayed with the Sequenom MassArray system (Sequenom Inc., San Diego, CA, USA), the primers and probes used in this method are listed in S1 Table. The remaining SNP of rs1157505 and rs6444435were genotyped by TaqMan SNP allelic discrimination assay (Applied Biosystems, Foster City, CA, USA). The catalogue number used for genotyping rs1157505 was AHZAA5R and rs6444435 was C_2782293_10. PCR cycling conditions for the TaqMan assay included:95 °C for 10 min, followed by 45 cycles of 92 °C for 15 s and 60 °C for 1 min. TaqMan data collection and analysis were performed with SDS 2.2.1. Finally, 15 SNPs were successfully genotyped with a call rate above 95%, except for rs6444435, which had a call rate of 93.7%.

Biological variable determination

Fasting blood glucose (FBG), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides (TG) were assayed using standard laboratory procedures in the clinical laboratory at Union Hospital [19].

IL-10 levels detection

IL-10 concentrations were measured using sandwich enzyme-linked immune-sorbent assay (Shu zhou, JiangShu, China, 4 A Biotecn). Test procedures were performed according to the manufacturer’s instructions.

Statistical analysis

Continuous data were compared by Student’s t-test or Mann–Whitney rank-sum test. Chi-square test was used to compare categorical variables and the Hardy–Weinberg equilibrium (HWE). Unconditional logistic regression analysis was used to estimate the associations between SNPs and EH risk by odds ratios (ORs) and 95% confidence intervals (CIs). The interactions of covariates with SNP genotypes were tested using the Wald test in unconditional logistic regression models. The significance of multiplicative interactions between SNPs and covariates was determined by the likelihood ratio test using the logistic regression model. Mann–Whitney rank-sum tests was used to examine differences in IL-10 levels in patients with different rs16865597 genotypes. Power calculations were performed using the QUANTO software program (version 1.2.3) [20]. All analyses were performed with the SPSS 12.0 (SPSS Inc., Chicago, IL, USA). P < 0.05 was considered significant.

Results

Characteristics of the study participants

Table 2 presents the characteristics of the 2,286 participants, including 1,151 EH patients and 1,135 controls. Both groups had a similar gender distribution, but EH patients were older and had higher body mass index (BMI), SBP, DBP, FBG, and TG levels compared to controls (P < 0.01). In addition, EH patients were more likely to have a history of coronary heart disease (CHD) and DM, and a family history of EH (P < 0.01). Interestingly, the healthy subjects showed higher levels of smoking and drinking than the EH patients (P < 0.01 for smoking and P = 0.012 for drinking), which may have been due to quitting smoking and alcohol abstinence after diagnosis. We also found that TC levels were significantly lower in EH patients than in controls (4.44 ± 1.04 mmol/L versus 4.59 ± 1.00mmol/L, P < 0.01), which might be attributed to cholesterol-lowering therapies in the patients.

Table 2 General characteristics of the study population
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Associations between IL-33 variants and EH risk

Most of the SNPs conformed to HWE (p > 0.05), except for rs1157505 and rs1624159 within the IL-33 gene, and rs1015704 and rs4687150 within the IL-1RAcP gene, which significantly deviated from HWE in both controls and cases (p < 0.05). Thus, 12 SNPs were selected for further analysis (Table 3).

Table 3 The frequencies of IL33 and IL1RAcP SNPs in the population under observation
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Then, we compared the allele and genotype frequencies of 12 SNPs between cases and controls. The association between these SNPs and the risk of EH was analyzed using additive/recessive models. Table 4 indicates that the genotype distribution of the three SNPs (rs1929992, rs10975520, and rs11792633) within the IL-33 gene did not show significant differences between cases and controls. The IL-33 SNPs rs1929992 (OR = 1.03, 95% CI = 0.90–1.19, P = 0.637), rs10975520 (OR = 1.05, 95% CI = 0.92–1.21, P = 0.480), and rs11792633 (OR = 1.03, 95% CI = 0.90–1.19, P = 0.637) were not associated with the risk of EH in the additive model after adjustment for conventional EH risk factors, such as age, sex, smoking, drinking, BMI, TG, FBG, and a family history of EH. We did not find any significant association between the three SNPs—rs1929992 (OR = 1.08, 95% CI = 0.87–1.33, P = 0.487), rs10975520 (OR = 1.11, 95% CI = 0.90–1.38, P = 0.324), and rs11792633 (OR = 1.07, 95% CI = 0.87–1.32, P = 0.526)—and the risk of EH in the recessive model.

Table 4 Genotype frequencies of 12 SNPs and their association with EH risk in the Chinese population
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Associations between IL-1RAcP variants and EH risk

We also investigated differences in the genotype distribution of 9 polymorphisms (rs9817203, rs1559018, rs3773986, rs6765375, rs4624606, rs16865597, rs3773958, rs3773981, and rs6444435) between cases and controls and analyzed the genotypes using dominant/recessive models. Table 4 shows that among the 9 SNPs evaluated, only rs16865597 exhibited a statistically significant association with EH risk in both the additive model (OR = 0.75, 95% CI = 0.59–0.94, P = 0.014) and the recessive model (OR = 0.72, 95% CI = 0.56–0.93, P = 0.011). Table 5 further details the genotype and allele frequency distribution for rs16865597 between the case and control groups. CT genotype showed a significant association with reduced EH risk (OR = 0.72, 95% CI = 0.56–0.93, P = 0.012) after adjusting for age, sex, smoking, drinking, BMI, TG, FBG, and family history of EH. For the C allele, a significant inverse association with EH risk was observed in the univariate analysis (OR = 0.80, 95% CI: 0.66–0.97, P = 0.024). In summary, the presence of the C allele of rs16865597 was negatively correlated with EH susceptibility. However, p-values for rs16865597 failed to reach significance after Bonferroni correction. (P < 0.05/9 = 0.0056).

Table 5 Genotype and allele frequency distribution for rs16865597 between the case and control groups
Full size table

Association analyses for stratified traditional risk factors

Stratification analyses were utilized to clarify the interactions between traditional risk factors (sex, smoking, drinking, BMI) and genetic polymorphism rs16865597 for EH risk. As shown in Table 6, rs16865597 was associated with decreased risk in males (ORadd = 0.73, 95% CI = 0.56–0.94, P = 0.015), nonsmokers (ORadd = 0.72, 95% CI = 0.54–0.96, P = 0.023), nondrinkers (ORadd = 0.70, 95% CI = 0.53–0.93, P = 0.013), and low-BMI subjects (ORadd = 0.69, 95% CI = 0.51–0.92, P = 0.013). We did not detect any interactions between rs16865597 and sex, smoking, drinking, and BMI (all p > 0.05).

Table 6 Stratification analysis for the association between rs16865597 and the risk of EH
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In vivo effect of the IL-1RAcP polymorphism rs16865597 on plasma IL-10 levels

To verify that the genetic polymorphisms in IL-33 pathways affect disease occurrence by modulating the function of this pathway, we examined the correlation between the genotype of rs16865597 and IL-10 plasma levels. ELISA was conducted to detect the plasma levels of IL-10 in 35 patients (median [25–75th percentile], 4.78 ng/ml [1.96–8.60 ng/ml]), while the genotype of rs16865597 was determined by a Taqman genotyping assay. We observed that plasma IL-10 concentrations were significantly lower in patients with TC + CC genotypes compared to those with TT genotypes (P < 0.05) (Fig. 1). These results suggest that rs16865597 C > T is associated with increased plasma IL-10 levels in vivo.

Fig. 1
figure 1

Correlation of plasma interleukin-10 levels and the IL-1RAcP SNP rs16865597. PBMCs were isolated from 35 essential hypertension subjects, and the genotype was determined by TaqMan assay. The plasma levels of IL-10 in 35 EH patients were determined by an enzyme linked immunosorbent assay. The figure showed the distribution of IL-10 plasma levels clustered according to different genotypes. IL-10 plasma levels elevated significantly in subjects carrying CC alleles (n = 1) + TC alleles (n = 13) compared with TT alleles(n = 21), as analyzed by the Mann-Whitney rank-sum test

Full size image

Discussion

This study enrolled 1,151 patients and 1,135 healthy controls to examine the role of IL-33 and IL-1RAcP genetic polymorphisms in the development of EH. The results suggest that individuals carrying the C allele of the rs16865597 polymorphism in the IL-1RAcP gene may have a reduced risk of developing EH. This association remained significant in both additive and recessive models after adjusting for age, sex, smoking, alcohol consumption, BMI, TG, FBG, and family history of EH. Furthermore, we observed that elevated IL-10 levels were correlated with the C genotype of rs16865597 in vivo.

IL-33 is a recently identified member of the interleukin-1 (IL-1) family, known to bind with ST2L and IL-1RAcP, initiating a Th2 immune response. Previous research, such as Ma and colleagues’ work, suggested that IL-33 plays a role in hypertension treatment [21]. Atles and colleagues also found that IL-33 levels in patients with primary hypertension were significantly lower compared to a control group [22]. These findings suggest the IL-33–ST2 signaling pathway may play a role in EH pathogenesis. To investigate further, we analyzed the association between IL-33 polymorphisms and EH. However, our study did not find a significant association between IL-33 SNPs (rs1929992, rs10975520, rs11792633) and EH risk in either additive or recessive models. Additionally, no significant interactions were observed between these SNPs and traditional EH risk factors. These findings align with Yin’s study, which found no significant differences in IL-33 levels between hypertensive patients and controls [15].

The IL-1RAcP gene, located on chromosome 3q28, encodes a co-receptor for IL-33. The soluble form of IL-1RAcP interacts with the sST2–IL-33 complex to inhibit IL-33 signaling [23]. Previous studies have shown that IL-1RAcP plays a crucial role in cardiovascular diseases, such as myocardial infarction and EH [24, 25]. For instance, Nikpay and colleagues found that the IL-1RAcP polymorphism rs4687150 was associated with increased risk of EH [25]. In our study, we conducted a large case–control analysis and found that rs16865597 was associated with a decreased risk of EH. This inverse association was particularly strong among males, nonsmokers, nondrinkers, and individuals with a low BMI. Additionally, individuals with the C genotype of rs16865597 exhibited significantly higher levels of IL-10, an important anti-inflammatory cytokine secreted primarily by Th2-type helper T cells [26, 27]. IL-10 plays a key role in modulating the immune system by promoting the production of Th2 cytokines, which counterbalance the pro-inflammatory effects of Th1 cytokines. This shift towards an anti-inflammatory state helps to reduce the risk of hypertension. As such, the C genotype of rs16865597 may lower the risk of EH by enhancing the production of Th2 cytokines and maintaining immune system balance.

This study has several strengths. First, it involved a large sample size and employed a case–control design to explore the relationship between IL-33 and IL-1RAcP gene variants and the risk of EH. This approach contributes to understanding the role of the IL-33/ST2 pathway in EH development. Second, to our knowledge, this is the first study to report an association between the IL-1RAcP rs16865597 polymorphism and EH.

However, the study also has limitations. One potential concern is selection bias, which may have impacted the results. Additionally, while the sample population was not perfectly matched, we accounted for this by using unconditional logistic regression analysis, adjusting for factors such as age, sex, smoking, alcohol consumption, BMI, TG, FBG, and family history of EH. Lastly, all participants were of Han Chinese ethnicity, so further research is needed to determine whether these genetic associations are consistent across other ethnic groups.

Conclusions

In summary, this study provides preliminary evidence that the IL-1RAcP rs16865597 polymorphism may play a role in reducing the risk of EH. The underlying mechanisms could involve immune modulation and cytokine regulation. However, further investigation is needed to elucidate the biological pathways and confirm these findings in other populations.

Data availability

The datasets generated and/or analyzed during the current study are available in the OMIX, China National Center for Bioinformation / Beijing Institute of Genomics, Chinese Academy of Sciences repository, (https://ngdc.cncb.ac.cn/omix: Accession No. OMIX009243). They are also available from the corresponding author upon reasonable request.

Abbreviations

BMI:

Body mass index

CI:

Confidence interval

EH:

Essential hypertension

FBG:

Fast blood glucose

MAF:

Minor allele frequency

SNP:

Single nucleotide polymorphism

OR:

Odds ratio

TG:

Triglyceride

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Acknowledgements

We very warmly thank Longxian Cheng (Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China) for his methodological assistance and scientific discussion, Meian He (Department of Occupational and Environmental Health, Key Laboratory of Environment and Health, Ministry of Education and State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.) for her assistance with study design and statistical analyses. Bo Song(Medint Cardiology, Yale University, New Haven County, Connecticut, United States) for his kind assistance with editing the English text of this manuscript.

Funding

The research was supported by grants from: National Natural Scientific Foundation of China (Grant No. 81172750 and 81700372); GuangDong Basic and Applied Basic Research Foundation(2020A1515010301); Department of Education of Guangdong Province(2020KTSCX034). The funding bodies played no role in the design, data collection, analysis, and paper writing.

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Authors and Affiliations

  1. Department of Cardiovascular Medicine, the Second Affiliated Hospital of Nanchang University, 1Minde Road, Nanchang, China

    Fangqin Wu, Xin Xia & Xinghua Jiang

  2. Department of Cardiovascular Medicine, the Second Affiliated Hospital of Shantou University Medical College, Shantou, China

    Dongchen Liu &  LuLi

  3. Biobank Center, The Second Affiliated Hospital of Nanchang University, No. 1 MinDe Road, Nanchang, China

    Xinlei Yang

  4. Department of Environment and Health, Shenzhen Center for Disease Control and Prevention, Shenzhen, China

    Suli Huang

  5. Guangdong Provincial Key Laboratory of Infectious Diseases and Molecular Immunopathology, Shantou University Medical College, Shantou, China

    LuLi

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  1. Fangqin Wu
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Contributions

Designing the experiments, Fangqin Wu and LuLi; methodology, Fangqin Wu; software, Xinlei Yang; formal analysis, Dongchen Liu; data curation, Suli Huang; writing—original draft preparation, Fangqin Wu and LuLi; writing—review and editing, Xin Xia, Dr. Xinghua Jiang. All authors agreed both to be personally accountable for the author’s contributions and ensure related to accuracy of this work. All authors have read and agreed to the published version of the manuscript.

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Correspondence to LuLi.

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The study was approved by the Ethics Committee of Tongji Medical College (project identification code: S073; 21 February, 2011) and the ethics committee of the Second Affiliated Hospital of Nanchang University (5 March, 2017). All participants provided written informed consent. All procedures performed in this study involving human participants were in accordance with the ethical standards of the 1964 Helsinki declaration and its later amendments or comparable ethical standards. All methods involved in this study were carried out in accordance with relevant guidelines and regulations. All participants provided their written informed consent in this study. Written informed consent was obtained for the publication of any original images or data included in this article.

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Wu, F., Liu, D., Xia, X. et al. Association of IL-1RAcP rs16865597 gene polymorphism with susceptibility to essential hypertension: a case-control study in the Chinese Han population. BMC Cardiovasc Disord 25, 172 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12872-025-04629-4

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BMC Cardiovascular Disorders

ISSN: 1471-2261

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