Association of Interleukin 17 Polymorphisms and IL17A Levels with Papillary Thyroid Carcinoma: A Hospital-Based Study in the Chinese Population

Abstract

Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, and inflammation and immune dysregulation contribute to its pathogenesis. Interleukin (IL)17A’s role has been demonstrated in PTC. Genetic variants in IL17A may affect susceptibility and progression; however, their impact in the Chinese population remains insufficiently understood. This hospital-based case–control study included 272 patients with PTC and 250 age/sex-matched controls. Four IL17A single-nucleotide polymorphisms—rs2275913, rs3748067, rs8193036, and rs3819024—were genotyped using TaqMan assays. IL17A plasma levels were measured by ELISA. Allele, genotype, and haplotype distribution among controls and patients, and IL17 variant associations with IL17A levels were analyzed using GraphPad Prism. The rs2275913 AA genotype and minor allele showed a higher frequency in patients with PTC compared to controls, indicating an increased risk of PTC (AA: odds ratio [OR] = 1.88, 95% confidence intervals [CI] = 1.17–2.95, P = 0.01; A: OR = 1.44, 95% CI = 1.12–1.84, P = 0.003). Patients with PTC had higher plasma IL17A levels than controls (P < 0.0001). IL17A genotypes, particularly rs2275913 AA, were associated with higher plasma IL17A concentrations. Genetic polymorphisms in IL17A (rs2275913) and elevated plasma IL17A levels correlate with PTC susceptibility in the Chinese cohort. These findings suggest IL17A’s potential as a biomarker for risk stratification and highlight inflammatory pathways in PTC pathogenesis.

Keywords

papillary thyroid carcinoma interleukin-17A genetic polymorphism single-nucleotide polymorphism cytokines case–control studies

Introduction

Papillary thyroid carcinoma (PTC) is the most prevalent form of thyroid malignancy, accounting for the majority of differentiated thyroid cancers globally (Arrangoiz et al., 2021). While the overall prognosis of PTC is favorable, a subset of patients experience aggressive disease characterized by local invasion, lymph node metastasis, and recurrence (Ito et al., 2018). The etiology of PTC is multifactorial, involving genetic, environmental, and immune-mediated factors (Bhattacharya et al., 2023). In recent years, the role of inflammation and immune dysregulation in the pathogenesis and progression of PTC has garnered increasing attention.

Interleukin-17A (IL-17A) is a proinflammatory cytokine encoded by the IL17A gene and produced primarily by activated T helper 17 (Th17) cells, as well as other immune cell subsets such as CD8 + T cells, γδ T cells, and innate lymphoid cells (Huangfu et al., 2023). IL-17A exerts its biological effects by binding to its receptor complex (IL-17RA/IL-17RC) on target cells, triggering downstream signaling cascades—including activation of NF-κB and mitogen-activated protein kinases—that culminate in the production of inflammatory cytokines, chemokines, and matrix metalloproteinases (Amatya et al., 2017). These mediators promote the recruitment of myeloid cells, enhance tissue inflammation, and contribute to tissue remodeling and angiogenesis (Zhang et al., 2024). While IL-17A plays a crucial role in host defense and mucosal barrier integrity, sustained or dysregulated IL-17A signaling is implicated in the pathogenesis of various autoimmune, inflammatory, and malignant diseases (Kuwabara et al., 2017; Zhao et al., 2020).

Accumulating evidence suggests that IL-17A is involved in the development and progression of several human cancers, including colorectal, gastric, and pancreatic carcinomas, where it can exert both pro-tumorigenic and anti-tumorigenic effects depending on the tumor microenvironment and immune contexture (Begagic et al., 2025; Mikkola et al., 2022). In the context of PTC, IL-17A has been shown to modulate tumor cell proliferation, invasion, and immune evasion, as well as to influence the tumor microenvironment by recruiting inflammatory cells and promoting angiogenesis (Banerjee et al., 2023). Elevated IL-17A expression has been reported in the tumor or adjacent tumor cells in PTC and the expression has been linked with bad prognosis (Carvalho et al., 2017). However, an earlier study in the plasma failed to detect IL17A in patients with PTC (Bertol et al., 2020). Interestingly, the experimental studies indicate that IL-17A can enhance the expression of major histocompatibility complex class I molecules and modulate T cell activation, potentially impacting anti-tumor immune responses (Han et al., 2019).

Genetic polymorphisms in cytokine genes, including IL17A, have been linked to inter-individual differences in immune responses and susceptibility to various cancers (Dai et al., 2016). Several single-nucleotide polymorphisms (SNPs) within the IL17A gene, such as rs2275913, rs3748067, rs8193036, and rs3819024, have been investigated for their association with cancer risk, disease progression, and cytokine expression levels (Niu et al., 2014; Liu et al., 2022). Meta-analyses and population-based studies have reported that certain IL17A SNPs, notably rs2275913, are associated with an increased risk of multiple cancers, including gastric and thyroid cancers, with potential ethnic and regional variations in their effects (Li et al., 2015; Li et al., 2022; Lu et al., 2016; Zhao et al., 2014). In PTC, specific IL17A variants have been linked to aggressive clinical features and poorer therapeutic responses (Bertol et al., 2022), although findings remain inconsistent across studies and populations (Bertol et al., 2022; Lee et al., 2015). Despite these advances, the precise contribution of IL17A genetic variation and circulating IL-17A levels to PTC susceptibility and clinical course remains incompletely understood, particularly in the Chinese population. Understanding the interplay between IL17A polymorphisms, cytokine expression, and PTC risk may provide new insights into disease mechanisms and identify potential biomarkers for risk stratification and therapeutic targeting.

The present hospital-based case–control study was designed to comprehensively investigate the association of IL17A gene polymorphisms and haplotypes with the risk of PTC in a Chinese cohort. In addition, we assessed plasma IL-17A levels in patients with PTC and healthy controls and explored the relationship between IL-17A genetic variants and cytokine expression. By integrating genetic and immunological data, this study aims to elucidate the role of IL17A in PTC pathogenesis and to inform future strategies for personalized risk assessment and management.

Materials and Methods

Study population

This hospital-based case–control study involved the enrolment of 272 patients with histologically confirmed PTC cases and 250 age- and sex-matched healthy controls from Yuyao People’s Hospital between January 2021 and December 2024. Participants with a history of autoimmune diseases, chronic infections, or other malignancies were excluded from the study. In addition, participants receiving systemic immunosuppressive therapy, corticosteroids, or other medications known to influence cytokine levels were also excluded from the study. Demographic and clinical data, including tumor size, lymph node involvement, and disease stage, were extracted from medical records. Written informed consent was obtained from all participants, and the study protocol received approval from the Institutional Review Board of Yuyao People’s Hospital (IRB Approval No: 2020/375). The research conformed to the principles outlined in the Declaration of Helsinki. Participant anonymity was preserved, and data were securely stored. Approximately 5 mL of peripheral venous blood was collected from each participant at the time of diagnosis and prior to any surgical or therapeutic intervention.

DNA extraction and genotyping

Genomic DNA was extracted from whole blood utilizing the QIAamp DNA Blood Mini Kit (Qiagen, Germany) in accordance with the manufacturer’s protocol. Four IL17A SNPs—rs2275913, rs3748067, rs8193036, and rs3819024—were genotyped using TaqMan SNP Genotyping Assays on a 7900HT Real-Time PCR System. Details of the probe were presented in the Supplementary Table S1. Each reaction comprised 10 ng of DNA, TaqMan Genotyping Master Mix, and allele-specific probes. For quality control purposes, 10% of the samples were randomly re-genotyped, demonstrating 100% concordance.

Plasma IL17A quantification

The collected whole blood, treated with EDTA solution, was centrifuged at 3,000 rpm for 15 min to separate the plasma. Plasma IL17A levels were measured in a subset of 100 patients with PTC and 100 healthy controls for whom sufficient plasma samples were available for cytokine analysis. The concentrations of IL17A were quantified using a commercially available enzyme-linked immunosorbent assay (ELISA) kit (Elbascience, USA), which has a detection range of 0.78–50 pg/mL. All samples were analyzed in duplicate, and absorbance was measured at 450 nm using a microplate reader.

Statistical analysis

The genotype and allele frequencies were determined through manual counting. The distribution of genotypes and alleles among healthy controls and patients with PTC was compared using Fisher’s exact test. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the associations between genotypes and the risk of PTC. The haplotype distribution among healthy controls and patients with PTC was analyzed using the SNPstat web server. A P value of less than 0.01 was considered statistically significant after applying the Bonferroni correction for the four SNPs examined in this study (0.05/4 = 0.012). The mean of continuous variables, such as plasma levels of IL17A in healthy controls and patients with PTC, was evaluated using Student’s t-test, and the distribution across different genotypes of IL17A polymorphisms was assessed by analysis of variance followed by Tukey’s post hoc test. Hardy–Weinberg equilibrium was verified for all SNPs in the control group using Microsoft Excel.

Results

Study population and baseline characteristics

A total of 600 subjects, comprising 250 healthy controls and 350 patients with PTC, were initially enrolled, of whom 78 were excluded from the present study per the exclusion criteria. Details are mentioned in the Figure 1. Finally, a total of 272 PTC and 250 healthy controls were enrolled in the present study. The baseline characteristics, including age, sex distribution, and relevant clinical parameters, are summarized in Table 1. There were no significant differences in age or sex between the PTC and control groups, indicating successful matching and minimizing potential confounding factors. The clinical characteristics of the patients with PTC, such as tumor size, lymph node involvement, and disease stage, are also presented, providing a comprehensive overview of the study population. Additionally, we have included data on family history of thyroid tumors and any radiation exposure in both cases and controls, with the prevalence not being statistically significant (Table 1). Furthermore, stages I and II of the TNM classification were more frequent among the enrolled cases, and approximately 69% of the patients exhibited BRAF mutations.

FIG. 1.

Flow chart of sample enrollment in the present study.

Table 1.

Baseline Characteristics of the Patients with PTC and Healthy Controls

Characteristics	Healthy Controls (n = 250)	PTC Patients (n = 272)
Age (years, mean ± SD)	43.3 ± 11.2	42.8 ± 10.9
Sex (male/female, %)	60/190	65/207
Body mass index (mean ± SD)	23.8 ± 3.2	23.7 ± 3.1
Family history of thyroid tumor	5 (2)	14 (5)
History of radiation exposure	2 (1)	6 (2)
Autoimmune thyroid disease	13 (5)	27 (10)
Tumor size ≥ 1cm	—	170 (62)
Multifocality	—	76 (28)
Capsule invasion	—	95 (35)
Extrathyroidal extension	—	33 (12)
Lymph node metastasis	—	103 (38)
TNM stage (I/II/III/IV)	—	204/41/22/5
BRAF mutation status	—	187 (69)

Data are presented in n(%).

PTC, papillary thyroid carcinoma.

Distribution of IL17A polymorphisms in healthy controls

In the present study, we examined four SNPs within the IL17A gene, specifically rs2275913, rs3748067, rs8193036, and rs3819024. The distribution of IL17A polymorphisms among the healthy control group is detailed in Table 2. For two SNPs, rs2275913 and rs3819024, the heterozygous genotypes were more prevalent among the healthy controls, with frequencies of 46% (GA) and 48% (AG), respectively. The minor allele frequencies for these SNPs were 48% and 45%, respectively. Conversely, for the other two polymorphisms, rs3748067 and rs8193036, the wild-type genotypes were more common (CC: 72% and 50%, respectively), with mutant allele frequencies of 16% and 31%, respectively. The genotype distributions for all four SNPs adhered to Hardy-Weinberg equilibrium (rs2275913: χ² = 1.55, P = 0.21; rs3748067: χ² = 0.84, P = 0.35; rs8193036: χ² = 3.12, P = 0.07; rs3819024: χ² = 0.10, P = 0.74).

Table 2.

Prevalence of IL17A Polymorphisms in Healthy Controls and Patients with Papillary Thyroid Carcinoma

IL17A Polymorphisms	Healthy Controls (n = 250)	PTC Patients (n = 272)	OR (95% CI)	P value
rs2275913 (G > A)
GG	72 (29)	62 (23)	1	Reference
GA	115 (46)	108 (40)	1.09 (0.70–1.68)	0.74
AA	63 (25)	102 (37)	1.88 (1.17–2.95)	0.01
GA + AA	178 (71)	210 (77)	1.37 (0.91–2.02)	0.13
G	259 (52)	232 (43)	1	Reference
A	241 (48)	312 (57)	1.44 (1.12–1.84)	0.003
rs3748067 (C > T)
CC	180 (72)	192 (71)	1	Reference
CT	62 (25)	68 (25)	1.02 (0.69–1.53)	0.91
TT	8 (3)	12 (4)	1.40 (0.59–3.39)	0.49
CC + CT	70 (28)	80 (29)	1.07 (0.73–1.56)	0.77
C	422 (84)	452 (83)	1	Reference
T	78 (16)	92 (17)	1.10 (0.79–1.53)	0.61
rs8193036 (C > T)
CC	125 (50)	142 (52)	1	Reference
CT	95 (38)	94 (35)	0.87 (0.60–1.27)	0.50
TT	30 (12)	36 (13)	1.05 (0.62–1.83)	0.89
CC + CT	125 (50)	130 (48)	0.91 (0.65–1.28)	0.66
C	345 (69)	378 (69)	1	Reference
T	155 (31)	166 (31)	0.97 (0.75–1.27)	0.89
rs3819024 (A > G)
AA	78 (31)	76 (28)	1	Reference
AG	121 (48)	135 (50)	1.14 (0.77–1.70)	0.54
GG	51 (21)	61 (22)	1.22 (0.74–2.02)	0.45
AG + GG	172 (69)	196 (72)	1.17 (0.80–1.69)	0.44
A	277 (55)	287 (53)	1	Reference
G	223 (45)	257 (47)	1.11 (0.86–1.41)	0.41

Data are shown in n (%).

CI, confidence interval; IL17A, interleukin-17A; OR, odds ratio.

Prevalence of IL17A polymorphisms in patients with PTC and controls

The distribution of IL17A gene polymorphisms among the study groups is presented in Table 2. The genotype and allele frequencies of these SNPs were compared between patients with PTC and healthy controls using Fisher’s exact test. ORs, 95% CIs, and P values were calculated. Notably, the frequency of the rs2275913 GA genotype was higher in patients with PTC compared to controls, with an associated increased odds ratio and 95% confidence interval, suggesting a potential association with PTC susceptibility (OR = 1.88, 95% CI = 1.17–2.95, P = 0.01). Similar trends were also observed in the distribution of the minor allele (A) for the rs2275913 polymorphism (OR = 1.44, 95% CI = 1.12–1.84, P = 0.003). The distribution of genotypes and alleles for other SNPs was comparable (Table 2).

IL17A haplotype distribution

Table 3 delineates the distribution of IL17A haplotypes among patients with PTC and healthy controls. Eight distinct haplotypes were identified with a frequency exceeding 1 percent. Among these, the haplotype G-C-C-A (rs2275913-rs3748067-rs8193036-rs3819024) was the most prevalent in both cases and controls, with a frequency of 37.78% in cases and 51.8% in controls. Notably, the haplotypes A-C-C-A and G-C-C-G were exclusively observed in cases, indicating a potential risk factor for the development of PTC, with an 8.49-fold increased predisposition rate in individuals harboring these haplotypes.

Table 3.

Distribution of IL17A Haplotypes Among the Healthy Controls and Patients with Papillary Thyroid Carcinoma

Haplotypes (rs2275913-rs3748067-rs8193036-rs3819024)	Healthy Control % (n = 250)	PTC % (n = 272)	OR (95% CI)	P value
G-C-C-A	51.8	37.78	1	Ref
A-C-T-G	20	20.82	1.16 (0.86–1.56)	0.34
A-C-C-G	9.8	9.24	1.26 (0.79–1.98)	0.33
A-T-T-G	7.8	7.4	1.28 (0.78–2.09)	0.33
A-T-C-G	7	7.06	1.28 (0.75–2.17)	0.36
A-C-C-A	0	10.95	8.49 (2.44–29.47)	0.0008
A-C-T-A	2.8	1.61	0.95 (0.33–2.72)	0.93
G-C-C-G	0	10.95	8.49 (2.44–29.47)	0.0008

Data are shown in frequency.

NA, not available; NC, not calculated.

Plasma IL17A levels in PTC patients and controls

Plasma IL17A concentrations were quantified in all participants utilizing ELISA, with the findings illustrated in Figure 2. Patients with PTC demonstrated significantly elevated plasma IL17A levels in comparison to healthy controls (PTC: 129.9 ± 47.84 pg/mL, HC: 17.08 ± 5.63 pg/mL, P < 0.0001, Student’s t-test). This increase indicates a potential involvement of IL17A in the pathogenesis or progression of PTC.

FIG. 2.

Plasma levels of IL17A in patients with PTC and healthy controls. The plasma levels of IL17A in patients with PTC and healthy controls were quantified using enzyme-linked immunosorbent assay (ELISA). A comparison of the mean IL17A levels between the healthy controls and patients with PTC was conducted using Student’s t-test. A P value of less than 0.05 was considered statistically significant. IL17A, interleukin-17A; PTC, papillary thyroid carcinoma.

Association of IL17A polymorphisms with plasma IL17A levels

Figure 3 investigates the relationship between common IL17A gene polymorphisms and plasma IL17A concentrations in patients with PTC and healthy controls. For each SNP analyzed (A: rs2275913, B: rs3748067, C: rs8193036, D: rs3819024), mean plasma IL17A levels were compared across genotypes using analysis of variance, followed by Tukey’s post hoc test. Statistically significant differences in IL17A levels were observed among different genotypes for rs2275913: The homozygous mutant exhibited significantly higher levels of IL17A than the heterozygous mutant (P = 0.002) and wild type (P < 0.0001). Similarly, in the rs3819024 polymorphism, the homozygous mutant demonstrated higher levels of IL17A than the wild type (P = 0.007). However, no significant association between the genotypes of the other two IL17A polymorphisms (rs3748067 and rs8193036) and plasma levels of IL17A was observed in the studied cohort (Fig. 3).

FIG. 3.

Association of IL17A polymorphisms with plasma levels of IL17A. Plasma levels of IL17A were quantified in both healthy controls and patients with PTC using an enzyme-linked immunosorbent assay. Common gene polymorphisms in the IL17A gene were investigated utilizing the TaqMan SNP typing system. Genotype data and IL17A levels from 100 healthy controls and 100 patients with PTC were analyzed and are presented in the figure (A: rs2275913, B: rs3748067, C: rs8193036, D: rs3819024). Mean plasma IL17A levels across different genotypes were compared using analysis of variance, followed by Tukey’s post hoc test. A P value of less than 0.05 was considered statistically significant. SNP, single-nucleotide polymorphism.

Discussions

This study presents evidence that genetic variation in the IL17A gene, particularly the rs2275913 polymorphism and associated haplotypes, increases the risk of susceptibility to PTC in a Chinese population. Additionally, elevated IL-17A levels were observed in patients, and the IL-17 rs2275913 genotypes were associated with plasma IL-17A levels, indicating a significant role of IL-17 polymorphism in determining plasma IL-17A levels and predisposing to PTC development.

Plasma concentrations of IL17A were markedly elevated in patients with PTC compared to control subjects. Interestingly, the IL17A mRNA expression and protein levels remained higher in the PTC than in adjacent normal thyroid tissue. IL-17 contributes to a pro-inflammatory tumor microenvironment by inducing the release of cytokines such as interleukin-6 (IL-6), which subsequently activates the STAT3 and NF-κB pathways, both of which are associated with tumor growth and survival (Gu et al., 2011; Ma et al., 2010). Furthermore, IL-17 enhances the expression of vascular endothelial growth factor (VEGF) and transforming growth factor-beta, thereby facilitating angiogenesis and metastasis (Pan et al., 2015; Perez et al., 2020). In addition, IL-17, in conjunction with its regulatory partner interleukin-23 (IL-23), forms a positive feedback loop that stabilizes Th17 cells and perpetuates inflammation, further supporting tumor progression (Bailey et al., 2014). Clinically, elevated IL-17 expression in PTC is correlated with unfavorable prognostic factors, including increased recurrence and mortality rates, as well as disease progression (Carvalho et al., 2017; Banerjee et al., 2023).

A significant correlation was observed between IL17A genotypes and plasma cytokine levels. Individuals possessing the rs2275913 AA genotype demonstrated higher mean IL17A concentrations compared to those with the GG genotype, across both patient and control groups. However, a prior study on PTC did not establish this genotype–phenotype association (Bertol et al., 2022). A potential explanation for this discrepancy could be variations in the enrolled population, as the mean levels of IL17A were notably low in the studied patients, with IL17A remaining undetectable in the majority (Bertol et al., 2022). The undetectable plasma IL-17A levels reported by Bertol et al. in patients with PTC may be attributable to extremely low circulating concentrations of this cytokine and to assay sensitivity limitations. Moreover, IL-17A is predominantly expressed within the tumor microenvironment rather than in the systemic circulation (Bailey et al., 2014 #33). Consistent with the current findings, a previous report identified an association between mutant genotypes and elevated serum levels of IL-17A for the IL-17 rs2275913 polymorphism in a Chinese population (Lang et al., 2021). The mechanism by which this polymorphism alters IL17A levels remains unknown. Stimulation of T cells from healthy subjects harboring allele ‘A’ results in greater IL17 production than in subjects with allele ‘G’ (Espinoza et al., 2011). Additionally, luciferase activity investigations further support the functional role of the rs2275913 polymorphism: allele A exhibited higher luciferase activity compared to allele G (Espinoza et al., 2011). Furthermore, allele A demonstrated a higher affinity for nuclear factor activated T cells than allele G (Espinoza et al., 2011), suggesting a significant role in determining IL17 expression and IL17A levels in the subjects. This genotype-phenotype correlation suggests a functional impact of these genetic variants on cytokine expression, potentially promoting an inflammatory microenvironment conducive to tumor development and progression.

Research investigating the relationship between common IL17A gene polymorphisms and the development of PTC remains sparse. A study conducted on a Korean cohort did not find an association between IL17A rs3819024 and rs2275913 and susceptibility to PTC (Lee et al., 2015). However, the dominant and co-dominant comparison models suggested a correlation with unifocality (Lee et al., 2015). Similarly, an independent study from Brazil also did not demonstrate an association between IL17A rs2275913 and susceptibility to PTC (Bertol et al., 2022). The relatively small sample sizes in both the Brazilian and Korean studies may have limited the power to detect any existing associations. In contrast, although our current investigation did not demonstrate associations of rs3748067, rs8193036, and rs3819024 polymorphisms with susceptibility to PTC, we identified rs2275913 as a risk factor for the development of PTC. Individuals possessing the minor allele or mutant genotype may exhibit increased expression of IL17A due to the enhanced binding of transcription factors. This elevated IL17A expression is ultimately associated with the development of PTC. The present study offers several advantages over previous reports (Bertol et al., 2022; Lee et al., 2015), including the consideration of a greater number of SNPs and a larger sample size.

Several limitations warrant consideration. Although the sample size is adequate for detecting moderate associations, it may constrain the ability to identify smaller effect sizes or interactions with environmental factors. The hospital-based design could introduce selection bias, and the absence of functional assays implies that the mechanistic link between genotype and cytokine production remains speculative. Furthermore, treatment heterogeneity among patients may affect cytokine levels, although the matching of controls helps mitigate this issue. Future research should aim to replicate these findings in larger and ethnically diverse populations, incorporate functional analyses to elucidate the biological mechanisms underlying the observed associations, and evaluate the prognostic value of IL17A genotyping and cytokine profiling in clinical practice. The integration of genetic and immunological markers holds promise for enhancing risk stratification and developing targeted interventions in PTC.

In conclusion, this study emphasizes the significance of IL17A genetic variation and cytokine expression in the pathogenesis of PTC. The findings lay the groundwork for further investigation into the role of inflammatory pathways in thyroid cancer and suggest potential directions for personalized risk assessment and therapeutic targeting in affected individuals.

Authors’ Contributions

S.Y.: Data curation, formal analysis, investigation, methodology, writing—original draft. K.L.: Data curation, formal analysis, investigation, methodology, writing—original draft. T.W.: Conceptualization, formal analysis, project administration, supervision, writing—original draft, writing—review and editing.

Ethics Approval and Consent to Participate

Written informed consent was obtained from all participants, and the study protocol received approval from the Institutional Review Board of Yuyao People’s Hospital (IRB Approval No: 2020/375).

Availability of Data and Materials

All data generated or analyzed during this study are included in this published article.

Footnotes

Acknowledgments

The authors thank all patients and controls for participating in the present study.

Author Disclosure Statement

The authors declare that they have no competing interests.

Funding Information

No specific fund has been received for the present report.

Supplemental Material

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Supplementary Material

Please find the following supplemental material available below.

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