Association study of functional −183G/A and 48892A/C polymorphisms of interleukin-6 receptor ( IL-6R ) gene in Japanese patients with migraine

Abstract

Aim

Although migraine has been associated with inflammation and vascular reactivity, its pathophysiology has remained unclear. The pro-inflammatory cytokine interleukin-6 (IL-6) has been implicated in pain modulation, immune regulation and vascular functions. In this study, we aimed to investigate the association between migraine and two single-nucleotide polymorphisms (SNPs) of interleukin-6 receptor (IL-6R).

Methods

In this case-control genetic association study, we analysed 63 patients with migraine with aura (MA), 113 patients with migraine without aura (MO), 35 patients with tension-type headache (TTH) and 62 healthy controls (CTL). All participants were unrelated Japanese individuals residing in the Sanin area of western Japan. A polymerase chain reaction-based restriction fragment length polymorphism assay was performed to detect the presence of two SNPs: −183G/A (rs4845617) in the promoter region and 48892A/C (rs8192284) in exon 9. Logistic regression analyses adjusted for age and sex were performed.

Results

The IL-6R 48892A/C C-allele was more prevalent in the MA group than in the CTL group (61.7% vs. 48.3%), with the homozygous 48892C/C genotype particularly enriched in the MA group (adjusted odds ratio 3.51, 95% CI 1.10–11.26, P = 0.034). No significant association was observed for the −183G/A polymorphism.

Conclusions

Our findings suggest that IL-6R 48892A/C (rs8192284) polymorphisms may be associated with susceptibility to migraine in the Sanin region of western Japan, with distinct associations observed for MA. These findings support the potential role of IL-6R–related inflammatory signalling in the pathophysiology of migraine.

Trial registration

Not applicable

Keywords

single-nucleotide polymorphisms inflammation vascular reactivity pain headaches

Introduction

Migraine is a prevalent neurological disorder characterised by recurrent severe headaches, often accompanied by nausea, vomiting, hypersensitivity to light and sound and autonomic symptoms. It is the second leading cause of years lived with disability worldwide, highlighting the need for novel treatment strategies.¹ Although the exact pathogenesis of migraine remains unclear, strong familial clustering suggests an underlying genetic component. Common forms of migraine are polygenic, with multiple genetic variants exerting smaller individual effects.² Previous studies have identified several gene polymorphisms associated with migraine susceptibility, including the serotonin transporter-linked polymorphic region,³ dopamine receptor D2,⁴ 5,10-methylenetetrahydrofolate reductase⁵ and P/Q-type calcium channel gene.⁶

Recent studies have highlighted neurovascular dysfunction and inflammation as key contributors to migraine pathophysiology.^7,8 In particular, interleukin-6 (IL-6), a pro-inflammatory cytokine involved in immune response regulation, has been implicated in pain modulation and vascular function. In addition, IL-6 contributes to central sensitisation and vascular reactivity, mechanisms thought to underlie migraine attacks. IL-6 signalling is mediated by its receptor (IL-6R), which exists in both membrane-bound and soluble forms.⁹ The soluble form of IL-6R (sIL-6R) is primarily generated through the shedding of the membrane-bound form.¹⁰ Genetic variations in IL-6R gene have been reported to alter IL-6 and IL-6R levels, potentially influencing inflammatory responses and vascular reactivity.¹¹

Given these mechanisms, investigating IL-6R polymorphisms may provide insights into migraine susceptibility. This study aimed to examine the association between IL-6R gene polymorphisms and migraine in the Sanin region of western Japan. Specifically, we focused on two IL-6R gene polymorphisms, −183G/A (rs4845617) and 48892A/C (rs8192284), which have been shown to influence IL-6 and IL-6R levels in previous studies.^12–14 By conducting a case-control study, we aimed to determine whether these genetic variants contribute to migraine susceptibility. We hypothesised that the frequencies of the variant alleles of these IL-6R polymorphisms would be significantly higher among patients with migraine (with and without aura) than in controls.

Methods

Participants

The present study population included patients with migraine with aura (MA), patients with migraine without aura (MO) and patients with episodic tension-type headache (TTH). To assess the specificity of IL-6R polymorphisms to migraine, we included patients with episodic TTH as a disease control group. All participants were recruited through a single-centre, hospital-based framework in the Sanin region of western Japan, with patients consecutively enrolled from the outpatient neurology clinic of Tottori University Hospital. All participants were unrelated Japanese individuals who resided in the same geographic region. Diagnosis of headache was assigned by board-certified neurologists based on all available information, including interviews, clinical observations and medical records, to ensure the standardised application of the International Classification of Headache Disorders 3rd edition (ICHD-3)¹⁵ criteria. This study is reported in accordance with the STROBE guidelines for this case-control genetic association study. Healthy volunteers without a history of recurrent headaches, confirmed via a questionnaire, medical record review, or clinical examination, were included in the control group (CTL). The healthy controls were recruited from the same geographic region through community-based health checkups and hospital staff volunteer programs.

The exclusion criteria included individuals with secondary headaches, neurological disorders other than primary headache disorders, autoimmune or inflammatory diseases and severe systemic illnesses. Individuals with a prior history of chronic or recurrent headaches or neurological diseases were excluded. To minimise potential confounding by age-related biological differences, participants aged ≥50 years were excluded, and all primary analyses were conducted within this age-defined cohort.

This study was approved by the relevant Ethics Committee of Tottori University, approval number (G-1 and 2713). Written informed consent was obtained from all participants for the genetic analysis, and an opt-out procedure was applied for the retrospective analysis according to institutional guidelines.

Genotyping

Genomic DNA was extracted from peripheral blood using the standard phenol/chloroform method. Genotyping was performed using a polymerase chain reaction-based restriction fragment length polymorphism (PCR-RFLP) assay, following previously published protocols. Primer sequences, PCR conditions and restriction enzymes were selected according to established methods.¹² PCR products were digested with the appropriate restriction enzymes and separated by agarose gel electrophoresis to determine genotypes based on fragment length patterns. Genotype determination was performed by investigators blinded to clinical diagnosis. Two single-nucleotide polymorphisms (SNPs) in IL-6R were analysed: −183G/A (rs4845617) in the promoter region and 48892A/C (rs8192284) in exon 9.

Statistical analysis

Age was compared between each headache group and controls using the Student's t-test. Sex distribution was compared using the Chi-squared test. Hardy–Weinberg equilibrium was assessed for each SNP in all groups using Pearson's Chi-squared test. Allele and genotype frequencies of patients and controls were calculated using the direct counting method, and differences between patients and controls (MA vs. CTL, MO vs. CTL and TTH vs. CTL for each SNP) were evaluated using Pearson's Chi-squared test.

Multiple logistic regression analyses were performed to estimate odds ratios (ORs) and 95% confidence intervals (CIs), with age and sex included as covariates. The results are reported as adjusted ORs (aORs). The risk of headache associated with the IL-6R −183G/A polymorphism was evaluated under a co-dominant (genotypic) model, comparing GA and AA genotypes independently with the GG genotype. Similarly, the risk associated with the IL-6R 48892A/C polymorphism was assessed under a co-dominant model by comparing the AC and CC genotypes independently with the AA genotype. Other inheritance models (dominant, recessive and additive) were examined in exploratory analyses. In addition, an exploratory analysis comparing MA and MO was performed using multiple logistic regression analysis adjusted for age and sex. A two-sided P-value < 0.05 was considered statistically significant. All statistical analyses were performed using StatFlex version 7 (Artech Co., Ltd, Osaka, Japan).

Results

The demographic characteristics of the study participants are summarised in Table 1. In the comparison between the MO group and the CTL group, a significantly higher proportion of females was observed in the MO group. No significant differences in age were observed among the four groups. All enrolled participants were included in the final analyses. No eligible cases were excluded after the screening. For genetic analyses, data were available for 228 participants for −183G/A and 265 participants for 48892A/C. Missing genotype calls were due to PCR amplification failure and occurred at similar proportions across diagnostic groups. All analyses were conducted using available genotype data for each SNP.

Table 1.

Genotype distributions and allele frequencies of IL-6R polymorphisms, −183G/A and 48892A/C, in cases and controls.

	MA	MO	TTH	CTL
N	63	113	35	62
Age (mean ± S.D.)	30.2 ± 8.9	31.9 ± 9.1	33.6 ± 10.0	30.8 ± 8.9
Female (%)	44 (69.8)	89 (78.8)*	25 (71.4)	40 (64.5)
−183G/A
N	48	98	29	53
Genotypes (%)^$
G/G	7 (14.6)	17 (17.3)	11 (37.9)	9 (17.0)
G/A	26 (54.1)	37 (37.8)	11 (37.9)	26 (49.1)
A/A	15 (31.3)	44 (44.9)	7 (24.1)	18 (34.0)
Allele, %
G	41.7	36.2	56.9	41.5
A	58.3	63.8	43.1	58.5
P (Allele vs CTL)	0.982	0.367	0.059	-
48892A/C
N	60	110	35	60
Genotypes (%)^$
A/A	7 (11.7)	26 (23.6)	11 (27.3)	14 (23.3)
A/C	32 (53.3)	54 (49.1)	12 (44.2)	34 (56.7)
C/C	21 (35.0)	30 (27.3)	12 (28.6)	12 (20.0)
Allele, %
A	38.3	48.2	48.6	51.7
C	61.7	51.8	51.4	48.3
P (Allele vs CTL)	0.041	0.115	0.128	-

The total is not necessarily 100% for fractions.

* P-Value < 0.05, versus CTL.

S.D., standard deviation.

MA, migraine with aura; MO, migraine without aura; TTH, tension-type headache; CTL, control.

The genotype distributions of the −183G/A and 48892A/C polymorphisms in IL-6R were consistent with the Hardy–Weinberg equilibrium in all groups (−183G/A: MA P = 0.43, MO P = 0.07, TTH P = 0.22, CTL P = 0.94; 48892A/C: MA P = 0.32, MO P = 0.86, TTH P = 0.06, CTL P = 0.30). Table 1 shows the genotype and allele frequencies of these polymorphisms. The IL-6R 48892A/C C-allele was significantly more frequent in the MA group (74/120 [61.7%]) than in the CTL group (58/120 [48.3%]). No significant differences in the genotype or allele frequencies of either IL-6R polymorphism were observed between the TTH and control groups.

The results of the multiple logistic regression analysis, adjusted for age and sex, are summarised in Table 2. In patients with MA, with the 48892A/A genotype as the reference, the aOR for the 48892C/C genotype was 3.51 (95% CI: 1.10–11.26). In an exploratory analysis comparing MA and MO, the 48892 CC genotype was more frequent in the MA group than in the MO group after adjusting for age and sex (Supplementary Table S1).

Table 2.

Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) from multiple logistic regression analysis of subjects and IL-6R genotypes in cases and controls

Groups	Genotypes	AOR	95% CIs	P-Value^*
	−183G/A
MA vs CTL	GG	1.0, reference
	GA	1.35	0.42–4.22	0.607
	AA	1.13	0.34–3.83	0.840
MO vs CTL	GG	1.0, reference
	GA	0.74	0.28–1.93	0.533
	AA	1.22	0.45–3.30	0.692
TTH vs CTL	GG	1.0, reference
	GA	0.32	0.10–1.03	0.056
	AA	0.30	0.08–1.06	0.061
	48892A/C
MA vs CTL	AA	1.0, reference
	AC	1.80	0.63–5.15	0.271
	CC	3.51	1.10–11.26	0.034
MO vs CTL	AA	1.0, reference
	AC	0.77	0.35–1.71	0.522
	CC	1.25	0.48–3.24	0.644
TTH vs CTL	AA	1.0, reference
	AC	0.35	0.12–1.06	0.062
	CC	1.10	0.35–3.53	0.867

P-value: age and sex adjusted.

MA, migraine with aura; MO, migraine without aura; TTH, tension-type headache; CTL, control; CI, confidence interval.

Discussion

In this study, we examined two functional IL-6R polymorphisms (−183G/A and 48892A/C) in a Japanese cohort. We observed a significant association between the 48892A/C polymorphism and MA, with the C allele being more frequent in MA than in CTL and the CC genotype showing an increased odds of MA in age- and sex-adjusted analyses. In contrast, no significant association was observed between the −183G/A polymorphism and migraine in this age-defined cohort. In an exploratory analysis, the 48892 CC genotype was also more frequent in MA than in MO, supporting the potential subtype-specific involvement of IL-6R variation. It was reported that sIL-6R, which facilitates IL-6 signalling, is affected by IL-6R polymorphism. The A allele of −183G/A was associated with higher sIL-6R levels than the G allele¹²; the 48892A/C polymorphism affected sIL-6R shedding by altering the cleavage site; and the C allele of the 48892A/C polymorphism was associated with higher sIL-6R levels than the A allele.¹⁴ These genetic variations may contribute to increased IL-6 signalling in patients with migraine, supporting the role of inflammatory mechanisms in disease susceptibility. To our knowledge, this is the first study to report an association between migraine and IL-6R polymorphisms, supporting the hypothesis that inflammatory pathways contribute to the pathogenesis of migraine. Importantly, the differential involvement of these polymorphisms in MA and MO also implies that distinct molecular mechanisms underlie the clinical heterogeneity of migraine. Therefore, our results provide a rationale for considering the broader role of IL-6 as an inflammatory mediator in pain and migraine pathophysiology.

A recent systematic review and meta-analysis of cytokines in primary headaches demonstrated significantly higher circulating levels of IL-6, TNF-α and IL-8 in patients with migraine than in controls, and increased IL-1β levels during migraine attacks then in the inter-ictal state.¹⁶ Among these, IL-6 showed the most robust association, further supporting its role as a key inflammatory mediator in migraine. Notably, these cytokine elevations were not observed in TTH, suggesting a degree of specificity for migraine.

The inclusion of an episodic TTH group allowed us to assess whether the observed genetic associations were specific to migraine rather than reflecting a general susceptibility to primary headache disorders. In the present study, neither IL-6R polymorphism showed significant differences between TTH patients and controls. This absence of association is consistent with previous reports indicating that inflammatory cytokine elevation is not a prominent feature of TTH, in contrast to migraine. Although no statistically significant association was observed in episodic TTH, the AC genotype of IL-6R 48892A/C showed a nonsignificant trend toward a lower odds ratio. Together, these findings support the possibility that IL-6–related mechanisms may be more relevant to migraine biology. However, given the modest sample size of the TTH group, these results should be interpreted cautiously and considered as exploratory.

Calcitonin gene-related peptide (CGRP), a key neuropeptide in migraine pathophysiology released during trigeminovascular activation, induces vasodilation and modulates inflammatory responses. Previous studies have demonstrated a close interplay between CGRP and IL-6 signalling in migraine, suggesting that IL-6 may act as a downstream mediator of CGRP-driven neurogenic inflammation.¹⁷ In this context, genetic variation in IL-6R may influence the inflammatory milieu associated with migraine biology. However, the present study did not assess treatment response or therapeutic outcomes. Therefore, the potential implications of IL-6R polymorphisms for treatment stratification or personalised medicine remain speculative and should be addressed in future pharmacogenetic studies.

Recent basic research has highlighted IL-6 as a pivotal mediator linking neuroinflammation and pathological pain. Experimental models of bone cancer, peripheral nerve injury, spinal cord injury and inflammatory pain have consistently shown upregulated IL-6 and IL-6R expression in the spinal cord and dorsal root ganglia. Exogenous IL-6 administration induces mechanical allodynia and thermal hyperalgesia, whereas neutralising antibodies against IL-6 or IL-6R alleviate these pain behaviours.¹⁸ These findings indicate that IL-6 not only serves as a systemic inflammatory marker but also actively regulates nociceptive sensitisation, which is highly relevant to migraine pathophysiology.

In the present study, a significant association with the IL-6R 48892A/C polymorphism was observed in patients with MA, whereas no significant association was detected in MO. Previous studies have demonstrated that the 48892A/C polymorphism affects IL-6R shedding, with the C allele being associated with increased circulating levels of soluble IL-6R.^12,14 This functional effect may provide a biological context for the observed association with MA. Cortical spreading depression (CSD) is widely considered a key pathophysiological mechanism underlying migraine aura, and experimental studies have shown that inflammatory cytokines, including IL-6 and TNF-α, can modulate susceptibility to CSD.^19,20 Enhanced IL-6 signalling may influence CSD susceptibility by activation of glial cells, altering blood–brain barrier permeability, and/or directly affecting neuronal excitability. While the CC genotype of 48892A/C showed a significant association in MA, the direct comparison between MA and MO did not provide evidence for a clearly different genotype effect between the two subtypes. In this context, elevated IL-6 signalling mediated by the 48892C/C genotype may influence the inflammatory and neurovascular processes relevant to CSD. Although these observations support a possible link between IL-6R–mediated inflammatory signalling and MA, the present findings should be interpreted cautiously, and the potential differences between migraine subtypes require confirmation in larger, independent cohorts.

Therapeutic agents targeting IL-6R, such as tocilizumab, sarilumab and satralizumab, have demonstrated efficacy in modulating inflammatory pathways in autoimmune diseases.²¹ While these observations raise the possibility that IL-6R inhibition could influence migraine-related inflammatory processes, the potential therapeutic implications remain speculative. Moreover, isolated reports of vascular adverse events, including reversible cerebral vasoconstriction syndrome following tocilizumab therapy,²² underscore the need for caution. Currently, no clinical evidence supports the use of IL-6R inhibitors for migraine treatment.

This study has several limitations that should be considered when interpreting the findings. First, this study focused on participants aged <50 years to minimise age-related biological confounding. While this design choice improved the comparability between groups, it limited the generalisability of the findings to older populations and may not have captured genetic effects relevant to late-onset headache phenotypes. Second, the overall sample size was modest, particularly for the subgroup analyses. Comparisons between migraine subtypes (e.g., MA vs. MO) and analyses involving the TTH group were therefore exploratory and may have been underpowered to detect small effect sizes, raising the possibility of a type II error. In addition, all participants were recruited from a single geographic region in western Japan, which may further limit the generalisability of the results to other populations. Third, multiple statistical comparisons were performed across SNPs and diagnostic groups, and no formal correction for multiple tests was applied. Accordingly, the observed associations—especially those derived from exploratory analyses – should be regarded as hypothesis-generating and require replication in independent cohorts. Fourth, we did not measure the circulating levels of IL-6 or soluble IL-6R, which precluded the direct evaluation of the functional consequences of the examined polymorphisms. Although previous studies have reported the functional effects of these variants, the absence of biomarker data limits the mechanistic interpretation in the present cohort. Genotype call rates differed between SNPs (−183G/A: 84.5% vs. 48892A/C: 96.1%); missingness was due to PCR amplification failure and occurred at similar proportions across groups, making major bias unlikely, although reduced precision cannot be excluded. Finally, detailed clinical information such as migraine frequency, chronic migraine status and treatment response was not available, which restricted the ability to explore genotype–phenotype correlations. Taken together, these limitations indicate that the present findings should be interpreted with caution and underscore the need for larger, well-characterised studies that incorporate functional and longitudinal data.

Conclusions

This study identified an association between the IL-6R 48892A/C polymorphism and MA in a Japanese population from western Japan. No significant association was observed for the −183G/A polymorphism in the present study. These findings suggest that IL-6R–related inflammatory signalling may contribute to the pathophysiology of MA. Further studies in larger and more diverse cohorts, incorporating functional and clinical validation, are required to clarify the contribution of IL-6R variants to migraine susceptibility.

Article highlights

Pathophysiology of migraine remains unclear.

Association between migraine and two SNPs of IL-6 receptors was studied.

The IL-6R 48892A/C polymorphism was associated with migraine with aura in a Japanese population.

These findings suggest a possible involvement of IL-6R-related inflammatory signalling in migraine.

IL-6R gene variants may be associated with migraine susceptibility.

Supplemental Material

sj-docx-1-rep-10.1177_25158163261447417 - Supplemental material for Association study of functional −183G/A and 48892A/C polymorphisms of interleukin-6 receptor (IL-6R) gene in Japanese patients with migraine

Supplemental material, sj-docx-1-rep-10.1177_25158163261447417 for Association study of functional −183G/A and 48892A/C polymorphisms of interleukin-6 receptor (IL-6R) gene in Japanese patients with migraine by Hiroshi Takigawa, Hisanori Kowa, Shinya Kawase, Toshiya Nakano, Kenji Nakashima and Ritsuko Hanajima in Cephalalgia Reports

Footnotes

Acknowledgements

The authors would like to thank all the participants who generously contributed to this study.

ORCID iD

Hiroshi Takigawa

Ethical considerations

This study was conducted with the approval from the Ethics Committee on Genetics of the Faculty of Medicine, Tottori University (approval number: G-1), and the Ethics Committee for Clinical Research of the same institution for the retrospective clinical study on headache (approval number: 2713). For the retrospective component, an opt-out approach was implemented in accordance with institutional guidelines. All methods were performed in accordance with relevant guidelines and regulations.

Consent to participate

Written informed consent was obtained from all participants before inclusion in the genetic study.

Consent for publication

The authors give their consent for the publication of this manuscript in Cephalalgia Reports.

Author contributions

Study conception and design were developed by HT, HK, KN and RH. Data acquisition, analysis and interpretation were developed by HT, HK, SK, TN, KN and RH. Statistical analysis was developed by HT and HK. Drafting of the manuscript was developed by HT and HK. Manuscript revision was developed by all authors. All authors approved the final version of the article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by a Grant-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (JSPS) [grant number 25K10682].

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Supplemental material

Supplemental material for this article is available online.

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