New insights into migraine etiology: the role of hepatocyte growth factor

By Pooja Toshniwal PahariaReviewed by Lily Ramsey, LLMNov 10 2023

In a recent study published in Scientific Reports, researchers evaluated the causal links between pro-inflammatory cytokine expression and migraine.

Study: Exploring the causal relationship between inflammatory cytokines and migraine: a bidirectional, two-sample Mendelian randomization study. Image Credit: Komsan Loonprom/Shutterstock.com

Background

Migraines are a chronic neurological condition characterized by frequent headaches, nausea, and vomiting. It is a significant cause of impairment in young individuals and is linked to neurogenic inflammation.

This inflammation is distinguished by the release of inflammatory mediators, increased vascular permeability, leukocyte infiltration, disruption to the blood-brain barrier, and glial cell activation.

When the trigeminal ganglion and its fibers are activated, neuropeptides are produced, which causes vasodilation and the production of inflammatory substances, which causes migraine episodes.

About the study

In the present study, researchers comprehensively investigated whether pro-inflammatory cytokines were causally linked to migraine.

A bi-directional Mendelian randomization (MR) analysis was performed using genomic data from publicly accessible genome-wide association studies (GWAS). The forward Mendelian randomization evaluation considered pro-inflammatory cytokines and chemokines as exposure variables and their influence on migraines as the study outcome.

Conversely, the reverse Mendelian randomization considered migraine and pro-inflammatory cytokines as exposure and outcome variables, respectively.

MR methods such as random-effects inverse-variance weighting (IVW), MR-Egger, and weighted median were used to evaluate the causal associations, and odds ratios (ORs) were calculated. In addition, a “leave-one-out” analysis was performed. 

Thresholds of P-value less than 5.0 × 10−6 and linkage disequilibrium (LD) of 10,000 kilobases (kb) with a r2 value of 0.001 were applied to select single-nucleotide polymorphisms (SNPs) strongly linked to pro-inflammatory cytokines in the forward MR analysis.

For the reverse MR analysis, the team identified SNPs significantly associated with migraines at the genome-wide level (P-value less than 5 × 10−8) and characterized by low LD (r2 less than 0.001, distance threshold of 10,000 kb).

The inflammatory cytokine GWAS dataset yielded 347 SNPs for 41 pro-inflammatory cytokines from 8,293 Finnish individuals who participated in the FINRISK survey (mean age, 60 years) and the Finnish Young Finns Study (YFS, mean age, 37 years).

The migraine GWAS dataset comprised United Kingdom Biobank (UKBB) data, including 13,597 migraine cases among Europeans and 449,336 controls of the same ancestry, all aged between 40 and 60 years.

Results

Hepatocyte growth factor (HGF) was positively associated with migraine risk (OR, 1.0), as indicated by the forward MR analysis, weighted mean, and MR-Egger analyses findings.

In the reverse MR analysis performed using 15 SNPs and the IVW approach, the team uncovered a probable association between increased migraine risk and diminished interleukin-2 (IL-2) levels (OR, 0.01), corroborated by the weighted median analysis.

The findings indicated that HGF may play a dominant role in the early onset of migraine, whereas IL-2 is more likely to be downstream in the disease progression. The “leave-one-out” sensitivity analyses yielded similar results, indicating the robustness of the primary analysis without any horizontal pleiotropy.

Migraine is characterized by an increase in the production of neurotransmitters, notably peptide neurotransmitters such as calcitonin gene-related peptide (CGRP). HGF, the scatter factor, is crucial for neuron formation, survival, growth, guidance, and muscle feeding.

It is a self-secreted component essential in developing and specializing nociceptors, sensory neurons emitting peptide neurotransmitters such as CGRP.

T lymphocyte proliferation, growth, and differentiation are stimulated by interleukin-2, an interleukin generated by activated T lymphocytes. Regulatory T (Treg) lymphocytes are more sensitive to interleukin-2 than effector T lymphocytes, and therefore, modest levels of interleukin-2 can activate regulatory T lymphocyte signaling pathways while leaving effector T cells alone.

This can modulate Treg cell amounts and activities and improve immunosuppression and immunological regulation.

Increased Treg cell counts can reduce mechanical allodynia in mouse models of neural damage and autoimmune encephalomyelitis, whereas depletion can worsen it.

IL-10, IL-35, and tumor growth factor -beta (TGF-β) decrease immune responses and preserve immunological homeostasis, reducing pain sensitivity in models of chronic pain. In a murine model of headache, interleukin-2 in low doses could inhibit and reverse hypersensitivity of pain.

Vasoactive intestinal peptide (VIP) and CGRP levels are reported to be significantly higher during the interictal state of migraine in comparison to non-migraine states, according to research.

VIP functions as a neurotransmitter and neuromodulator in the gastrointestinal system, controlling smooth muscle action, blood flow, and the secretion of epithelial cells.

Conclusions

Based on the study findings, hepatocyte growth factor may be a potential cause of migraine, and migraine may lead to decreased interleukin-2 levels. However, the study included only European individuals, limiting their generalizability.

Moreover, the lack of detailed clinical data prevented subgroup analyses, preventing the identification of specific causal associations. Future studies could include diverse populations and subgroups to standardize the results.