In a recently published study, Dr Scientific reportResearchers evaluated causal links between pro-inflammatory cytokine expression and migraine.
Study: Exploring the causal relationship between inflammatory cytokines and migraine: a two-way, two-sample Mendelian randomization study.. Image credit: Komsan Loonprom/Shutterstock.com
Migraine is a chronic neurological condition characterized by frequent headaches, nausea and vomiting. It is a significant cause of frailty in young adults and is associated with neurogenic inflammation.
This inflammation is characterized by the release of inflammatory mediators, increased vascular permeability, leukocyte infiltration, blood-brain barrier disruption, and glial cell activation.
When the trigeminal ganglion and its fibers are activated, neuropeptides are produced, which cause vasodilation and the production of inflammatory substances, which cause migraine episodes.
About the study
In the current study, the researchers comprehensively investigated whether pro-inflammatory cytokines were functionally associated with migraine.
A bidirectional Mendelian randomization (MR) analysis was performed using genomic data from publicly accessible genome-wide association studies (GWAS). Forward Mendelian randomization evaluation considered pro-inflammatory cytokines and chemokines as exposure variables and their effects on migraine as study outcomes.
Conversely, 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 medians were used to assess causal associations, and odds ratios (ORs) were calculated. In addition, a “leave-one-out” analysis was performed.
A P-value threshold of less than 5.0 × 10−6 and a linkage disequilibrium (LD) of 10,000 kilobases (kb) with an r2 value of 0.001 were applied to select single-nucleotide polymorphisms (SNPs) strongly associated with pro-inflammatory cytokines. Forward MR analysis.
For reverse MR analysis, the team identified SNPs significantly associated with migraine at the genome-wide level (p-value less than 5 × 10−8) and characterized by low LD (r2 less than 0.001, distance 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 study (mean age, 60 years) and the Finnish Young Finns Study (YFS, mean age, 37).
The Migraine GWAS dataset consists of UK Biobank (UKBB) data, including 13,597 migraine cases in Europeans and 449,336 controls of the same ancestry, aged between 40 and 60 years.
Hepatocyte growth factor (HGF) was positively associated with the risk of migraine (OR, 1.0), as indicated by the results of forward MR analysis, weighted mean, and MR-Agar analysis.
In inverse MR analysis performed using 15 SNPs and the IVW method, the team uncovered a possible association between increased migraine risk and reduced interleukin-2 (IL-2) levels (OR, 0.01), which was confirmed by weighted median analysis.
The findings indicate that HGF may play a dominant role in the early onset of migraine, whereas IL-2 is more likely downstream in disease progression. “Leave-one-out” sensitivity analyzes yielded similar results, indicating the robustness of the initial analysis with no horizontal pleiotropy.
Migraines are characterized by increased production of neurotransmitters, particularly 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 essential component in the development and specialization of nociceptors, sensory neuron releasing peptide neurotransmitters such as CGRP.
The proliferation, growth, and differentiation of T lymphocytes are stimulated by interleukin-2, an interleukin produced 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 left alone by effector T cells can activate regulatory T lymphocyte signaling pathways.
It can modulate the quantity and activities of Treg cells and improve immunosuppression and immunological regulation.
An increase in Treg cell numbers can reduce mechanical allodynia in mouse models of neurological damage and autoimmune encephalomyelitis, whereas a decrease can worsen it.
IL-10, IL-35, and tumor growth factor-beta (TGF-β) reduce the immune response and preserve immunological homeostasis, reducing pain sensitivity in models of chronic pain. In a murine model of headache, low doses of interleukin-2 can inhibit and reverse pain hypersensitivity.
According to studies, vasoactive intestinal peptide (VIP) and CGRP levels have been reported to be significantly higher during the interstitial state of migraine compared to non-migraine state.
VIP acts as a neurotransmitter and neuromodulator in the gastrointestinal system, regulating smooth muscle action, blood flow, and epithelial cell secretion.
Based on the results of the study, hepatocyte growth factor may be a possible cause of migraine and may reduce migraine interleukin-2 levels. However, the studies included only European individuals, limiting their generalizability.
Furthermore, the lack of detailed clinical data precluded subgroup analysis, preventing the identification of specific causal associations. Future studies may include different populations and subgroups to standardize results.