TRPM8 genetic variant is associated with chronic migraine and allodynia

Abstract

Background: Many single nucleotide polymorphisms (SNPs) have been reported to be associated with migraine susceptibility. However, evidences for their associations with migraine endophenotypes or subtypes are scarce. We aimed to investigate the associations of pre-identified migraine susceptibility loci in Taiwanese with migraine endophenotypes or subtypes, including chronic migraine and allodynia. Methods: The associations of six SNPs identified from our previous study, including TRPM8 rs10166942, LRP1 rs1172113, DLG2 rs655484, GFRA1 rs3781545, UPP2 rs7565931, and GPR39 rs10803531, and migraine endophenotypes, including chronic migraine and allodynia were tested. Significant associations in the discovery cohort were validated in the replication cohort. The adjusted odds ratios (aOR) were calculated after controlling for confounders.Results: In total, 1904 patients (mean age 37.5 ± 12.2 years old, female ratio: 77.7%) including 1077 in the discovery cohort and 827 in the replication cohort were recruited. Of them, 584 (30.7%) had chronic migraine. Of the 6 investigated SNPs, TRPM8 rs10166942 T allele-carrying patients were more likely to have chronic migraine than non-T allele carriers in both discovery and replication cohorts and combined samples (33.7% vs. 25.8%, p = 0.004, aOR = 1.62). In addition, T allele carriers reported more allodynic symptoms than non-T allele carriers (3.5 ± 3.7 vs. 2.6 ± 2.8, p < 0.001). However, allodynia severity did not differ between episodic and chronic migraine patients. No further correlations between genetic variants and endophenotypes were noted for the other SNPs. Conclusions: TRPM8 may contribute to the pathogenesis of chronic migraine. However, our study did not support allodynia as a link between them. The underlying mechanisms deserve further investigations.

Trigeminal Neuralgia TRPM8 Mutation

“…A number of studies suggest that the activation of TRPM8 exaggerates pain sensation. 11,12 In support of these results, selective TRPM8 antagonists reduced chronic pain and allodynia in animal models. 10,37 In contrast, other studies report that TRPM8 agonists have analgesic properties.…”

“…6 Notably, the patient was heterozygous for a variant, c.89 G > A (p.Arg30Gln; 9/ 282,688 on gnomAD v2), in TRPM8. Given the expression of TRPM8 within trigeminal ganglia [7][8][9] and reported association of TRPM8 with pain, [10][11][12] we asked whether this variant might produce any functional changes in the TRPM8 channel or within cells expressing it.…”

TRP Channels Regulation of Rho GTPases in Brain Context and Diseases

“…Migraines (Gavva et al, 2019;Ling et al, 2019), Glioblastoma (Zeng et al, 2019) Regulation of cerebral arterial vasodilation…”

“…TRPM8 has a polymodal gating and is activated by cold and different cooling compounds, such as menthol and icilin (McKemy et al, 2002). Several single nucleotide polymorphisms (SNPs) related to the TRPM8 gene are associated with either the risk (Ling et al, 2019) or protection (Gavva et al, 2019) from migraines. Although the exact mechanisms are unknown, a possible mechanism for TRPM8-mediated risk of migraine headaches might be related to this channel's role in vasoconstriction regulation, which has been related to migraine development (Jacobs and Dussor, 2016).…”

Chronic migraine: Genetics or environment?

“…Some environmental factors such as medication-overuse are known, but a genetic disposition is also an obvious possibility. There have been attempts to find genetic risk factors for CM [11][12][13][14][15][16][17] These studies have, however, used a candidate-gene approach comparing CM with healthy controls and not with EM. No studies have to date investigated whether a genetic component promotes the development of EM into CM.…”