TRPM8 genetic variant is associated with chronic migraine and allodynia

DOI: https://doi.org/10.1186/s10194- 019- 1064- 2

Abstract-Summary Many single nucleotide polymorphisms (SNPs) have been reported to be associated with migraine susceptibility.

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.

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.

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 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).

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2 Mechanisms

Allodynia severity did not differ between episodic and chronic migraine patients. TRPM8 may contribute to the pathogenesis of chronic migraine. Extended: The data that support the findings of this study are available from the

corresponding author on reasonable request.

Introduction Among the Han Chinese population in Taiwan, several novel variants were identi- fied to be associated with migraine in a two-stage GWAS [93], including rs655484 in disks large homolog 2 (DLG2) and rs3781545 in GDNF family receptor alpha-1 (GFRA1), rs10803531 in G protein-coupled receptor 39 (GPR39), and rs7565931 in uridine phosphorylase 2 (UPP2).

The association of some endophenotypes and migraine implicit genotypes have

been studied and reported [94, 95].

Allodynia is another widely-studied endophenotype of migraine. We aimed to investigate the association between migraine endophenotypes, especially for chronic migraine and allodynia, and known susceptible genes of migraine in Taiwan.

In the replication cohort, we also evaluated the cutaneous allodynia profile in patients with migraine using a 17-item questionnaire, aiming to obtain the evidence for the association between genetic variants and cutaneous allodynia, a clinical marker signaling the sensitisation of trigeminovascular system and a potential pre- dictor of migraine chronification [96].

Materials and Methods The discovery and replication cohorts were recruited based on the time they entered the study and whether they completed the allodynia assessment.

Based on the finding of our prior work [93], all participants in discovery cohort were genotyped for six SNPs known to be associated with migraine in Taiwanese, including rs10166942  in TRPM8, rs1172113  in LRP1, rs7565931  in UPP2, rs10803531 in GPR39, rs655484 in DLG2, and rs3781545 in GFRA1.

In the replication cohort, every participant was genotyped for rs10166942  in

TRPM8—the only significant one identified in the discovery cohort.

We assessed the allodynia profile of all participants in the replication cohort. Using the 17-item allodynia assessment questionnaire specific for migraine patients, the participants were asked to recall any allodynic symptoms they had dur- ing a migraine attack [97].

Results We genotyped all six susceptible variants in all participants and explored their pos- sible associations with endophenotypes of migraine.

Among the six investigated SNPs, we found that only TRPM8 variant rs10166942

was associated with chronic migraine.

Discussion Our study also demonstrates the association between the TRPM8 rs10166942 T allele and allodynia severity.

2.1 Genetics

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The association between the TRPM8 genetic variant and allodynia has never

been reported in human studies with migraine.

Unlike a previous study [98], our data did not show associations between chronic

migraine and the severity of allodynia.

One paediatric study also did not demonstrate an association between allodynia

and chronic migraine [99].

Regardless of the discrepancy, our results showed that allodynia was positively associated with the disease duration of migraine, which is in line with a previous study [100].

The T allele in the TRPM8 variant rs10166942 is a risk allele for migraine, and

our results further indicate that it is also a risk allele to allodynia in migraineurs.

Based on our findings, a longitudinal study is warranted to elucidate the asso- ciation between the TRPM8 genetic variant rs10166942 and the evolution of migraine.

Conclusions Our study shows that the TRPM8 variant rs10166942 is associated with chronic migraine and allodynia in patients with migraine.

Further investigation regarding the role of TRPM8 in allodynia pathogenesis and

migraine chronification may provide a novel treatment strategy.

Acknowledgement A machine generated summary based on the work of Ling, Yu-Hsiang; Chen, Shih- Pin; Fann, Cathy Shen-Jang; Wang, Shuu-Jiun; Wang, Yen-Feng. 2019  in The Journal of Headache and Pain.

Genetic variants in migraine: a field synopsis and systematic re-analysis of meta-analyses