Exploring the Association of Migraine Susceptibility SNPs With the Risk of Chronic Migraine

Background: Although robust genetic markers for episodic migraine (EM) have been identified, variants associated with chronic migraine (CM) are still unknown. Given the potential pathophysiologic overlap between EM and CM, we investigated whether six single nucleotide polymorphisms (SNPs), robustly associated with EM susceptibility (LRP1 rs11172113, PRDM16 rs10797381, FHL5 rs7775721, TRPM8 rs10166942, near TSPAN2 rs2078371 and MEF2D rs1925950) also play a role in the risk of developing CM. Methods: A total of 200 EM and 202 CM participants were prospectively included. Genotyping of selected SNPs was performed by TaqMan real-time PCR in 192 individuals with EM and 198 with CM who consented to genetic analysis. A validation group of 312 healthy individuals was used. Genetic associations were assessed by logistic regression using dominant, recessive, and allelic models. Results: In multivariable logistic regression analysis, LRP1 rs11172113 T>C and (near) TSPAN2 rs2078371 T>C were nominally associated with CM. However, only the association for LRP1 rs11172113 survived Bonferroni correction, with carriers of the minor C allele (genotypes T/C or C/C) having a lower risk of CM compared to wild-type homozygous subjects (OR: 0.38; 95% CI: 0.20–0.71; p-value: 0.0025). This protective effect was also observed in the analysis comparing CM participants with healthy controls. Conclusion: Carriers of the minor allele of LRP1 rs11172113 have a reduced risk of CM. However, further large-scale studies, ideally with a multicentre design, are warranted to confirm the association between LRP1 rs11172113 and CM. Significance Statement: This study identified an association between the minor allele of LRP1 rs11172113 (low-density lipoprotein receptor-related protein 1, a receptor with key roles in lipid metabolism, vascular integrity, and inflammation control) and a reduced risk of chronic migraine. These findings support the hypothesis that episodic and chronic migraine share genetic risk factors and suggest a potential protective role for this variant.