Implications for the migraine SNP rs1835740 in a Swedish cluster headache population

BACKGROUND: Cluster headache is a severe headache disorder with unknown aetiology. The pathophysiology and symptoms present certain common features with migraine. Specifically, activation of the trigeminal vascular system seems to be involved in both disorders, which is hypothesized to result in neurogenic inflammation and vasodilation of the cerebral vessels. In addition, genetic factors have been implicated in both migraine and cluster headache. OBJECTIVE: In order to determine whether or not migraine and cluster headache share genetic risk factors, we screened two genetic variants known to increase the risk of migraine in Sweden in a Swedish cluster headache case-control study population. METHODS: In all, 541 patients and 581 control subjects were genotyped for rs1835740 in close proximity to MTDH (metadherin) and rs2651899 in the PRDM16 (PR/SET domain 16) gene, using TaqMan® real-time PCR and pyrosequencing. In addition, we analyzed MTDH gene expression in a subset of the material, using reverse transcription real-time PCR to determine relative mRNA levels in primary fibroblast cell lines from patients and controls. RESULTS: We found a trend for association between rs1835740, which is reported to affect MTDH mRNA levels, and cluster headache in our Swedish case-control material (p = 0.043, Χ(2) = 4.102). This association was stronger in a subgroup of patients suffering from both cluster headache and migraine (p = 0.031, Χ(2) = 6.964). We could further confirm that rs1835740 has an effect on the transcriptional activity of MTDH. In this Swedish cluster headache cohort we did not find an association with the rs2651899 variant. CONCLUSIONS: We conclude that rs1835740 is a potential risk factor for cluster headache in Sweden. Our data indicates that rs1835740 and MTDH might be involved in neurovascular headaches in general whilst rs2651899 is specifically related to migraine.