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

DOI: https://doi.org/10.1186/s10194- 018- 0937- 0

Abstract-Summary Genetic factors have been implicated in both migraine and cluster headache.

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.

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, Χ2 = 4.102).

This association was stronger in a subgroup of patients suffering from both clus-

ter headache and migraine (p = 0.031, Χ2 = 6.964).

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2 Mechanisms

In this Swedish cluster headache cohort we did not find an association with the

rs2651899 variant.

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 neurovascu-

lar headaches in general whilst rs2651899 is specifically related to migraine.

Extended: We conclude that rs1835740  in MTDH is associated not only with migraine but also with CH, whilst rs2651899 in PRDM16 seems to be specifically related to migraine in Sweden.

Background Migraine and cluster headache (CH) are two primary headache disorders that share pathological features and a majority of CH patients are successfully treated with drugs used for migraine, such as triptans [111–114].

There are also phenotypic similarities between CH and migraine, such as recur- ring attacks of headache, lateralized pain and associated autonomic symptoms [113, 114].

There are marked differences in the clinical manifestations and associated symp-

toms between migraine and CH.

Genetic factors are likely to influence the risk of developing both migraine

and CH [3].

The aim of this study was to investigate whether migraine and CH might share genetic determinants since similar pathophysiological events occur in both disorders. Analysis of the distribution of the genetic migraine markers rs2651899 and

rs1853740 has not previously been performed in CH.

We therefore screened a large Swedish CH case-control population and per- formed an association analysis of these two markers that have been shown to increase the risk for migraine in Sweden.

Material and Methods The material consisted of 541 CH cases and 581 controls where 571 of the controls were anonymous healthy blood donors, these samples were obtained from local blood donation centres in 2003–2005.

Medical journals of all 541 CH patients were reviewed by a neurologist (one of the co-authors A.S., E.W. or C.S.) in order to confirm the diagnosis according to the International Classification of Headache Disorders (ICHD-II) [115].

23 of the CH cases were obtained from the TwinGene study, conducted between 2004 and 2008, the procedure of identifying individuals with cluster headache, blood sampling, genotyping and quality control of the array data has been described in previous publications [116, 117].

Primary fibroblast cell lines derived from 12 CH patients and 12 control subjects were obtained from skin biopsies performed on the inside of research subjects’ upper arm.

Results Both the TT and the CT genotypes were more common in patients than controls, but there was no significant genotypic association.

2.1 Genetics

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Since these two SNPs are known to influence the risk of migraine, and many CH patients in our material also suffer from migraine, we performed a stratified analysis with respect to migraine.

When comparing the allele and genotype frequencies, the mutated allele became increasingly more common in the group of patients suffering from both CH and migraine; 21.1% in CH patients and 26.2% in CH patients with migraine, as com- pared to the control group where the MAF was 18.5%.

The genetic association discovered here between CH and rs1835740, in combi- nation with the discovery study reporting that rs1835740 potentially affects the expression levels of the MTDH gene lead us to also investigate the MTDH mRNA expression levels in a subset of patients and controls [64].

Discussion and Conclusion A more detailed analysis of rs1835740 revealed that the association was even stron- ger in a subgroup of patients that have both CH and migraine.

In a former GWAS suggesting MTDH as a candidate gene for migraine, the effect of the rs1835740 association was stronger in a subgroup of patients suffering from migraine with aura (MA) than in patients with migraine without aura (MO), which is also an indication of this SNP being associated with more complex head- ache phenotypes [64].

In a study on rs1835740 and migraine by Azimova and others (2015) small groups of CH patients (n = 9) and chronic tension type headache patients (n = 20) were used as control groups.

We studied the MTDH mRNA levels in individuals with different rs1835740

genotype, and also analyzed expression with respect to CH diagnosis.

Acknowledgement A machine generated summary based on the work of Ran, Caroline; Fourier, Carmen; Zinnegger, Margret; Steinberg, Anna; Sjöstrand, Christina; Waldenlind, Elisabet; Belin, Andrea Carmine. 2018 in The Journal of Headache and Pain.

rs2651899 variant is associated with risk for migraine without aura from North Indian population