PER Gene Family Polymorphisms in Relation to Cluster Headache and Circadian Rhythm in Sweden

Abstract

The trigeminal autonomic cephalalgia, cluster headache (CH), is one of the most painful disorders known to man. One of the disorder’s most striking features is the reported diurnal rhythmicity of the attacks. For a majority of patients, the headache attacks occur at approximately the same time every day. Genetic variants of genes involved in the circadian rhythm such as Period Circadian Regulator 1, 2, and 3 (PER1, 2 and 3) are hypothesized to have an effect on the rhythmicity of the attacks. Six PER1, 2 and 3 genetic markers; the indel rs57875989 and five single nucleotide polymorphisms (SNPs), rs2735611, rs2304672, rs934945, rs10462020, and rs228697, were genotyped, using TaqMan® or regular polymerase chain reaction (PCR), in a Swedish CH case control material. Logistic regression showed no association between CH and any of the six genetic variants; rs57875989, p = 0.523; rs2735611, p = 0.416; rs2304672, p = 0.732; rs934945, p = 0.907; rs10462020, p = 0.726; and rs228697, p = 0.717. Furthermore, no difference in allele frequency was found for patients reporting diurnal rhythmicity of attacks, nor were any of the variants linked to diurnal preference. The results of this study indicate no involvement of these PER genetic variants in CH or diurnal phenotype in Sweden.

The genetics and chronobiology of cluster headache

“…The minor allele of rs10462020 in PER3 has been associated with altered morningness/eveningness score and delayed sleep phase syndrome while another PER3 SNP, rs228697 is significantly associated with evening preference (79)(80)(81). All these PER markers have been screened in a Swedish CH cohort, in addition to rs57875989 in PER3, linked to diurnal preference and screened in a Norwegian CH cohort, but no association has been found (47,82).…”

“…Both CACNA1 and HCRTR2 had previously been screened in linkage studies, but with no significant findings, likely on account of small pedigrees (55,57). Results from replication studies of these candidate genes have in addition so far been conflicting, which could be due to potential geographical differences and small sample sizes and thereby low power (82,88,89). In a transcriptional study comparing lymphoblasts from patients with CH, respectively bipolar disorder selected for positive response to lithium and healthy controls dysregulation of two circadian genes was implicated; RNA binding motif protein 3 ( RBM3 ) and nuclear receptor subfamily 1, group D, member 1 ( NR1D1 ) (90).…”

“…The 15–180 min attacks of severe unilateral headache with accompanying autonomic features which may occur up to eight times a day (1–5), have a clear nocturnal preference. Apart from this circadian rhythmicity, CH also occurs, or worsens, at specific times of the year in clusters (circannual/infradian rhythmicity), hence the name (2,6–8). The presence and duration of the resultant intermittent remissions dichotomizes the disorder into an episodic and rarer chronic diagnostic entity (5).…”