Abstract
BackgroundMigraine is a polygenic multifactorial disease, possessing environmental and genetic causative factors with multiple involved genes. Mutations in various ion channel genes are responsible for a number of neurological disorders. KCNN3 is a neuronal small conductance calcium-activated potassium channel gene that contains two polyglutamine tracts, encoded by polymorphic CAG repeats in the gene. This gene plays a critical role in determining the firing pattern of neurons and acts to regulate intracellular calcium channels.MethodsThe present association study tested whether length variations in the second (more 3') polymorphic CAG repeat in exon 1 of the KCNN3 gene, are involved in susceptibility to migraine with and without aura (MA and MO). In total 423 DNA samples from unrelated individuals, of which 202 consisted of migraine patients and 221 non-migraine controls, were genotyped and analysed using a fluorescence labelled primer set on an ABI310 Genetic Analyzer. Allele frequencies were calculated from observed genotype counts for the KCNN3 polymorphism. Analysis was performed using standard contingency table analysis, incorporating the chi-squared test of independence and CLUMP analysis.ResultsOverall, there was no convincing evidence that KCNN3 CAG lengths differ between Caucasian migraineurs and controls, with no significant difference in the allelic length distribution of CAG repeats between the population groups (P = 0.090). Also the MA and MO subtypes did not differ significantly between control allelic distributions (P > 0.05). The prevalence of the long CAG repeat (>19 repeats) did not reach statistical significance in migraineurs (P = 0.15), nor was there a significant difference between the MA and MO subgroups observed compared to controls (P = 0.46 and P = 0.09, respectively), or between MA vs MO (P = 0.40).ConclusionThis association study provides no evidence that length variations of the second polyglutamine array in the N-terminus of the KCNN3 channel exert an effect in the pathogenesis of migraine.
Highlights
Migraine is a polygenic multifactorial disease, possessing environmental and genetic causative factors with multiple involved genes
We investigated the possibility of an association between migraine (MA and migraine without aura (MO) affected) and the second CAG repeat polymorphism length variation within the KCNN3 gene, using a case-control study of unrelated Australian Caucasian migraine patients and ethnically matched controls
In a meta-analysis of association studies for schizophrenia and bipolar disorder with the CAG-repeat length in KCNN3, the results demonstrated that the risks for both of these disorders were largely, if not entirely, independent of the CAG-repeat in the KCNN3 gene [34]
Summary
Migraine is a polygenic multifactorial disease, possessing environmental and genetic causative factors with multiple involved genes. KCNN3 is a neuronal small conductance calcium-activated potassium channel gene that contains two polyglutamine tracts, encoded by polymorphic CAG repeats in the gene. This gene plays a critical role in determining the firing pattern of neurons and acts to regulate intracellular calcium channels. Migraine is a common, debilitating neurovascular disease characterised by severe recurrent headache, nausea and vomiting, photophobia and phonophobia [1]. It is clinically diagnosed based on criteria specified by the International Headache Society (IHS), defining two major classes of migraine: migraine with aura (MA) and migraine without aura (MO). Association studies are most powerful when a plausible candidate gene and a sequence variant with potential functional relevance is examined [6]
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