Migraine is a common, debilitating neurovascular disease characterised by severe recurrent headache, nausea and vomiting, photophobia and phonophobia . 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). MA sufferers experience neurovascular disturbances that precede the headache phase of an attack. Although migraine is partly influenced by environmental determinants, there is a significant genetic component, with disease heritability estimated to be up to 60%  and mode of transmission multifactorial. The disorder is common with a large Dutch study reporting lifetime prevalence estimates of 33% in women and 13.3% in men .
Allelic candidate gene, studies provide the most suitable method for locating genes of small effect contributing to complex genetic disorders, such as migraine [4, 5]. In particular, association studies are most powerful when a plausible candidate gene and a sequence variant with potential functional relevance is examined .
Mutations in various ion channel genes are responsible for neuromuscular and other neurological disorders. Inherited ion channel mutations or "channelopathies" are increasingly found to be the cause of various neurological disorders in humans (see review ). In familial hemiplegic migraine (FHM), a rare subtype of migraine with aura, mutations in the CACNA1A gene (localised at C19p13) have been found (FHM1) . This gene codes for the alpha1A subunit of the neuronal voltage-dependent P/Q-type calcium channel. Recently a second gene, ATP1A2 (FHM2) (localised at C1q23), was implicated in some FHM families . The ATP1A2 ion channel gene, codes for the alpha2 subunit of the Na+, K+ ion ATPase pump. These findings of mutations in these genes have focused attention on central nervous system ionic channels and helped to better understand FHM pathophysiology , where the best genetic evidence providing molecular insight into migraine still comes from the mutations detected in the rare form of migraine with aura; FHM . The CACNA1A and ATP1A2 genes have both previously been tested in the common forms of migraine, but no new mutations or the FHM mutations were detected in these MA/MO affected samples [12–14]. Since FHM2-ATP1A2 is partly a potassium channel gene and is localised nearby to the potassium channel KCNN3, it may be interesting to investigate this gene in the common forms of migraine. In general, potassium (K+) channels set the resting membrane potential and regulate the action potential, whereby they control neuronal excitability. The small conductance (SK) calcium (Ca2+) activated K+ channels are responsible for the "after-hyperpolarization" of neurons, which follows a train of action potentials, being activated by the increase in neuronal Ca2+ . The KCNN3 gene (C1q21.3) (a neuronal small conductance calcium-activated potassium channel, localised close to FHM2-ATP1A2;C1q23) encodes a protein of 731 amino acids containing two adjacent polyglutamine arrays (encoded by CAG repeats) in its N-terminal domain separated by 25 amino acids . The first CAG repeat, coding for a polyglutamine stretch in exon 1 at nucleotide 88, also contains a CAA sequence anomaly after 7 repeats of CAG. However this CAG repeat region is not suitable for association studies as it is only slightly polymorphic having usually 12 CAG repeats [15, 16]. The second, C-terminal, polyglutamine array, located 111 nucleotides downstream from the initial CAG repeat of the first polyglutamine stretch in exon 1, is highly polymorphic in Caucasian populations with a modal allele length of 19 and a repeat range of 10 to 28 glutamine – CAG repeats [see  and ]. Small conductance calcium-activated potassium channels (such as KCNN3) play a critical role in determining the firing pattern of neurons via the generation of slow after-polarization and the regulation of intracellular calcium channels .
KCNN3, localized at C1q21.3 , is positioned close to familial hemiplegic migraine (FHM) type 2, C1q23 [9, 18], which is a severe autosomal dominant type of MA . In 1999, Austin et al  suggested a mechanistic analogy for the KCNN3 polymorphism may be the small polyglutamine number variations in the calcium channel α1a subunit, encoded by CAG expansions in CACNA1A (a calcium channel implicated in FHM1)  which are thought to cause Spinocerebellar ataxia type 6 (SCA6)  by loss of channel function mechanism .
Polymorphic CAG repeats in the KCNN3 channels affect the regulation of intracellular calcium channels . Since calcium channels regulate numerous processes critical to neuronal function including secretion of neurotransmitters , abnormal alterations in calcium channels can cause alterations in the release of neurotransmitters such as serotonin, norepinephrine, and dopamine, which all have been shown to be involved in migraine disease [23–25].
Given that FHM2 maps to C1q23 and KCNN3 localizes nearby at C1q21.3, it may be important to examine the prevalence of the second (highly polymorphic) KCNN3 CAG polymorphism in populations affected and unaffected with migraine. In the current study, we investigated the possibility of an association between migraine (MA and MO affected) and the second (more 3') CAG repeat polymorphism length variation within the KCNN3 gene, using a case-control study of unrelated Australian Caucasian migraine patients and ethnically matched controls.