Chromosomal area 19p13 contains two migraine associated genes: a Ca(v)2.1 (P/Q-type) calcium channel alpha(1) subunit gene, CACNA1A, and an insulin receptor gene, INSR. Missense mutations in CACNA1A cause a rare Mendelian form of migraine, familial hemiplegic migraine type 1 (FHM1). Contribution of CACNA1A locus has also been studied in the common forms of migraine, migraine with (MA) and without aura (MO), but the results have been contradictory. The role of INSR is less well established: A region on 19p13 separate from CACNA1A was recently reported to be a major locus for migraine and subsequently, the INSR gene was associated with MA and MO. Our aim was to clarify the role of these loci in MA families by analyzing 72 multigenerational Finnish MA families, the largest family sample so far. We hypothesized that the potential major contribution of the 19p13 loci should be detected in a family sample of this size, and this was confirmed by simulations. We genotyped eight polymorphic microsatellite markers surrounding the INSR and CACNA1A genes on 757 individuals. Using parametric and non-parametric linkage analysis, none of the studied markers showed any evidence of linkage to MA either under locus homogeneity or heterogeneity. However, marginally positive lod scores were observed in three families, and thus for these families the results remain inconclusive. The overall conclusion is that our study did not provide evidence of a major MA susceptibility region on 19p13 and thus we were not able to replicate the INSR locus finding.
"One group reported a link between insulin receptor gene polymorphism at locus 19p13.3/2 and migraine with aura (McCarthy et al., 2001; Kaunisto et al., 2005; Curtain, 2006; Netzer et al., 2008), although it is unclear if this polymorphism confers a loss or gain of function. While insulin receptors are found in many regions of the brain, the signals that these receptors propagate and the effect of resistance on their activity remains unclear. "
[Show abstract][Hide abstract] ABSTRACT: Migraine and metabolic syndrome are highly prevalent and costly conditions. The two conditions coexist, but it is unclear what relationship may exist between the two processes. Metabolic syndrome involves a number of findings, including insulin resistance, systemic hypertension, obesity, a proinflammatory state, and a prothrombotic state. Only one study addresses migraine in metabolic syndrome, finding significant differences in the presentation of metabolic syndrome in migraineurs. However, controversy exists regarding the contribution of each individual risk factor to migraine pathogenesis and prevalence. It is unclear what treatment implications, if any, exist as a result of the concomitant diagnosis of migraine and metabolic syndrome. The cornerstone of migraine and metabolic syndrome treatments is prevention, relying heavily on diet modification, sleep hygiene, medication use, and exercise.
Frontiers in Neurology 11/2012; 3(article 161):161. DOI:10.3389/fneur.2012.00161
"Indeed, in parallel with the association study, the same group published evidence for an MA susceptibility locus on chromosome 19p13 distinct from the FHM1 gene , and the INSR gene is located within the critical region between D19S427 and D19S592. On the other hand, the chromosome 19p locus was later on excluded in Finnish MA families . Also in a Caucasian migraine pedigree with linkage to 19p (for which CACNA1A mutations had been excluded) no coding mutations in the INSR gene were identified  . "
[Show abstract][Hide abstract] ABSTRACT: We performed the first replication study for the reported association of the insulin receptor gene (INSR) with migraine with aura (MA). Two of 35 SNPs (rs1052371 and rs2860174) reached borderline significance (best uncorrected allelic p value of 0.052 for rs2860174) in stage 1 of our study (270 MA patients, 280 controls). As rs2860174 was 1 of the 5 SNPs with prior evidence of association, we also genotyped this SNP in our stage 2 sample (679 MA patients, 368 controls), and it was nonsignificant (allelic p value 0.478). The combined analysis of our samples showed just a nonsignificant trend for rs2860174 (p=0.1). However, the joint analysis of our study and the initial study reporting an association-including 1278 Caucasian MA patients and 1337 Caucasian controls altogether-displayed a significant allelic p value of 0.005. In conclusion, further association studies for rs2860174 with even larger numbers of individuals are required to exclude or confirm definitely a small effect of this SNP on migraine susceptibility.
"Thus, the genes involved in FHM pathogenesis could be possible therapeutic targets, although the many studies investigating the role of CACNA1A gene in common forms of migraine have produced contradictory results [17, 18]. "
[Show abstract][Hide abstract] ABSTRACT: Migraine is a complex disorder caused by a combination of genetic and environmental factors.
Although family and twin studies show that there is a genetic component in migraine, no genes predisposing to common forms of the disorder, migraine with and without aura, have been identified. Patients with migraine respond differently to a given drug administered. The efficacy of therapy and the occurrence of adverse drug response are a consequence of individual variability. Genetic profiling of predisposition to migraine should facilitate the development of more effective diagnostic and therapeutic applications. The development of International Hap Map project could provide a powerful tool for identification of the candidate genes in this complex disease and pharmacogenomics research could be the promise for individualized treatments and prevention of adverse drug response.
The Journal of Headache and Pain 01/2008; 8(6):334-9. DOI:10.1007/s10194-007-0427-2 · 2.80 Impact Factor
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