PDF(Pubmed)
Abstract：
Dysfunction in ion channels or processes involved in maintaining ionic homeostasis is thought to lower the threshold for cortical spreading depression (CSD), and plays a role in susceptibility to associated neurological disorders, including pathogenesis of a migraine. Rare pathogenic variants in specific ion channels have been implicated in monogenic migraine subtypes. In this study, we further examined the channelopathic nature of a migraine through the analysis of common genetic variants in three selected ion channel or transporter genes: SLC4A4, SLC1A3, and CHRNA4. Using the Agena MassARRAY platform, 28 single-nucleotide polymorphisms (SNPs) across the three candidate genes were genotyped in a case-control cohort comprised of 182 migraine cases and 179 matched controls. Initial results identified significant associations between migraine and rs3776578 (p = 0.04) and rs16903247 (p = 0.05) genotypes within the SLC1A3 gene, which encodes the EAAT1 glutamate transporter. These SNPs were subsequently genotyped in an independent cohort of 258 migraine cases and 290 controls using a high-resolution melt assay, and association testing supported the replication of initial findings-rs3776578 (p = 0.0041) and rs16903247 (p = 0.0127). The polymorphisms are in linkage disequilibrium and localise within a putative intronic enhancer region of SLC1A3. The minor alleles of both SNPs show a protective effect on migraine risk, which may be conferred via influencing the expression of SLC1A3.
摘要：
离子通道或维持离子稳态过程的功能障碍被认为会降低皮质扩散抑制（CSD）的阈值，并在相关神经系统疾病的易感性中起作用，包括偏头痛的发病机制。特定离子通道中的罕见致病变异与单基因偏头痛亚型有关。在这项研究中,我们通过分析3个选定的离子通道或转运蛋白基因:SLC4A4,SLC1A3和CHRNA4的常见遗传变异,进一步研究了偏头痛的通道病变性质.使用AgenaMassARRAY平台,在由182例偏头痛病例和179例匹配对照组成的病例对照队列中，对三个候选基因的28个单核苷酸多态性（SNP）进行了基因分型。初步结果确定了SLC1A3基因中偏头痛与rs3776578（p=0.04）和rs16903247（p=0.05）基因型之间的显着关联，编码EAAT1谷氨酸转运体。这些SNP随后在258例偏头痛病例和290例对照的独立队列中使用高分辨率解链测定法进行基因分型。和关联测试支持初始发现的复制-rs3776578(p=0.0041)和rs16903247(p=0.0127).多态性处于连锁不平衡状态，并位于SLC1A3的推定内含子增强子区域内。两个SNP的次要等位基因对偏头痛风险显示出保护作用，这可能是通过影响SLC1A3的表达来实现的。
