Song I-Wen, Sung Chih-Chien, Chen Chien-Hsiun, Cheng Chih-Jen, Yang Sung-Sen, Chou Yi-Chun, Yang Jenn-Hwai, Chen Yuan-Tsong, Wu Jer-Yuarn, Lin Shih-Hua
From the Institute of Biomedical Sciences (I.-W.S., C.-H.C., Y.-C.C., J.-H.Y., Y.-T.C., J.-Y.W.), Academia Sinica; Graduate Institute of Life Science (I.-W.S.), Division of Nephrology, Department of Medicine, Tri-Service General Hospital (C.-C.S., C.-J.C., S.-S.Y., S.-H.L.), and Graduate Institute of Medical Science (C.-C.S., S.-S.Y., S.-H.L.), National Defense Medical Center, Taipei, Taiwan; Department of Pediatrics (Y.-T.C.), Duke University Medical Center, Durham, NC; and Graduate Institute of Chinese Medical Science (J.-Y.W.), China Medical University, Taichung, Taiwan.
Neurology. 2016 Mar 29;86(13):1190-8. doi: 10.1212/WNL.0000000000002524. Epub 2016 Mar 2.
To identify susceptibility genes to nonfamilial hypokalemic periodic paralysis (hypoKPP) consisting of thyrotoxic periodic paralysis (TPP) and sporadic periodic paralysis (SPP) and explore the potential pathogenic mechanisms.
We enrolled patients with nonfamilial hypoKPP not carrying mutations in CACNA1S, SCN4A, KCNJ18, or KCNJ2 and conducted genome-wide association analyses comparing 77 patients with TPP and 32 patients with SPP with 1,730 controls in a Han Chinese population in Taiwan. Replication was performed using an independent Han Chinese cohort of 50 patients with TPP, 22 patients with SPP, and 376 controls.
We identified 4 single nucleotide polymorphisms (rs312692, rs312736, rs992072, rs393743) located about 100 Kb downstream of KCNJ2 on chromosome 17q24.3 associated with both TPP and SPP reaching genome-wide significance (p < 9 × 10(-8)). rs312736 was mapped to CTD-2378E21.1, a lincRNA, and direct sequencing revealed an exon variant rs312732 (risk allele A) highly associated with both TPP (p = 1.81 × 10(-12); odds ratio [OR] 3.22 [95% confidence interval (CI) 2.36-4.40]) and SPP (p = 8.6 × 10(-12); OR 5.4 [95% CI 3.17-9.18]). Overexpression of C (normal allele) CTD-2378E21.1 in C2C12 skeletal muscle cell, but not A (risk allele) CTD-2378E21.1, showed significantly decreased Kcnj2 expression, indicating A-type CTD-2378E21.1 has lost the ability to regulate Kcnj2.
Our study reveals a shared genetic predisposition between TPP and SPP. CTD-2378E21.1 is a novel disease-associated gene for both TPP and SPP and may negatively regulate KCNJ2 expression. These findings provide new insights into the pathogenesis of nonfamilial hypoKPP.
鉴定由甲状腺毒症性周期性瘫痪（TPP）和散发性周期性瘫痪（SPP）组成的非家族性低钾性周期性瘫痪（低钾性周期性麻痹，hypoKPP）的易感基因，并探索潜在的致病机制。
我们纳入了未携带CACNA1S、SCN4A、KCNJ18或KCNJ2基因突变的非家族性低钾性周期性瘫痪患者，在台湾的汉族人群中对77例TPP患者和32例SPP患者与1730名对照进行全基因组关联分析。使用由50例TPP患者、22例SPP患者和376名对照组成的独立汉族队列进行重复验证。
我们在17号染色体q24.3上KCNJ2下游约100 Kb处鉴定出4个单核苷酸多态性（rs312692、rs312736、rs992072、rs393743），它们与TPP和SPP均相关，达到全基因组显著性水平（p < 9 × 10⁻⁸）。rs312736定位于一种长链非编码RNA（lincRNA）CTD - 2378E21.1，直接测序显示一个外显子变体rs312732（风险等位基因A）与TPP（p = 1.81 × 10⁻¹²；优势比[OR] 3.22 [95%置信区间（CI）2.36 - 4.40]）和SPP（p = 8.6 × 10⁻¹²；OR 5.4 [95% CI 3.17 - 9.18]）高度相关。在C2C12骨骼肌细胞中过表达C（正常等位基因）CTD - 2378E21.1，而非A（风险等位基因）CTD - 2378E21.1，显示Kcnj2表达显著降低，表明A型CTD - 2378E21.1已失去调节Kcnj2的能力。
我们的研究揭示了TPP和SPP之间存在共同的遗传易感性。CTD - 2378E21.1是TPP和SPP的一个新的疾病相关基因，可能对KCNJ2表达起负调控作用。这些发现为非家族性低钾性周期性瘫痪的发病机制提供了新的见解。
