I-Wen Song1, Chih-Chien Sung1, Chien-Hsiun Chen1, Chih-Jen Cheng1, Sung-Sen Yang1, Yi-Chun Chou1, Jenn-Hwai Yang1, Yuan-Tsong Chen1, Jer-Yuarn Wu2, Shih-Hua Lin2. 1. 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. 2. 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. l521116@gmail.com jywu@ibms.sinica.edu.tw.
Abstract
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.
Authors: Maria Clara C Melo; Janaína S de Souza; Marina M L Kizys; Angela C Vidi; Haron S Dorta; Ilda S Kunii; Gisele Giannocco; Gianna Carvalheira; Magnus R Dias-da-Silva Journal: J Endocr Soc Date: 2017-02-28