title: Novel susceptibility gene for nonfamilial hypokalemic periodic paralysis.
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.
authors.affiliation: 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.
authors.forename: I-Wen
authors.initials: IW
authors.lastname: Song
authors.affiliation: 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.
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Sung
authors.affiliation: 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.
authors.forename: Chien-Hsiun
authors.initials: CH
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Chih-Jen
authors.initials: CJ
authors.lastname: Cheng
authors.affiliation: 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.
authors.forename: Sung-Sen
authors.initials: SS
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Chou
authors.affiliation: 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.
authors.forename: Jenn-Hwai
authors.initials: JH
authors.lastname: Yang
authors.affiliation: 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.
authors.forename: Yuan-Tsong
authors.initials: YT
authors.lastname: Chen
authors.affiliation: 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.
authors.forename: Jer-Yuarn
authors.initials: JY
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Shih-Hua
authors.initials: SH
authors.lastname: Lin
mesh_terms: D001483:Base Sequence; D002460:Cell Line; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology* / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D020514:Hypokalemic Periodic Paralysis / Q000175:diagnosis / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D013624:Taiwan / Q000453:epidemiology