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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.
GLOSSARY
- FPP=
- familial periodic paralysis;
- GWAS=
- genome-wide association studies;
- hypoKPP=
- hypokalemic periodic paralysis;
- lincRNA=
- long intergenic noncoding RNA;
- PCA=
- principal component analysis;
- QC=
- quality control;
- RT-q-PCR=
- real-time quantitative PCR;
- SNP=
- single nucleotide polymorphism;
- SPP=
- sporadic periodic paralysis;
- TPP=
- thyrotoxic periodic paralysis
Footnotes
↵* These authors contributed equally to this work.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Supplemental data at Neurology.org
- Received June 30, 2015.
- Accepted in final form December 10, 2015.
- © 2016 American Academy of Neurology
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