Novel susceptibility gene for nonfamilial hypokalemic periodic paralysis

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 −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.