Genetic variant rs623011 (17q24.3) associates with non-familial thyrotoxic and sporadic hypokalemic paralysis Pei-Yi Chu a , Chih-Jen Cheng b , Min-Hua Tseng a, c , Sung-Sen Yang a, b , Hsiang-Cheng Chen d , Shih-Hua Lin a, b, ⁎ a Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan b Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Taipei, Taiwan c Department of Pediatric, Chang Gung Memorial Hospital at Linkou, Taoyuan, Taiwan d Divison of Rheumatology, Allergy, and Immunology, Department of Medicine, Tri-Service General Hospital, Taipei, Taiwan abstract article info Article history: Received 19 June 2012 Received in revised form 1 August 2012 Accepted 4 August 2012 Available online 15 August 2012 Keywords: Gene Hypokalemia Paralysis Potassium channel Hyperthyroidism Background: A recent genome-wide association study of Thai patients with thyrotoxic periodic paralysis (TPP) identified a novel genetic variant rs623011 located in chromosome 17q24.3, which may potentially reduce the transcription of Kir2.1 and total Kir current. Purpose: The aim of this study was to evaluate whether this genetic variant was present in Chinese patients with TPP and sporadic periodic paralysis (SPP), the second leading cause of non-familial hypokalemic periodic paralysis (hypoKPP) in Asia. Methods: Ninety patients with TPP, 61 SPP, and 100 age and sex-matched healthy subjects were performed. Genomic DNA was isolated from blood leukocytes and analysis of rs623011 was performed by polymerase chain reaction and direct sequencing. Results: Compared with normal control, the frequency of the risk allele A of rs623011 was significantly higher in both TPP and SPP patients (73.9% versus 53.5%, p = 0.001; 82.0% versus 53.5%, p b 0.001, respectively) with the Odds ratios (95% confidence interval) 2.426 (1.348–4.369) and 4.488 (2.265–8.891), respectively. The frequency of the A allele of rs623011 was similar between TPP and SPP. Conclusions: TPP and SPP have the same susceptible gene variant rs623011 and may share the pathogenic mechanism of reduced Kir current in skeletal muscle independent of thyroid hormone. © 2012 Elsevier B.V. All rights reserved. 1. Introduction Hypokalemic periodic paralysis (hypoKPP) is characterized by abrupt muscle weakness to paralysis associated with ictal hypokale- mia due to an acute shift of K + into cells [1]. HypoKPP exists in familial or non-familial form. Familial form of periodic paralysis (FPP) is more common in western country and autosomal-dominant inheritance predominantly caused by mutations in genes encoding for skeletal muscle-specific voltage-gated Na + channel Na v 1.4 (SCN4A) or Ca 2+ channel Ca v 1.1 (CACNA1S) [2,3]. The majority of mutations in Ca v 1.1 or Na v 1.4 occur in the S4 voltage sensors, changing positively charged amino acids to uncharged [4]. Recent studies indicate that mutations in the voltage sensor create an aberrant conducting pore (“gating pore”) that allows passage of small cations (Na + and H + ) at hyperpolarized resting membrane poten- tials, leading to hypokalemia-induced paradoxical depolarization of sarcolemma, a hallmark of hypoKPP during hypokalemic attacks [5,6]. Non-familial hypoKPP is more common in Asia and mainly consists of thyrotoxic (TPP) [7,8] and sporadic periodic paralysis (SPP) without a family history of periodic paralysis and hyperthyroidism [9–11]. The pathogenesis of non-familial TPP and SPP remains elusive. Due to indistinguishable feature with FPP, TPP and SPP may share the similar pathogenic mechanism with FPP and have defects in ion channels [11–13]. However, no TPP patient and only very few SPP patients have mutation in SCN4A or CACNA1S responsible for FPP [14]. In recent studies, a newly-identified Kir channel, Kir2.6, has been reported to predispose TPP patients to acute paralytic attack [14]. Kir2.6 is a skeletal muscle specific Kir channel and can be regulated by thyroid hormone through upstream thyroid hormone response element (TRE) of KCNJ18 gene encoding Kir2.6 [15]. We also found three additional loss-of-function mutations in Kir2.6 channel in both TPP and SPP patients [16] and suggested that the reduced outward Kir current either due to Kir channel mutations or inhibition that can potentially inhibits total K + efflux may be involved in TPP and SPP [17]. Although these recent studies provide new insights into the pathogenesis of non-familial TPP and SPP, the reasons remain Clinica Chimica Acta 414 (2012) 105–108 ⁎ Corresponding author at: Division of Nephrology, Department of Medicine, Tri- Service General Hospital, No 325, Section 2, Cheng-Kung Road, Neihu 114, Taipei, Taiwan. Tel.: +886 2 87927213; fax: +886 2 87927134. E-mail address: l521116@ndmctsgh.edu.tw (S.-H. Lin). 0009-8981/$ – see front matter © 2012 Elsevier B.V. All rights reserved. doi:10.1016/j.cca.2012.08.004 Contents lists available at SciVerse ScienceDirect Clinica Chimica Acta journal homepage: www.elsevier.com/locate/clinchim