甲狀腺毒性週期性癱瘓之全基因體相關研究

Abstract

甲狀腺毒性週期性癱瘓是一種由甲狀腺機能亢進引起的少見併發症，大部分發生在葛瑞夫茲氏病患者身上，尤以亞洲的男性最為常見。患者通常因急性的四肢無力、癱軟的症狀進入急診，經抽血檢驗會發現程度不等的低血鉀現象，惟詳細的致病機轉尚未完全清楚。在大量攝入碳水化合物、酒精或者劇烈運動之後是發作的高峰期，症狀嚴重的程度因人而異，從輕微的肌肉無力至嚴重的全身性癱瘓皆有，但大多會在發作後的72小時內恢復正常。 西元2010年，相關文獻發表指出鉀離子通道蛋白Kir2.6(KCNJ18)的基因突變與甲狀腺毒性週期性癱瘓有關，在高加索族群中約有三分之一的患者帶有此基因變異，然而在發生率較高的亞洲族群中反而少有患者帶有這樣的突變，暗示應有其他基因參與其中。西元2012年，分別以中國大陸南方族群和泰國群族進行的全基因體相關研究一致指出在染色體17q24.3位置的核苷酸多型性與甲狀腺毒性週期性癱瘓有關，其上游的KCNJ2基因被認為可能扮演重要的角色。 在本篇論文中我們以臺大醫院收案之甲狀腺毒性週期性癱瘓者共53位男性做為研究對象，使用153位不曾出現週期性癱瘓症狀之男性葛瑞夫茲氏病患者做為對照進行全基因組相關分析，結果發現到位於17q24.3區域的單核苷酸多型性rs992072與此症具有最高的相關性(P=3.18×10-7,odds ratio=3.8)。此外針對可能的致病基因KCNJ2與KCNJ18施行直接定序，結果顯示在53位甲狀腺毒性週期性癱瘓者中並沒有任何患者帶有KCNJ2或KCNJ18的致病突變。我們的研究結果與其他團隊先前發表的文獻大致相符，再度證實KCNJ18基因突變並非亞洲族群甲狀腺毒性週期性癱瘓的主要致病原因，而染色體17q24.3區域的核苷酸多型性也確實具有相當程度的影響力，可能的分子機制還需要更進一步研究。

Thyrotoxic periodic paralysis (TPP) is a rare complication of hyperthyroidism that most often affects East Asian males. It is most commonly observed in Graves’ disease(GD) patients but may occur with any etiology of thyrotoxicosis. The typical presentations of TPP are muscle paralysis and a variable degree of hypokalemia. Patients usually seek medical attention at the emergency room because of acute muscle weakness. The attacks are often preceded by heavy carbohydrate-rich meal, alcohol abuse or strenuous exercise, varying from mild weakness to total paralysis with complete recovery within 72 hours. The pathogenesis of TPP still remains unclear, but it is known to be associated with hypokelamia which is caused by a massive shift of potassium into the intracellular compartments. In 2010, KCNJ18 gene mutations which alter the function of an inwardly rectifying potassium channel named Kir2.6 were identified as a cause of TPP. These KCNJ18 mutations are highly prevalent in individuals with TPP in Caucasian populations but are not common in individuals from Asia. This suggests that additional genetic variants may also contribute to TPP susceptibility, especially in Asian populations. In 2012, genome-wide association studies(GWAS) of TPP in a Thai population and southern Chinese independently identified a susceptibility locus on chromosome 17q24.3 which might have functions on regulating the expression of another potassium channel gene named KCNJ2. In this study, we performed GWAS with 53 male TPP patients and 153 male GD controls diagnosed at National Taiwan University Hospital and identified a susceptibility locus also at 17q24.3 (rs992072: P=3.18×10-7,odds ratio=3.8). Direct sequencing of the coding region of KCNJ2 and KCNJ18 genes in TPP patients found no obvious disease-causing variants. Our results were compatible with previous studies from Thai and southern Chinese populations. Further work is needed to characterize the 17q24.3 region and to delineate the functional significance of the variant(s) in TPP susceptibility.