Assessment of Molecular Subtypes in Thyrotoxic Periodic Paralysis and Graves Disease Among Chinese Han Adults
Authors: Shuang-Xia Zhao, Wei Liu, Jun Liang, Guan-Qi Gao, Xiao-Mei Zhang, Yu Yao, Hai-Ning Wang, Fei-Fei Yuan, Li-Qiong Xue, Yu-Ru Ma, Le-Le Zhang, Xiao-Ping Ye, Qian-Yue Zhang, Feng Sun, Rui-Jia Zhang, Shao-Ying Yang, Ming Zhan, Wen-Hua Du, Bing-Li Liu, Xia Chen, Zhi-Yi Song, Xue-Song Li, Ping Li, Ying Ru, Chun-Lin Zuo, Sheng-Xian Li, Bing Han, Hui Zhu, Jie Qiao, Miao Xuan, Bin Su, Fei Sun, Jun-Hua Ma, Jia-Lun Chen, Hao-Ming Tian, Sai-Juan Chen, Huai-Dong Song
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Thyrotoxic periodic paralysis (TPP) is a potentially lethal complication of hyperthyroidism. However, only 1 specific susceptibility locus for TPP has been identified. Additional genetic determinants should be detected so that a prediction model can be constructed. <h3>Objective</h3> To investigate the genetic architecture of TPP and distinguish TPP from Graves disease cohorts. <h3>Design, Setting, and Participants</h3> This population-based case-control study used a 2-stage genome-wide association study to investigate the risk loci of TPP and weighted genetic risk score to construct a TPP prediction model with data from a Chinese Han population recruited in hospitals in China from March 2003 to December 2015. The analysis was conducted from November 2014 to August 2016. <h3>Main Outcomes and Measures</h3> Loci specifically associated with TPP risk and those shared with Graves disease and prediction model of joint effects of TPP-specific loci. <h3>Results</h3> A total of 537 patients with TPP (mean [SD] age, 35 [11] years; 458 male) 1519 patients with Graves disease and no history of TPP (mean [SD] age, 38 [13] years; 366 male), and 3249 healthy participants (mean [SD] age, 46 [10] years; 1648 male) were recruited from the Han population by hospitals throughout China. Two new TPP-specific susceptibility loci were identified:<i>DCHS2</i>on 4q31.3 (rs1352714: odds ratio [OR], 1.58; 95% CI, 1.35-1.85;<i>P</i> = 1.24 × 10<sup>−8</sup>) and<i>C11orf67</i>on 11q14.1 (rs2186564: OR, 1.50; 95% CI, 1.29-1.74;<i>P</i> = 2.80 × 10<sup>−7</sup>). One previously reported specific locus was confirmed on 17q24.3 near<i>KCNJ2</i>(rs312729: OR, 2.08; 95% CI, 1.83-2.38;<i>P</i> = 8.02 × 10<sup>−29</sup>). Meanwhile, 2 risk loci (MHC and Xq21.1) were shared by Graves disease and TPP. After 2 years of treatment, the ratio of persistent thyrotropin receptor antibody positivity was higher in patients with TPP than in patients with Graves disease and no history of TPP (OR, 3.82; 95% CI, 2.04-7.16;<i>P</i> = 7.05 × 10<sup>−6</sup>). The prediction model using a weighted genetic risk score and 11 candidate TPP-specific single-nucleotide polymorphisms had an area under the curve of 0.80. <h3>Conclusions and Relevance</h3> These findings provide evidence that TPP is a novel molecular subtype of Graves disease. The newly identified loci, along with other previously reported loci, demonstrate the growing complexity of the heritable contribution to TPP pathogenesis. A complete genetic architecture will be helpful to understand the pathophysiology of TPP, and a useful prediction model could prevent the onset of TPP.