Abstract
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. To investigate the genetic architecture of TPP and distinguish TPP from Graves disease cohorts. 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. Loci specifically associated with TPP risk and those shared with Graves disease and prediction model of joint effects of TPP-specific loci. 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: DCHS2 on 4q31.3 (rs1352714: odds ratio [OR], 1.58; 95% CI, 1.35-1.85; P = 1.24 × 10-8) and C11orf67 on 11q14.1 (rs2186564: OR, 1.50; 95% CI, 1.29-1.74; P = 2.80 × 10-7). One previously reported specific locus was confirmed on 17q24.3 near KCNJ2 (rs312729: OR, 2.08; 95% CI, 1.83-2.38; P = 8.02 × 10-29). 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; P = 7.05 × 10-6). 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. 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.
Highlights
Thyrotoxic periodic paralysis (TPP) is a potentially life-threatening complication of hyperthyroidism characterized by symptoms that include muscle weakness or paralysis, acute serum hypokalemia, and thyrotoxicosis.1 The condition can occur in any ethnicity2,3 but predominantly affects Asian populations.1,4 Incidence of TPP in Chinese and Japanese patients with thyrotoxicosis is 1.8%5 and 1.9%,6 respectively
Two new TPP-specific susceptibility loci were identified: DCHS2 on 4q31.3 and C11orf67 on 11q14.1
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; P = 7.05 × 10−6)
Summary
Thyrotoxic periodic paralysis (TPP) is a potentially life-threatening complication of hyperthyroidism characterized by symptoms that include muscle weakness or paralysis, acute serum hypokalemia, and thyrotoxicosis. The condition can occur in any ethnicity but predominantly affects Asian populations. Incidence of TPP in Chinese and Japanese patients with thyrotoxicosis is 1.8%5 and 1.9%,6 respectively. Thyrotoxic periodic paralysis (TPP) is a potentially life-threatening complication of hyperthyroidism characterized by symptoms that include muscle weakness or paralysis, acute serum hypokalemia, and thyrotoxicosis.. The condition can occur in any ethnicity but predominantly affects Asian populations.. Incidence of TPP in Chinese and Japanese patients with thyrotoxicosis is 1.8%5 and 1.9%,6 respectively. Despite a higher incidence of thyrotoxicosis in women (the female to male ratio is between 4:1 and 10:1), TPP predominantly affects men (the male to female ratio is between 22:1 and 76:1).. In Chinese populations, TPP occurs in 13% of male and 0.17% of female patients with thyrotoxicosis.. Based on the higher prevalence of TPP in Asian populations than in European populations, we hypothesize that Asian populations have a genetic predisposition to develop TPP Despite a higher incidence of thyrotoxicosis in women (the female to male ratio is between 4:1 and 10:1), TPP predominantly affects men (the male to female ratio is between 22:1 and 76:1). In Chinese populations, TPP occurs in 13% of male and 0.17% of female patients with thyrotoxicosis. Based on the higher prevalence of TPP in Asian populations than in European populations, we hypothesize that Asian populations have a genetic predisposition to develop TPP
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