Assessment of Molecular Subtypes in Thyrotoxic Periodic Paralysis and Graves Disease Among Chinese Han Adults A Population-Based Genome-Wide Association Study
Assessment of Molecular Subtypes in Thyrotoxic Periodic Paralysis and Graves Disease Among Chinese Han Adults A Population-Based Genome-Wide Association Study
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中国汉族成年人甲状腺毒性周期性麻痹和格雷夫斯病的分子亚型评估：一项基于人群的全基因组关联研究
DOI：
10.1001/jamanetworkopen.2019.3348
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发表时间：
2019-05-01
影响因子：
13.8
通讯作者：
Zhao, Jia-Jun
中科院分区：
文献类型：
--
作者：
Zhao, Shuang-Xia;Liu, Wei;Zhao, Jia-Jun
甲状腺毒性周期性麻痹（TPP）是甲状腺功能亢进症的一种潜在致命并发症。然而，只有1个特定的敏感位点的TPP已被确定。目的探讨TPP的遗传结构，并将TPP与Graves病的队列进行区分。设计，地点，实验室。这项基于人群的病例对照研究使用了2阶段基因组，广泛关联研究，以探讨TPP的危险位点和加权遗传风险评分，以构建TPP预测模型与中国汉族数据2003年3月至2015年12月在中国医院招募的人群。分析时间为2014年11月至2016年8月。主要结果与指标TPP风险特异性相关位点和与Graves病共有位点以及TPP特异性位点联合效应预测模型。（平均[SD]年龄，35 [11]岁; 458例男性）1519例无TPP病史的Graves病患者在中国各地的医院从汉族人群中招募了3249名健康受试者（平均[SD]年龄，38 [13]岁; 366名男性）和3249名健康受试者（平均[SD]年龄，46 [10]岁; 1648名男性）。发现了两个新的TPP特异性易感位点：位于4q31.3的DCHS 2。（rs 1352714：比值比[OR]，1.58; 95% CI，1.35-1.85; P = 1.24 x 10（-8））和11q14.1上的C11 orf 67（rs2186564：OR，1.50; 95%CI，1.29-1.74; P = 2.80 x 10（-7））。在KCNJ 2附近的17q24.3上证实了一个先前报道的特异性位点（rs312729：OR，2.08; 95%CI，1.83-2.38; P = 8.02 x 10（-29））。Graves病和TPP有2个共同的危险基因座（MHC和Xq21.1）。治疗2年后，TPP患者持续促甲状腺素受体抗体阳性的比例高于Graves病和无TPP病史的患者（OR，3.82; 95%CI，2.04-7.16; P = 7.05 x 10（-6））。使用加权遗传风险评分和11个候选TPP特异性单核苷酸多态性的预测模型的曲线下面积为0.80。结论和相关性这些发现为TPP是Graves病的一种新的分子亚型提供了证据。新发现的基因座，沿着其他先前报道的基因座，证明了TPP发病机制的遗传贡献日益复杂。一个完整的遗传结构将有助于了解TPP的病理生理学，一个有用的预测模型可以防止TPP的发病。
IMPORTANCE 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.OBJECTIVE To investigate the genetic architecture of TPP and distinguish TPP from Graves disease cohorts.DESIGN, SETTING, AND PARTICIPANTS 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.MAIN OUTCOMES AND MEASURES Loci specifically associated with TPP risk and those shared with Graves disease and prediction model of joint effects of TPP-specific loci.RESULTS 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 x 10(-8)) and C11orf67 on 11q14.1 (rs2186564: OR, 1.50; 95% CI, 1.29-1.74; P = 2.80 x 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 x 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 x 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.CONCLUSIONS AND RELEVANCE 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.