The clinical and genetic features in a cohort of mainland Chinese patients with thyrotoxic periodic paralysis

BACKGROUND Thyrotoxic periodic paralysis (TPP) is a life-threatening channelopathy manifesting as recurrent episodes of hypokalemia and muscle weakness in the presence of hyperthyroidism. Recent findings indicate defects of inward rectifying K+ (Kir) channels are associated with some TPP patients. The associations are not only found in Caucasian population (mainly Brazilian), but also in Singaporean population. However, potential genetic risk factors for mainland Chinese patients, the largest group of TPP cases in the world, have been largely unexplored. METHODS Samples of DNA from 127 individuals with TPP and 102 hyperthyroidism male controls self-reported as mainland Chinese were collected from 5 clinical centers from Jan 2011 to Jan 2014. The KCNJ2 gene, KCNJ18 gene, as well as loci polymorphisms (rs623011and rs312691) at 17q24.3 were directly sequenced in TPP patients and controls. Clinical data were summarized from TPP participants for genotype/phenotype correlations. RESULTS 3.1% of TPP cases harbored KCNJ18 gene mutations in mainland Chinese patients. Patients with KCNJ18 mutation had shorter attack duration, higher prevalence of muscle soreness and weakness recurrence than patients without KCNJ18 mutation. The alleles at 17q24.3 (rs623011and rs312691) were more common in patients with TPP than in controls, and therefore were significant risk factors for TPP (odds ratio, 11.94 and 10.57; 95% CI, 5.93-24.05 and 5.48-20.40; P = 1.81 × 10(-14) and 1.07 × 10(-14) respectively). CONCLUSIONS This study demonstrates that the KCNJ18 variants are only responsible for a small proportion of TPP patients in mainland China. There are significant clinical differences between patients with KCNJ18 mutations and patients without KCNJ18 mutations. In addition, the rs623011and rs312691 loci are significantly associated with TPP patients in mainland China, and highlight the Kir2.1 channel as a causative target in TPP.