A number of genetic association studies on TPP had been reported. Associations with the human leukocyte antigen (HLA) genotypes HLA B46, DR9, and DQBl*0303 were reported in Hong Kong Chinese, A2 Bw22, AW19, and B17 in Singapore Chinese, and DRW8 in Japanese. However, it is uncertain whether these as sociations were related to the genetic predisposition to Graves’ dis ease rather than to TPP, especially when the majority of these TPP patients had an underlying autoimmune thyroid disease.
In view of the similar presentations between TPP and FHPP, the role of the voltage- dependent calcium channel or dihydropyridine- sensitive L- type calcium channel receptor (Cav 1.1), which is associated with FHPP- 1, was studied in TPP patients. None of the few mutation hot spots associated with FHPP was present in Asian or non- Asian patients with TPP. However, certain single nucleotide polymorphisms (SNPs) of Cav 1.1, including nucleotide (nt)— 476, intron 2 nt 57, and intron 26 nt 67 were associated with TPP in southern Chinese. The location of these SNPs lies at or close to the TRE of the gene, and it is likely that they affect the binding affinity of TRE and modulate the stimulation of thyroid hormone on the Cav 1.1 gene. Similarly, isolated case reports with mutations in other skeletal muscle ionic channels were reported in Caucasian subjects but were not identified in other populations.
In view of the insulin resistance and increased Na/ K- ATPase activity and increased adrenergic response observed in TPP patients, the genes encoding for the 1- , 2- , ß1- , ß2- , and ß4- subunits of Na/ K- ATPase and ß- adrenergic receptor were examined. So far, no mutations or polymorphisms in these genes have been identified to be associated with TPP.
Since TPP is considered a channelopathy, with hypokalaemic being the hallmark of the disease, an international collaborative sequencing project of candidate genes of potassium voltage- gated channel subfamily J (KCNJ) gene family discovered a novel unreported gene, KCNJ18 that encodes inwardly rectifying potassium (Kir) channel 2.6, as a novel susceptibility gene of TPP. Mutations in KCNJ18 were found to be highly prevalent in TPP patients from Singapore (25.9%), and Brazil, France, and the United States (33.3%), but not in patients from Hong Kong (1.2%) or Thailand (0%). Subsequently, genome- wide association studies conducted in Hong Kong and Thailand found a common variant on chromosome 17q24.3 near KCNJ2, that encodes Kir2.1, was significantly associated with TPP. Notably, mutation in KCNJ2 has been implicated in Andersen– Tawil syndrome (ATS), a rare genetic disease that is characterized by periodic paralysis and arrhythmia. Thyrotoxicosis has been reported to severely exacerbate the periodic paralysis in ATS patients. Altogether, these genetic studies uncovered the importance of both common and rare variant in members of KCNJ gene family in TPP susceptibility.
