Contribution of Asian Haplotype of KCNJ18 to Susceptibility to and Ethnic Differences in Thyrotoxic Periodic Paralysis

Abstract

Context and Objectives Thyrotoxic periodic paralysis (TPP) is an acute complication of thyrotoxicosis that can be lethal. TPP is rare in Caucasians but often affects young men in East Asian populations. This study aimed to clarify the contribution of KCNJ18 to susceptibility to TPP in East Asian populations. Participants and Methods The study comprised 635 participants including 13 Japanese patients with TPP, 208 Japanese patients with Graves disease without TPP, and 414 healthy control subjects from the Japanese (n = 208), Korean (n = 111), and Caucasian populations (n = 95). DNA samples from 29 participants (13 with TPP, 8 with Graves disease, and 8 controls) were sequenced for KCNJ18, and all participants (n = 635) were genotyped for six variants of KCNJ18 and a polymorphism of KCNJ2 (rs312691). Results Six single-nucleotide variants (SNVs) with amino acid substitutions were identified by direct sequencing of KCNJ18. Among these, four SNVs comprised three haplotypes under strong linkage disequilibrium. Haplotype 1 (AAAG) of KCNJ18 was significantly associated with susceptibility to TPP in the Japanese population (OR = 19.6; 95% CI, 1.5 to 256.9; P = 0.013). Haplotype frequencies in the general East Asian (Japanese and Korean) and Caucasian populations differed significantly (haplotype 1: 80.8% vs 48.4%, P = 1.1×10−27). Conclusion A major haplotype of KCNJ18 in East Asian populations is significantly associated with susceptibility to TPP. The haplotype is much more common in East Asian than Caucasian populations, suggesting its contribution to the high prevalence of TPP in East Asian populations.

Thyrotoxic periodic paralysis in a Caucasian man without identifiable genetic predisposition: a case report

“…The KCNJ18 gene (potassium inwardly rectifying channel subfamily J member 18) encodes the inwardly rectifying potassium channel, Kir2.6. The locus is regulated by thyroid hormone, and variants in KCNJ18 have been associated with TPP [ 4 , 7 , 10 , 15 ]. A major haplotype of KCNJ18 in East Asian populations is significantly associated with susceptibility to TPP, and this haplotype is much more common in East Asian than Caucasian populations [ 10 ].…”

Epidemiology of Ocular Manifestations in Autoimmune Disease

“…Although earlier findings had suggested Hashimoto’s thyroiditis is more common amongst White populations ( 213 ), more recent research suggests Japanese and Korean Graves’ disease patients are at greater risk of disease complications when compared to Caucasian people ( 214 ). In addition, a study in a South African cohort has shown White populations to be at higher risk of developing myasthenia gravis.…”

Epidemiologie okulärer Manifestationen bei Autoimmunkrankheiten

“…Obwohl frühere Befunde darauf hindeuteten, dass die Hashimoto-Thyreoiditis in der weißen Bevölkerung häufiger vorkommt [213], deuten neuere Untersuchungen darauf hin, dass japanische und koreanische Patienten mit Morbus Basedow ein höheres Risiko für Krankheitskomplikationen haben als kaukasische Menschen [214]. Darüber hinaus hat eine Studie in einer südafrikanischen Kohorte gezeigt, dass weiße Bevölkerungsgruppen ein höheres Risiko haben, an Myasthenia gravis zu erkranken.…”