ハマダ　ヒロミチ   Hamada Hiromichi   濱田　洋通    所属   その他 その他    職種   登録医
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	Investigation of novel variations of ORAI1 gene and their association with Kawasaki disease.
掲載誌名	正式名：Journal of human genetics 略　 称：J Hum Genet ISSNコード：(1435-232X)1434-5161(Linking)
掲載区分	国外
巻・号・頁	10.1038/s10038-019-0588-2,pp.10.1038/s10038-019-0588-2-10.1038/s10038-019-0588-2
著者・共著者	Hamada Hiromichi
発行年月	2019/03
概要	ORAI1 encodes a calcium channel essential in the store-operated calcium entry mechanism. A previous genetic association study identified a rare in-frame insertion variant of ORAI1 conferring Kawasaki disease (KD). To deepen our understanding of the involvement of rare variants of ORAI1 in KD pathogenesis, we investigated 3812 patients with KD and 2644 healthy individuals for variations in the protein-coding region of ORAI1. By re-sequencing the study participants' DNA, 27 variants with minor allele frequencies (MAFs) < 0.01 that had not been examined in the previous study were identified. Although no significant association with KD was observed either in single-variant analyses or in a collapsing method analysis of the 27 variants, stratification by MAFs, variant types, and predicted deleteriousness revealed that six rare, deleterious, missense variants (MAF < 0.001, CADD C-score ≥ 20) were exclusively present in KD patients, including three refractory cases (OR = ∞, P = 0.046). The six missense variants include p.Gly98Asp, which has been demonstrated to result in gain of function leading to constitutive Ca2+ entry. Conversely, five types of frameshift variants, all identified near the N terminus and assumed to disrupt ORAI1 function, showed an opposite trend of association (OR = 0.35, P = 0.24). These findings support our hypothesis that genetic variations causing the upregulation of the Ca2+/NFAT pathway confer susceptibility to KD. Our findings also provide insights into the usefulness of stratifying the variants based on their MAFs and on the direction of the effects on protein function when conducting association studies using the gene-based collapsing method.
DOI	10.1038/s10038-019-0588-2
PMID	30853710