Abstract
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.
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31 July 2019
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Acknowledgements
This study was supported by grants from the Millennium Project, Japan Kawasaki Disease Research Center (2009 to YO), the Ministry of Education, Culture, Sports, and Technology (25293139 to YO), the Ministry of Health, Labour and Welfare (0401040 to AH), and the Japan Agency for Medical Research and Development (JP17ek0410039 to TH). We are grateful to the participants in this study and the medical staff caring for the patients. We also thank Ms. Yoshie Kikuchi for her technical assistance.
Japan Kawasaki Disease Genome Consortium
Hiroshi Masuda7, Tohru Kobayashi7, Toshiaki Jibiki8, Taro Yamazaki9, Yoshiaki Ohkuma10, Maya Fujiwara11, Tomio Kobayashi12, Harumitsu Takeuchi13, Kazunobu Ouchi14, Yumi Mizuno15, Shigeto Fuse16, Nobuhiro Fukazawa17, Tsutomu Saji18, Shinichi Takatsuki18, Kenichiro Nishimura19, Hiromichi Hamada20, Ryuji Fukazawa21, Hideko Nishumura22, Kentaro Aso23, Tomoyo Matsubara24, Takahisa Mizuno25, Satoru Iwashima26, Mamoru Ayusawa27, Kazuyuki Ikeda28, Takashi Kosuda29, Kunio Hashimoto30, Kunio Hirasawa31, Masaru Miura32, Junpei Somura33, Emi Toba34, Keiichi Hirono35, Yuichi Nomura36, Hirokazu Arakawa37, Shouhei Ogata38, Hiroki Kajino39, Seiji Kawamura40, Hayato Aoyagi41, Hiroshi Suzuki42, Kouta Ichinose43, Ayako Shimozono44, Yoshiaki Kato45, Masamune Higashikawa46, Youichi Kawamura47, Masahiro Misawa48, Noriko Nagai49, Taichi Kato50, Dan Nagata51, Akiko Okamoto52, Hiroyuki Suzuki53, Masahiko Kishiro54, Junko Shiono55, Kouji Higashi56, Naoki Yokoyama57, Ryota Ebata58, Yoshihiro Onouchi59.
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Thiha, K., Mashimo, Y., Suzuki, H. et al. Investigation of novel variations of ORAI1 gene and their association with Kawasaki disease. J Hum Genet 64, 511–519 (2019). https://doi.org/10.1038/s10038-019-0588-2
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DOI: https://doi.org/10.1038/s10038-019-0588-2
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