发现川崎病相关基因CASP3

日本理化研究所研究人员日前宣布，他们发现了与川崎病发病有关的基因，这一基因只要出现微小差异，川崎病的发病风险就会大幅提高。

理化研究所基因组医学研究中心发布公报说，该中心研究人员此前依靠全基因组扫描，发现有10个基因组区域与川崎病相关。在这次研究中，他们重点调查了其中的4号染色体上的区域，发现基因CASP3的一处单核苷酸多态性与川崎病的发病相关。他们分析了约900名川崎病患者和约1400名正常人的CASP3基因后发现，如果存在这处单核苷酸多态性，川崎病的发病风险就会提高至1.4倍。

单核苷酸多态性是指在基因组水平上由单个核苷酸变异所引起的脱氧核糖核酸（DNA）序列多态性。单核苷酸多态性与患特定的疾病有关。

在确定CASP3为川崎病发病相关基因后，研究小组表示，他们认为还有9个基因组区域也可能存在该病相关基因。基因组医学研究中心研究员尾内善广说，他们将调查是否还有其他的川崎病相关基因，从而弄清发病机理。

川崎病又称皮肤黏膜淋巴结综合征，是一种原因未明的小儿急性发热出疹性疾病，主要表现为皮肤黏膜出疹、淋巴结肿大和多发性动脉炎。川崎病急性期可引起心肌炎、*炎，15％至20％的川崎病患者可能患上冠状动脉瘤。日本每年约有1万例川崎病新增病例。

Common variants in CASP3 confer susceptibility to Kawasaki disease
Yoshihiro Onouchi1,*, Kouichi Ozaki1, Jane C. Buns2,3,25, Chisato Shimizu2,3,25, Hiromichi Hamada4, Takafumi Honda4, Masaru Terai4, Akihito Honda5, Takashi Takeuchi6, Shoichi Shibuta6, Tomohiro Suenaga6, Hiroyuki Suzuki6, Kouji Higashi7, Kumi Yasukawa7, Yoichi Suzuki8, Kumiko Sasago8, Yasushi Kemmotsu9, Shinichi Takatsuki9, Tsutomu Saji9, Tetsushi Yoshikawa10, Toshiro Nagai11, Kunihiro Hamamoto12, Fumio Kishi13, Kazunobu Ouchi14, Yoshitake Sato15, Jane W. Newburger16,25, Annette L. Baker16,25, Stanford T. Shulman17,25, Anne H. Rowley17,25, Mayumi Yashiro18, Yoshikazu Nakamura18, Keiko Wakui19, Yoshimitsu Fukushima19, Akihiro Fujino20, Tatsuhiko Tsunoda21, Tomisaku Kawasaki22, Akira Hata8, Yusuke Nakamura23,24 and Toshihiro Tanaka1

1 Laboratory for Cardiovascular diseases, Center for Genomic Medicine RIKEN, Yokohama 230-0045, Japan, 2 Department of Pediatrics, School of Medicine, University of California San Diego, La Jolla, CA, USA, 3 Rady Children's Hospital San Diego, CA 92093-0641, USA, 4 Department of Pediatrics, Tokyo Women's Medical University Yachiyo Medical Center, Yachiyo 276-8524, Japan, 5 Department of Pediatrics, Asahi General Hospital, Asahi 289-2511, Japan, 6 Department of Pediatrics, Wakayama Medical University, Wakayama 641-0012, Japan, 7 Department of Pediatrics and 8 Department of Public Health, Chiba University Graduate School of Medicine, Chiba 260-8670, Japan, 9 Department of Pediatrics, Toho University School of Medicine, Tokyo 143-8541, Japan, 10 Department of Pediatrics, Fujita Health University, Toyoake 470-1192, Japan, 11 Department of Pediatrics, Dokkyo Medical University, Koshigaya Hospital, Koshigaya 343-8555, Japan, 12 Department of Speech and Hearing Sciences, International University of health and welfare, Fukuoka 831-8501, Japan, 13 Department of Molecular Genetics and 14 Department of Pediatrics, Kawasaki Medical School, Kurashiki 701-0192, Japan, 15 Department of Pediatrics, Fuji Heavy Industry LTD, Health Insurance Society General Ohta Hospital, Ohta 373-8585, Japan, 16 Department of Cardiology, Boston Children's Hospital, Boston, MA 02115, USA, 17 Department of Pediatrics, Feinberg School of Medicine Northwestern University, Children's Memorial Hospital, Chicago, IL 60611, USA, 18 Department of Public Health, Jichi Medical School, Minamikawachi 329-0498, Japan, 19 Department of Preventive Medicine, Shinshu University School of Medicine, Matsumoto 390-8621, Japan, 20 Department of Surgery, National Center for Child Health and Development, Tokyo 157-8535, Japan, 21 Laboratory for Medical Informatics, Center for Genomic Medicine, RIKEN, Yokohama 230-0045, Japan, 22 Japan Kawasaki Disease Research Center, Tokyo 101-0041, Japan, 23 Laboratory for Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan, 24 Center for Genomic Medicine RIKEN, Yokohama 230-0045, Japan and 25 U. S. KD Genetics Consortium

Kawasaki disease （KD; OMIM 611775 [OMIM] ） is an acute vasculitis syndrome which predominantly affects small- and medium-sized arteries of infants and children. Epidemiological data suggest that host genetics underlie the disease pathogenesis. Here we report that multiple variants in the caspase-3 gene （CASP3） that are in linkage disequilibrium confer susceptibility to KD in both Japanese and US subjects of European ancestry. We found that a G to A substitution of one commonly associated SNP located in the 5' untranslated region of CASP3 （rs72689236; P = 4.2 x 10–8 in the Japanese and P = 3.7 x 10–3 in the European Americans） abolished binding of nuclear factor of activated T cells to the DNA sequence surrounding the SNP. Our findings suggest that altered CASP3 expression in immune effecter cells influences susceptibility to KD.