Emiko Noguchi1, Masato Akiyama2, Akiko Yagami3, Tomomitsu Hirota4, Yukinori Okada5, Zenichiro Kato6, Reiko Kishikawa7, Yuma Fukutomi8, Michihiro Hide9, Eishin Morita10, Michiko Aihara11, Makiko Hiragun9, Yuko Chinuki10, Takahiro Okabe12, Akiko Ito13, Atsuko Adachi14, Atsushi Fukunaga15, Yumiko Kubota16, Toshiyuki Aoki17, Youko Aoki18, Kazue Nishioka19, Tetsuya Adachi20, Nobuo Kanazawa21, Hitoshi Miyazawa22, Hiroyuki Sakai23, Takehito Kozuka24, Hideo Kitamura25, Hideo Hashizume26, Chiharu Kanegane27, Koji Masuda28, Kumiya Sugiyama29, Reiko Tokuda30, Junichi Furuta31, Ikkou Higashimoto32, Atsuko Kato33, Mariko Seishima34, Akihiko Tajiri35, Atsuko Tomura36, Hiroko Taniguchi37, Hiroto Kojima38, Hidenori Tanaka38, Aiko Sakai39, Wataru Morii40, Masashi Nakamura41, Yoichiro Kamatani42, Atsushi Takahashi43, Michiaki Kubo44, Mayumi Tamari4, Hirohisa Saito45, Kayoko Matsunaga46. 1. Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. Electronic address: enoguchi@md.tsukuba.ac.jp. 2. Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Ophthalmology, Graduate school of Medical Sciences, Kyushu University, Fukuoka, Japan. 3. Department of Allergology, Fujita Health University School of Medicine, Nagoya, Japan. 4. Laboratory for Respiratory and Allergic Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Core Research Facilities for Basic Science (Molecular Genetics), Research Center for Medical Science, Jikei University School of Medicine, Tokyo, Japan. 5. Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan; Laboratory of Statistical Immunology, Immunology Frontier Research Center (WPI-IFReC), Osaka University, Osaka, Japan. 6. Structural Medicine, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan; Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu, Japan. 7. Department of Allergology, National Hospital Organization Fukuoka National Hospital, Fukuoka, Japan. 8. Clinical Research Center for Allergy and Rheumatology, National Hospital Organization Sagamihara Hospital, Sagamihara, Japan. 9. Department of Dermatology, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. 10. Department of Dermatology, Shimane University Faculty of Medicine, Izumo, Japan. 11. Department of Dermatology, Yokohama City University School of Medicine, Yokohama, Japan. 12. Okabe Allergy Clinic, Fukuoka, Japan. 13. Department of Dermatology, Niigata University Medical & Dental Hospital, Niigata, Japan. 14. Department of dermatology, Hyogo Prefectural Kakogawa Hospital, Kakogawa, Japan. 15. Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan. 16. Department of Dermatology, Fukuoka Sanno Hospital, Fukuoka, Japan. 17. Aoki Skin and Allergy Clinic for Itchy Skin Diseases, Osaka, Japan. 18. Aoki Dermatology, Miyazaki, Japan. 19. Joy Dermatological Clinic, Sanyo-Onoda, Japan. 20. Musashino Allergy Clinic, Tokyo, Japan. 21. Department of Dermatology, Wakayama Medical University, Wakayama, Japan. 22. Nishi-Sapporo Skin and Allergy Clinic, Sapporo, Japan. 23. Department of Dermatology, Asahikawa City Hospital, Asahikawa, Japan. 24. Section of Dermatology, Hino Clinic, Sakai, Japan. 25. Department of Dermatology, Aomori Prefectural Central Hospital, Aomori, Japan. 26. Department of Dermatology, Shimada Municipal Hospital, Shimada, Japan. 27. Department of Allergy, National Hospital Organization Toyama Hospital, Toyama, Japan. 28. Department of Dermatology, Kyoto Prefectural University of Medicine, Kyoto, Japan. 29. Department of Respiratory Medicine and Clinical Immunology, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan. 30. National Mie Hospital, Tsu, Japan. 31. Department of dermatology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. 32. Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan. 33. Department of Dermatology, Osaka Kaisei Hospital, Osaka, Japan. 34. Department of Dermatology, Gifu University Graduate School of Medicine, Gifu, Japan. 35. Tajiri Dermatology Clinic, Miyazaki, Japan. 36. Tomura Clinic Dermatology, Akita, Japan. 37. Department of Dermatology, Kudanzaka Hospital, Tokyo, Japan. 38. HLA Foundation Laboratory, Kyoto, Japan. 39. Department of Child Health, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. 40. Department of Medical Genetics, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan. 41. Department of Integrative Medical Science for Allergic Disease, Fujita Health University School of Medicine, Nagoya, Japan. 42. Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Kyoto-McGill International Collaborative School in Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan. 43. Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Genomic Medicine, Research Institute, National Cerebral and Cardiovasular Center, Osaka, Japan. 44. RIKEN Center for Integrative Medical Sciences, Yokohama, Japan. 45. Department of Allergy and Clinical Immunology, National Research Institute for Child Health & Development, Tokyo, Japan. Electronic address: saito-hr@ncchd.go.jp. 46. Department of Integrative Medical Science for Allergic Disease, Fujita Health University School of Medicine, Nagoya, Japan. Electronic address: kamatsu@fujita-hu.ac.jp.
Abstract
BACKGROUND: Food allergy is a growing health problem worldwide because of its increasing prevalence, life-threatening potential, and shortage of effective preventive treatments. In an outbreak of wheat allergy in Japan, thousands of patients had allergic reactions to wheat after using soap containing hydrolyzed wheat protein (HWP). OBJECTIVES: The aim of the present study was to investigate genetic variation that can contribute to susceptibility to HWP allergy. METHODS: We conducted a genome-wide association study of HWP allergy in 452 cases and 2700 control subjects using 6.6 million genotyped or imputed single nucleotide polymorphisms. Replication was assessed by genotyping single nucleotide polymorphisms in independent samples comprising 45 patients with HWP allergy and 326 control subjects. RESULTS: Through the genome-wide association study, we identified significant associations with the class II HLA region on 6p21 (P = 2.16 × 10-24 for rs9271588 and P = 2.96 × 10-24 for HLA-DQα1 amino acid position 34) and with the RBFOX1 locus at 16p13 (rs74575857, P = 8.4 × 10-9). The associations were also confirmed in the replication data set. Both amino acid polymorphisms (HLA-DQβ1 amino acid positions 13 and 26) located in the P4 binding pockets on the HLA-DQ molecule achieved the genome-wide significance level (P < 5.0 × 10-8). CONCLUSIONS: Our data provide the first demonstration of genetic risk for HWP allergy and show that this genetic risk is mainly represented by multiple combinations of HLA variants.
BACKGROUND:Food allergy is a growing health problem worldwide because of its increasing prevalence, life-threatening potential, and shortage of effective preventive treatments. In an outbreak of wheatallergy in Japan, thousands of patients had allergic reactions to wheat after using soap containing hydrolyzed wheat protein (HWP). OBJECTIVES: The aim of the present study was to investigate genetic variation that can contribute to susceptibility to HWP allergy. METHODS: We conducted a genome-wide association study of HWP allergy in 452 cases and 2700 control subjects using 6.6 million genotyped or imputed single nucleotide polymorphisms. Replication was assessed by genotyping single nucleotide polymorphisms in independent samples comprising 45 patients with HWP allergy and 326 control subjects. RESULTS: Through the genome-wide association study, we identified significant associations with the class II HLA region on 6p21 (P = 2.16 × 10-24 for rs9271588 and P = 2.96 × 10-24 for HLA-DQα1 amino acid position 34) and with the RBFOX1 locus at 16p13 (rs74575857, P = 8.4 × 10-9). The associations were also confirmed in the replication data set. Both amino acid polymorphisms (HLA-DQβ1 amino acid positions 13 and 26) located in the P4 binding pockets on the HLA-DQ molecule achieved the genome-wide significance level (P < 5.0 × 10-8). CONCLUSIONS: Our data provide the first demonstration of genetic risk for HWP allergy and show that this genetic risk is mainly represented by multiple combinations of HLA variants.