title: The regulation of soluble receptor for AGEs contributes to carbonyl stress in schizophrenia.
abstract: Our previous study showed that enhanced carbonyl stress is closely related to schizophrenia. The endogenous secretory receptor for advanced glycation end-products (esRAGE) is a splice variant of the AGER gene and is one of the soluble forms of RAGE. esRAGE is considered to be a key molecule for alleviating the burden of carbonyl stress by entrapping advanced glycation end-products (AGEs). In the current study, we conducted genetic association analyses focusing on AGER, in which we compared 212 schizophrenic patients to 214 control subjects. We also compared esRAGE levels among a subgroup of 104 patients and 89 controls and further carried out measurements of total circulating soluble RAGE (sRAGE) in 25 patients and 49 healthy subjects. Although the genetic association study yielded inconclusive results, multiple regression analysis indicated that a specific haplotype composed of rs17846798, rs2071288, and a 63 bp deletion, which were in perfect linkage disequilibrium (r2= 1), and rs2070600 (Gly82Ser) were significantly associated with a marked decrease in serum esRAGE levels. Furthermore, compared to healthy subjects, schizophrenia showed significantly lower esRAGE (p = 0.007) and sRAGE (p = 0.03) levels, respectively. This is the first study to show that serum esRAGE levels are regulated by a newly identified specific haplotype in AGER and that a subpopulation of schizophrenic patients are more vulnerable to carbonyl stress.
authors.affiliation: Project for Schizophrenia Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan; Department of Psychiatry, Shinshu University School of Medicine, Matsumoto, Japan. Electronic address: miyashita-mt@igakuken.or.jp.
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Miyashita
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Takuo
authors.initials: T
authors.lastname: Watanabe
authors.affiliation: Project for Schizophrenia Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Tomoe
authors.initials: T
authors.lastname: Ichikawa
authors.affiliation: Project for Schizophrenia Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Toriumi
authors.affiliation: Project for Schizophrenia Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Yasue
authors.initials: Y
authors.lastname: Horiuchi
authors.affiliation: Project for Schizophrenia Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kobori
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Itaru
authors.initials: I
authors.lastname: Kushima
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Ryota
authors.initials: R
authors.lastname: Hashimoto
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Motoyuki
authors.initials: M
authors.lastname: Fukumoto
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Koike
authors.affiliation: Ujike Nishiguchi Clinic, Okayama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ujike
authors.affiliation: Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba, Japan.
authors.forename: Tadao
authors.initials: T
authors.lastname: Arinami
authors.affiliation: Affective Disorder Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Tatebayashi
authors.affiliation: Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Kasai
authors.affiliation: Department of Psychiatry, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Masatoshi
authors.initials: M
authors.lastname: Takeda
authors.affiliation: Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Ozaki
authors.affiliation: Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okazaki
authors.affiliation: Laboratory for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan.
authors.forename: Takeo
authors.initials: T
authors.lastname: Yoshikawa
authors.affiliation: Department of Psychiatry, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Naoji
authors.initials: N
authors.lastname: Amano
authors.affiliation: Department of Psychiatry, Shinshu University School of Medicine, Matsumoto, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Washizuka
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Molecular Medicine and Therapy, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Toshio
authors.initials: T
authors.lastname: Miyata
authors.affiliation: Project for Schizophrenia Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan; Department of Psychiatry, Tokyo Metropolitan Matsuzawa Hospital, Tokyo, Japan.
authors.forename: Masanari
authors.initials: M
authors.lastname: Itokawa
authors.affiliation: Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Project for Schizophrenia Research, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Arai
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D005838:Genotype; D017127:Glycation End Products, Advanced / Q000097:blood; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D050050:Protein Carbonylation; D000067759:Receptor for Advanced Glycation End Products / Q000097:blood* / Q000235:genetics; D012044:Regression Analysis; D012559:Schizophrenia / Q000097:blood* / Q000235:genetics
chemical_list: D005819:Genetic Markers; D017127:Glycation End Products, Advanced; D000067759:Receptor for Advanced Glycation End Products
keywords: Advanced glycation end-products (AGEs); Carbonyl stress; Endogenous secretory RAGE (esRAGE); Receptor for AGEs (RAGE); Schizophrenia; Soluble RAGE (sRAGE)