Takeo Yoshikawa, Yasue Horiuchi, Hiroshi Ujike, Shinsuke Koike, Hiroshi Yamamoto, Toshio Miyata, Masatoshi Takeda, Motoyuki Fukumoto, Makoto Arai, Mitsuhiro Miyashita, Tadao Arinami, Yuji Okazaki, Itaru Kushima, Norio Ozaki, Masanari Itokawa, Takuo Watanabe, Yoshitaka Tatebayashi, Akiko Kobori, Kiyoto Kasai, Naoji Amano, Kazuya Toriumi, Ryota Hashimoto, Shinsuke Washizuka, Tomoe Ichikawa, and Yasuhiko Yamamoto
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.