Functional polymorphisms of HSPA5: Possible association with bipolar disorder

Teikyo University, Edo, Tōkyō, Japan
Biochemical and Biophysical Research Communications (Impact Factor: 2.28). 12/2005; 336(4):1136-43. DOI: 10.1016/j.bbrc.2005.08.248
Source: PubMed

ABSTRACT Altered endoplasmic reticulum stress (ER) response signaling is suggested in bipolar disorder. Previously, we preliminarily reported the genetic association of HSPA5 (GRP78/BiP) with bipolar disorder. Here, we extended our analysis by increasing the number of Japanese case-control samples and NIMH Genetics Initiative bipolar trio samples (NIMH trios), and also analyzed schizophrenia samples. In Japanese, nominally significant association of one haplotype was observed in extended samples of bipolar disorder but not in schizophrenia. In NIMH trios, no association was found in total samples. However, an exploratory analysis suggested that the other haplotype was significantly over-transmitted to probands only from the paternal side. The associated haplotype in Japanese or NIMH pedigrees shared three common polymorphisms in the promotor, which was found to alter promotor activity. These findings suggested promotor polymorphisms of HSPA5 may affect the interindividual variability of ER stress response and may confer a genetic risk factor for bipolar disorder.

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Available from: Kazuo Yamada, Aug 23, 2015
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    • "Some previous studies have suggested an involvement of UPR dysfunction in the pathophysiology of BD. For instance, genetic studies have observed an association of a polymorphism in the promoter region of XBPI (a transcription factor that induces the expression of ER chaperones) (Kakiuchi et al., 2003) and in GRP78 (Kakiuchi et al., 2005) with BD. This suggests that alterations in these pathways may be a risk factor for developing the disorder. "
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    • "An initial associated promoter polymorphism in XBP1 was not replicated in a large Caucasian and a smaller Chinese population [132] [133]. Nominal association was found with SNP's of HSPA5 in a Japanese populations and no association was found in the NIMH trios [134] [129]. "
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    • "Meanwhile, the UPR decreases the biosynthetic burden of the secretory pathway by down-regulating expression of genes encoding secreted proteins (Schröder and Kaufman 2005). Contrary to the unaffected ER response rate observed in SHSY5Y cells (Kakiuchi et al. 2005), in cells with the low basal activity -415 A/-180 G allele, induction of HSPA5 expression after ER stress was notably (HEK-293 and SK-N-SH) or significantly (lymphoblastoid) increased (Fig. 1 "
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