Functional polymorphisms of HSPA5: Possible association with bipolar disorder

Teikyo University, Edo, Tōkyō, Japan
Biochemical and Biophysical Research Communications (Impact Factor: 2.3). 12/2005; 336(4):1136-43. DOI: 10.1016/j.bbrc.2005.08.248
Source: PubMed


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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    • "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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    ABSTRACT: Bipolar disorder (BD) is a severe chronic psychiatric disorder that has been associated with cellular dysfunctions related to mitochondria, neurotrophin levels, and oxidative stress. Evidence has shown that endoplasmic reticulum (ER) stress may be a common pathway of the cellular changes described in BD. In the present study we assessed unfolded protein response (UPR) and the effects of this cellular process on lymphocytes from patients with BD. We also evaluated whether the stage of chronicity of BD was associated with changes in UPR parameters. Cultured lymphocytes from 30 patients with BD and 32 age- and sex-matched controls were treated with tunicamycin, an ER stressor, for 12 or 24 h to measure levels of UPR-related proteins (GRP78, eIF2α-P, and CHOP) using flow cytometry, and for 48 h to analyse ER stress-induced cell death. In healthy controls but not in patients we found an increase in levels of GRP78, eIF2α-P, and CHOP after ER stress induction. In addition, tunicamycin-induced cell death was significantly higher in patients compared to controls. More importantly, early-stage patients did not differ from controls while the late-stage patients showed an impaired ER stress response. Thus, dysfunction in ER-related stress response may be associated with decreased cellular resilience in BD and illness progression.
    The International Journal of Neuropsychopharmacology 05/2014; 17(09):1-11. DOI:10.1017/S1461145714000443 · 4.01 Impact Factor
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    • "As all of the mentioned studies included relatively small cohort sizes, here we tested the utility of serum levels of the above mentioned NAbs as potential markers of presence and severity (including cognitive dysfunction) of PD in a considerably larger cohort of PD patients and controls, using a comprehensive test battery including demographic, clinical and neurodegenerative parameters. Moreover, we evaluated respective NAb titres in association with different single nucleotide polymorphisms (SNPs) of genes which either have been reported to influence the activity of the adaptive immune system, the amyloid cascade or have been associated with the occurrence of PD (APOE [17], [18], GSK3B [19], [20], HLA-DRA [21], [22], HSPA5 [23], [24], SNCA [25]–[27], and STK39 [28], [29]). "
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    ABSTRACT: Naturally occurring autoantibodies (NAbs) against a number of potentially disease-associated cellular proteins, including Amyloid-beta1-42 (Abeta1-42), Alpha-synuclein (Asyn), myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), and S100 calcium binding protein B (S100B) have been suggested to be associated with neurodegenerative disorders, in particular Alzheimer's (AD) and Parkinson's disease (PD). Whereas the (reduced) occurrence of specific NAbs in AD is widely accepted, previous literature examining the relation of these NAb titres between PD patients and controls, as well as comparing these levels with demographic and clinical parameters in PD patients have produced inconsistent findings. We therefore aimed, in a cross-sectional approach, to determine serum titres of the above NAbs in a cohort of 93 PD patients (31 of them demented) and 194 controls. Levels were correlated with demographic and clinical variables, cerebrospinal fluid Abeta1-42, total tau and phospho-tau levels, as well as with single nucleotide polymorphisms (SNPs) of genes which either have been reported to influence the immune system, the amyloid cascade or the occurrence of PD (ApoE, GSK3B, HLA-DRA, HSPA5, SNCA, and STK39). The investigated NAb titres were neither significantly associated with the occurrence of PD, nor with demographic and clinical parameters, neurodegenerative markers or genetic variables. These results argue against a major potential of blood-borne parameters of the adaptive immune system to serve as trait or state markers in PD.
    PLoS ONE 02/2014; 9(2):e88604. DOI:10.1371/journal.pone.0088604 · 3.23 Impact Factor
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    • "The four SNPs examined located not within but upstream of ERSE. GRP78 promoter haplotypes may affect the individual variability of ER stress response and has been reported to be a potential risk factor for bipolar disorder in a Japanese population [24]. These suggested that the promoter haplotypes in the GRP78 gene were significantly associated with the functional SNPs, which were involved in the promoter activity. "
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    ABSTRACT: Hepatitis B virus (HBV) infection causes large amount of unfolding or false-folding protein accumulation in the endoplasmic reticulum (ER), which in turn induces the expression of glucose-regulated protein 78 (GRP78). The aim in the present study was to analyse the potential association between GRP78 single-nucleotide polymorphisms (SNPs) and the risk of HBV infection. The associations between seven common GRP78 polymorphisms in the promoter (rs391957, rs17840762, rs17840761, rs11355458) and in the 3' untranslated region (UTR) (rs16927997, rs1140763, rs12009) and possible risk of chronic HBV infection were assessed in a case-control study. 496 cases and 539 individually matched healthy controls were genotyped. Overall, no associations were observed in genotypic analyses. In addition, haplotypes and diplotypes combining those SNPs in the promoter or in the 3' UTR in high linkage disequilibrium (LD) were also not associated with HBV risk. These observations do not support a role for GRP78 polymorphisms in HBV infection in a predominantly Chinese Han population.
    BMC Medical Genetics 06/2010; 11(1):83. DOI:10.1186/1471-2350-11-83 · 2.08 Impact Factor
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