Article

GAB2 is not associated with late-onset Alzheimer's disease in Japanese

Department of Molecular Genetics, Bioresource Science Branch, Center for Bioresources, Brain Research Institute, Niigata University, Niigata, Japan.
European journal of human genetics: EJHG (Impact Factor: 4.23). 11/2008; 17(5):682-6. DOI: 10.1038/ejhg.2008.181
Source: PubMed

ABSTRACT The varepsilon4 allele of the apolipoprotein E gene (APOE) is unequivocally recognized as a genetic risk factor for late-onset Alzheimer's disease (LOAD). Recently, single-nucleotide polymorphisms (SNPs) of the GRB2-associated binding protein 2 gene (GAB2) were shown to be associated with LOAD in Caucasians carrying the APOE-varepsilon4 allele through a genome-wide association study. Here, we attempted to replicate the finding by genotyping these SNPs in a large clinical cohort of Japanese. We observed no association of any of the SNPs with LOAD. GAB2 may not be a disease susceptibility gene for LOAD in Japanese.

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    • ". A large proportion of the clinically-verified subjects were the same (74.8%) as those in the overall sample set used in our previous genetic study on GAB2 [22]. The LOAD patients met the criteria of the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association for a diagnosis of probable AD [23]. "
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    ABSTRACT: Rare non-synonymous variants of TREM2 have recently been shown to be associated with Alzheimer's disease (AD) in Caucasians. We here conducted a replication study using a well-characterized Japanese sample set, comprising 2,190 late-onset AD (LOAD) cases and 2,498 controls. We genotyped 10 non-synonymous variants (Q33X, Y38C, R47H, T66M, N68K, D87N, T96K, R98W, H157Y, and L211P) of TREM2 reported by Guerreiro et al. (2013) by means of the TaqMan and dideoxy sequencing methods. Only three variants, R47H, H157Y, and L211P, were polymorphic (range of minor allele frequency [MAF], 0.0002-0.0059); however, no significant association with LOAD was observed in these variants. Considering low MAF of variants examined and our study sample size, further genetic analysis with a larger sample set is needed to firmly evaluate whether or not TREM2 is associated with LOAD in Japanese.
    Journal of Alzheimer's disease: JAD 04/2014; 41(4). DOI:10.3233/JAD-140225 · 4.15 Impact Factor
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    • "The rs10793294 polymorphism within the GAB2 gene was one of the ten SNPs found to be highly correlated with an increased risk of AD in APOEε4 carriers (P = 1.59E − 07, OR = 2.83, 95% CI = 1.90–4.21) in the original Caucasian study [12]. Two replication studies failed to replicate the results in Caucasian and Japanese populations [15] [19]. Clinica Chimica Acta 412 (2011) 446–449 ⁎ Corresponding authors. "
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    ABSTRACT: Toll-like receptors 2 (TLR2) and TLR4 are involved in the microglia-mediated inflammatory response, Aβ plaque formation and Aβ clearance in Alzheimer's disease (AD). Our previous studies have shown that variants in the TLR2 and TLR4 genes are associated with the risk of AD. Therefore, we hypothesize that there may be significant changes in TLR2 and TLR4 expressions on peripheral blood mononuclear cells (PBMCs) from patients with AD when compared to healthy control subjects. Sixty patients with late-onset AD (LOAD) and 60 healthy controls matched for sex and age were recruited. Flow cytometry (FCM) was used to detect expressions of TLR2 and TLR4 proteins and real-time quantitative RT-PCR was performed to determine TLR2 and TLR4 mRNAs. Compared with controls, expressions of TLR2 and TLR4 mRNAs were up-regulated in LOAD patients (TLR2/beta-actin mRNA: 0.390±0.204 versus 0.281±0.167, P<0.01; TLR4/beta-actin mRNA: 0.503±0.195 versus 0.322±0.183, P<0.01). The proteins levels were higher in LOAD patients than in controls (TLR2: 97.12±1.67% versus 41.07±18.44%, P<0.01, TLR4: 66.56±23.74% versus 14.83±4.31, P<0.01). In both cases, either AD or control group, TLR2 and TLR4 mRNAs expressions were positively correlated with the levels of proteins (TLR2: r=0.980 and 0.976,P<0.01; TLR4: r=0.938 and 0.970, P<0.01), respectively. There were significant negative correlations between TLR levels and MMSE score (TLR2: r=-0.32; P=0.01; TLR4: r=-0.29; P=0.02). In addition, CC genotype can increase the expression of TLR4 in AD patients. This study gives the first evidence that expressions of TLR2 and TLR4 in PBMCs were markedly elevated in LOAD patients.
    Journal of the neurological sciences 12/2011; 315(1-2):67-71. DOI:10.1016/j.jns.2011.11.032 · 2.26 Impact Factor
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    • "The rs10793294 polymorphism within the GAB2 gene was one of the ten SNPs found to be highly correlated with an increased risk of AD in APOEε4 carriers (P = 1.59E − 07, OR = 2.83, 95% CI = 1.90–4.21) in the original Caucasian study [12]. Two replication studies failed to replicate the results in Caucasian and Japanese populations [15] [19]. Clinica Chimica Acta 412 (2011) 446–449 ⁎ Corresponding authors. "
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    ABSTRACT: GRB-associated binding protein 2 (GAB2) may function as a risk factor in the pathogenesis of Alzheimer disease (AD). A recent large genome-wide association study (GWAS) has identified a significant association of rs10793294 polymorphism within the GAB2 gene with AD in Caucasians. While there are no studies on the association of rs10793294 polymorphism with AD risk in the Chinese population. The study investigated 358 sporadic late-onset AD (LOAD) and 366 healthy controls matched for sex and age in a Han Chinese population. The rs10793294 polymorphism within the GAB2 gene was genotyped using MALDI-TOF mass spectrometry. The C allele of the rs10793294 polymorphism within GAB2 was significantly associated with an increased risk of LOAD (OR=1.33, 95% CI=1.04-1.72, P=0.029). Significance was observed in APOEε4 carriers (genotype P=0.039, allele P=0.016). While in APOE ε4 non-carriers, significant differences were observed in alleles (P=0.039) but not in genotypes (P=0.304). Logistic regression revealed that rs10793294 polymorphism was still strongly associated with LOAD in dominant model (OR=2.58, 95% CI=1.22-5.45, P=0.013) and additive model (OR=1.38, 95% CI=1.05-1.80, P=0.020) after adjusting for age, gender, and the APOE ε4 status. Our findings implicate GAB2 as a susceptibility gene for LOAD in Han Chinese.
    Clinica chimica acta; international journal of clinical chemistry 02/2011; 412(5-6):446-9. DOI:10.1016/j.cca.2010.11.022 · 2.76 Impact Factor
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