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Aging and disease    2019, Vol. 10 Issue (1) : 94-101     DOI: 10.14336/AD.2018.0116
Orginal Article |
REST rs3796529 Genotype and Rate of Functional Deterioration in Alzheimer’s Disease
Poyin Huang1,2,3,4, Cheng-Sheng Chen5, Yuan-Han Yang6, Mei-Chuan Chou6, Ya-Hsuan Chang7, Chiou-Lian Lai1,*, Hsuan-Yu Chen3,7,8,*, Ching-Kuan Liu2,*
1Department of Neurology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
2Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan.
3Ph.D. Program in Translational Medicine, Kaohsiung Medical University and Academia Sinica, Taiwan.
4Department of Neurology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
5Department of Psychiatry, Kaohsiung Medical University, Kaohsiung, Taiwan.
6Department of Neurology, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung, Taiwan.
7Institute of Statistical Science, Academia Sinica, Taipei, Taiwan.
8Graduate institute of medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
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Abstract  

Recently, REST (RE1-silencing transcription factor) gene has been shown to be lost in Alzheimer’s disease (AD), and a missense minor REST allele rs3796529-T has been shown to reduce the rate of hippocampal volume loss. However, whether the REST rs3796529 genotype is associated with the rate of functional deterioration in AD is unknown. A total of 584 blood samples from Taiwanese patients with AD were collected from January 2002 to December 2013. The diagnosis of AD was based on the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria. The allele frequency of rs3796529-T was compared between the AD cohort and 993 individuals from the general population in Taiwan. Kaplan-Meier analysis, the log rank test and a multivariate Cox model were then used to evaluate the association between rs3796529-T and functional deterioration in the AD cohort. The allele frequency of rs3796529-T was significantly lower in the AD cohort compared to the general population cohort (36.82% vs. 40.73%, p=0.029). Kaplan-Meier analysis and the log rank test showed that the AD patients carrying the rs3796529 T/T genotype had a longer progression-free survival than those with the C/C genotype (p=0.012). In multivariate analysis, the rs3796529 T/T genotype (adjusted HR=0.593, 95% CI: 0.401-0.877, p=0.009) was an independent protective factor for functional deterioration. The rs3796529 T/T genotype was associated with slower functional deterioration in patients with AD. This finding may lead to a to better understanding of the molecular pathways involved, and prompt further development of novel biomarkers to monitor AD.

Keywords genetics      biomarker      dementia      prognosis     
Corresponding Authors: Lai Chiou-Lian,Chen Hsuan-Yu,Liu Ching-Kuan   
About author:

These authors equally contributed to the work.

Issue Date: 02 October 2017
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Huang Poyin
Chen Cheng-Sheng
Yang Yuan-Han
Chou Mei-Chuan
Chang Ya-Hsuan
Lai Chiou-Lian
Chen Hsuan-Yu
Liu Ching-Kuan
Cite this article:   
Huang Poyin,Chen Cheng-Sheng,Yang Yuan-Han, et al. REST rs3796529 Genotype and Rate of Functional Deterioration in Alzheimer’s Disease[J]. Aging and disease, 2019, 10(1): 94-101.
URL:  
http://www.aginganddisease.org/EN/10.14336/AD.2018.0116     OR     http://www.aginganddisease.org/EN/Y2019/V10/I1/94
REST rs3796529Total ANT allele AN (%)Odds ratio (95% CI)p value
AD patients (n=584)1168430 (36.82%)
ExAC East Asian86423493 (40.42%)1.164 (1.026-1.321)0.018
1000 Genomes Han Chinese416145 (34.85%)0.918 (0.727-1.161)0.475
1000 Genomes East Asian1008380 (37.69%)1.039 (0.872-1.236)0.671
Taiwan Biobank Taiwanese1986402 (40.73%)1.180 (1.017-1.369)0.029
Table 1  Allele frequencies, allele numbers and odds ratios of rs3796529-T in patients with AD and East Asian general populations.
Figure 1.  Bar chart of allele frequencies of rs3796529-T in patients with AD and East Asian general populations.
AD patients (n=584)C/C (n=239)C/T (n=260)T/T (n=85)p value
Age (years)
(n=559)
79.10±8.10
(n=228)
79.49±7.68
(n=249)
78.70±7.64
(n=82)
0.745
Gender (Male)
(n=566)
29.9%
(n=69)
29.4%
(n=74)
28.9%
(n=24)
0.985
Education (years)
(n=540)
5.71±4.87
(n=223)
6.13±4.78
(n=240)
6.14±5.00
(n=77)
0.599
APOE E4 carrier
(n=274)
32.4%
(n=36)
38.1%
(n=43)
30.0%
(n=15)
0.525
Baseline CDR (0.5 or 1)
(n=550)
80.5%
(n=178)
75.0%
(n=186)
80.2%
(n=65)
0.305
Baseline stages of AD0.140
Early (CDR=0.5 or 1)80.5% (n=178)75% (n=186)80.2% (n=65)
Middle (CDR=2)19% (n=42)24.6% (n=61)17.3% (n=14)
Late (CDR=3)0.5% (n=1)0.4% (n=1)2.5% (n=2)
(n=550)(n=221)(n=248)(n=81)
Medication- Donepezil69.1%71.3%73.7%0.476
Rivastigmine24.2%18.4%22.4%
Galantamine4.8%6.7%2.6%
Memantine1.9%3.6%1.3%
(n=506)(n=203)(n=227)(n=76)
Table 2  Basic characteristics of the AD patients categorized by rs3796529 genotype.
Figure 2.  The 1-survival probability curve of the progression of AD for REST rs3796529 C/C was above that of REST rs3796529 C/T and T/T; p value according to the log-rank test.
VariableHazard ratio (95% CI)p value
Male0.868 (0.639-1.181)0.368
Age (years)0.983 (0.967-0.998)0.031
Education (years)1.016 (0.988-1.045)0.257
Baseline CDR score0.590 (0.451-0.773)<0.001
REST rs3796529 genotype (C/C as reference)
C/T0.793 (0.607-1.035)0.088
T/T0.593 (0.401-0.877)0.009
Table 3  Adjusted hazard ratios of risk factors in AD progression.
[1] Reitz C (2016). Toward precision medicine in Alzheimer’s disease. Ann Transl Med, 4:107
[2] Cruchaga C, Karch CM, Jin SC, et al (2014). Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer’s disease. Nature, 505:550-4
[3] Guerreiro R, Wojtas A, Bras J, et al (2013). TREM2 variants in Alzheimer’s disease. N Engl J Med, 368:117-27
[4] Jonsson T, Stefansson H, Steinberg S, et al (2013). Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med, 368:107-16
[5] Collins FS, VarmusH. A new initiative on precision medicine (2015). N Engl J Med, 372:793-5
[6] Olfson E, Cottrell CE, Davidson NO, et al (2015). Identification of Medically Actionable Secondary Findings in the 1000 Genomes. PLoS One, 10:e0135193
[7] Lu T, Aron L, Zullo J, et al (2014). REST and stress resistance in ageing and Alzheimer’s disease. Nature, 507:448-454
[8] Nho K, Kim S, Risacher SL, et al (2015). Protective variant for hippocampal atrophy identified by whole exome sequencing. Ann Neurol, 77:547-552
[9] Li K, Jiang Q, Xu A, Liu G (2015). REST rs3796529 variant does not confer susceptibility to Alzheimer’s disease. Ann Neurol, 78:835-6
[10] Jiang Q, Liu G (2016). REST rs3796529 variant does not influence human subcortical brain structures. Ann Neurol, 79:334-5
[11] Exome Aggregation Consortium (ExAC) doi :http://dx.doi.org/10.1101/030338
[12] 1000 Genomes Project Consortium, Auton A, Brooks LD, et al (2015). A global reference for human genetic variation. Nature, 526:68-74
[13] Noh KM, Hwang JY, Follenzi A, et al (2012). Repressor element-1 silencing transcription factor (REST)-dependent epigenetic remodeling is critical to ischemia-induced neuronal death. Proc Natl Acad Sci USA, 109: E962-71
[14] Huang Z, Wu Q, Guryanova OA, et al (2011). Deubiquitylase HAUSP stabilizes REST and promotes maintenance of neural progenitor cells. Nat Cell Biol, 13:142-52
[15] Zhang D, Li Y, Wang R, et al (2016). Inhibition of REST Suppresses Proliferation and Migration in Glioblastoma Cells. Int J Mol Sci, 17: E664
[16] Soldati C, Bithell A, Johnston C, Wong KY, Stanton LW, Buckley NJ (2013). Dysregulation of REST-regulated coding and non-coding RNAs in a cellular model of Huntington’s disease. J Neurochem, 124:418-30
[17] Zhao Y, Zhu M, Yu Y, et al (2017). Brain REST/NRSF Is Not Only a Silent Repressor but Also an Active Protector. Mol Neurobiol, 54(1):541-550
[18] Cavadas MA, Mesnieres M, Crifo B, et al (2015). REST mediates resolution of HIF-dependent gene expression in prolonged hypoxia. Sci Rep, 5:17851
[19] Hwang JY, Kaneko N, Noh KM, Pontarelli F, Zukin RS (2014). The gene silencing transcription factor REST represses miR-132 expression in hippocampal neurons destined to die. J Mol Biol, 426:3454-66
[20] Sedaghat Y, Bui HH, Mazur C, Monia BP (2013). Identification of REST-regulated genes and pathways using a REST-targeted antisense approach. Nucleic Acid Ther, 23:389-400
[21] Charbord J, Poydenot P, Bonnefond C, et al (2013). High throughput screening for inhibitors of REST in neural derivatives of human embryonic stem cells reveals a chemical compound that promotes expression of neuronal genes. Stem Cells, 31:1816-28
[22] Rossbach M (2011). Non-Coding RNAs in Neural Networks, REST-Assured. Front Genet, 2:8
[23] Gao Z, Ure K, Ding P, et al (2011). The master negative regulator REST/NRSF controls adult neurogenesis by restraining the neurogenic program in quiescent stem cells. J Neurosci, 31:9772-86
[24] Ravache M, Weber C, Mérienne K, Trottier Y (2010). Transcriptional activation of REST by Sp1 in Huntington’s disease models. PLoS One, 5: e14311
[25] Bithell A (2011). REST: transcriptional and epigenetic regulator. Epigenomics, 3:47-58
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