16 May 2015: Meta-Analysis
Butyrylcholinesterase K Variant and Alzheimer’s Disease Risk: A Meta-Analysis
Zongcheng Wang ABCDEFG , Yuren Jiang ABCDEF , Xi Wang BCD , Yangsen Du BCD , Dandan Xiao CF , Youchao Deng C , Jinlian Wang D
DOI: 10.12659/MSM.892982
Med Sci Monit 2015; 21:1408-1413
Abstract
BACKGROUND: Although many studies have estimated the association between the butyrylcholinesterase (BCHE) K variant and Alzheimer’s disease (AD) risk, the results are still controversial. We thus conducted this meta-analysis.
MATERIAL AND METHODS: We searched NCBI, Medline, Web of Science, and Embase databases to find all eligible studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association.
RESULTS: We found a significant association between BCHE K variant and AD risk (OR=1.20; 95% CI 1.03–1.39; P=0.02). In the stratified analysis by ethnicity, we observed a significant association between BCHE K variant and AD risk in Asians (OR=1.32; 95% CI 1.02–1.72; P=0.04). However, no significant association between BCHE K variant and AD risk in Caucasians was found (OR=1.14; 95% CI 0.95–1.37; P=0.16). When stratified by the age of AD onset, we found that late-onset AD (LOAD) was significantly associated with BCHE K variant (OR=1.44; 95% CI 1.05–1.97; P=0.02). No significant association between BCHE K variant and early-onset AD (EOAD) risk was observed (OR=1.16; 95% CI 0.89–1.51; P=0.27). Compared with non-APOE ε4 and non-BCHE K carriers, no significant association between BCHE K variant and AD risk was found (OR=1.11; 95% CI 0.91–1.35; P=0.30). However, APOE ε4 carriers showed increased AD risk in both non-BCHE K carriers (OR=2.81; 95% CI 1.75–4.51; P=0.0001) and BCHE K carriers (OR=3.31; 95% CI 1.82–6.02; P=0.0001).
CONCLUSIONS: The results of this meta-analysis indicate that BCHE K variant might be associated with AD risk.
Keywords: Age of Onset, Aged, 80 and over, Alzheimer Disease - genetics, Apolipoprotein E4 - genetics, Asian Continental Ancestry Group - genetics, Butyrylcholinesterase - genetics, European Continental Ancestry Group - genetics, Genetic Predisposition to Disease, Odds Ratio, Polymorphism, Single Nucleotide, Publication Bias, Risk, Sensitivity and Specificity
Background
Alzheimer’s disease (AD) is one of the most common forms of dementia. The clinical manifestations of AD include loss of memory, and behavioral and cognitive disorders [1]. The survival time for patients with AD is generally 4 to 6 years after diagnosis. Thus, AD is a major public health concern. However, the etiology and pathogenesis of AD remain unclear. Recently, accumulating evidence shows that genetic factors might be involved in the development of AD [2].
Butyrylcholinesterase (BCHE) is a hydrolytic enzyme that can catalyze the hydrolysis of excess acetylcholine neurotransmission in the synaptic space. Darreh-Shori et al. suggested that low cerebrospinal fluid (CSF) levels of BCHE might predict extensive incorporation in neuritic plaques, greater central neurodegeneration, and increased neurotoxicity [3]. They also found that BCHE levels correlated with cerebral glucose metabolism, cerebral β-amyloid load, and CSF P-tau [4]. Diamant et al. reported an association of the BChE-K variant with impaired interaction with the fibrillogenic beta-amyloid protein [5]. Shenhar-Tsarfaty also suggested that this variant could influence metabolic syndrome [6].
BCHE K variant is one of the most common polymorphism in the BCHE gene. This is an alanine-to-threonine substitution in the 539 amino acid position (Ala539Thr). This polymorphism is associated with a 30% reduction of serum BCHE activity [7]. Many studies have been conducted to evaluate the association between BCHE K variant and AD risk [8–32]. However, the results are controversial and inconsistent. Therefore, we performed a meta-analysis to assess the association between BCHE K variant and AD risk.
Material and Methods
SEARCH FOR STUDIES:
We searched NCBI, Medline, Web of Science, and Embase databases to find all eligible studies. The last retrieval date was October 29, 2014. The following terms and keywords were used: (“Alzheimer’s disease” or “Alzheimer disease”) and (“Butyrylcholinesterase” or “BCHE”). All relevant studies were retrieved.
INCLUSION AND EXCLUSION CRITERIA:
The inclusion criteria were as follows: (1) the study should be case-control or a cohort design; and (2) the study should focus on the association between BCHE K variant and AD risk. The exclusion criteria were as follows: (1) animal studies; (2) reviews or abstracts; and (3) duplications.
DATA EXTRACTION:
According to the inclusion criteria, 2 investigators extracted the data independently. Any discrepancy was adjudicated by the third investigator. The following data was extracted from each study: first author, year, ethnicity, age and sex of patients, sample size, and genotyping results from BCHE and APOE genes.
STATISTICAL ANALYSIS:
The odds ratio (OR) and its 95% confidence interval (95% CI) were used to estimate the strength of the association between BCHE K variant and AD risk. A recessive model (KK
Results
STUDY CHARACTERISTICS:
A total of 25 eligible case-control studies (3850 cases and 3947 controls) met the inclusion criteria [8–32]. Among these 25 case-control studies, 5 studies focused on Asians and 20 focused on Caucasians. The main characteristics of the included studies investigating the association of BCHE K variant and AD risk are presented in Table 1.
ASSOCIATION BETWEEN BCHE K VARIANT AND AD RISK:
We found a significant association between BCHE K variant and AD risk (OR=1.20; 95% CI 1.03–1.39; P=0.02; Figure 1). In the stratified analysis by ethnicity (Table 2), we observed a significant association between BCHE K variant and AD risk in Asians (OR=1.32; 95% CI 1.02–1.72; P=0.04), but no significant association between BCHE K variant and AD risk in Caucasians was found (OR=1.14; 95% CI 0.95–1.37; P=0.16). When stratified by age at AD onset, we found that late-onset AD (LOAD) was significantly associated with BCHE K variant (OR=1.44; 95% CI 1.05–1.97; P=0.02). No significant association between BCHE K variant and early-onset AD (EOAD) risk was observed (OR=1.16; 95% CI 0.89–1.51; P=0.27).
Compared with non-APOE ɛ4 and non-BCHE K carriers, no significant association between BCHE K variant and AD risk was found (OR=1.11; 95% CI 0.91–1.35; P=0.30). However, APOE ɛ4 carriers showed increased AD risk in both non-BCHE K carriers (OR=2.81; 95%CI 1.75–4.51; P=0.0001) and BCHE K carriers (OR=3.31; 95% CI 1.82–6.02; P=0.0001). Results are listed in Table 3.
SENSITIVITY ANALYSIS AND PUBLICATION BIAS:
In the sensitivity analysis, the impact of each study on the pooled OR was checked by repeating the meta-analysis when omitting each study. This sensitivity analysis validated the stability of the results from this meta-analysis (Figure 2). The shape of funnel plots did not show any evidence of obvious asymmetry (Figure 3). Furthermore, the Egger’s test result suggested that there was no significant publication bias (P=0.67).
Discussion
This meta-analysis with a total of 3850 cases and 3947 controls systematically evaluated the association between BCHE K variant and AD risk. Results from this meta-analysis suggested that BCHE K variant was significantly associated with AD risk. In the subgroup analysis by ethnicity, a significant association between BCHE K variant and AD risk in Asians was found, but this result was not found in Caucasians. This difference suggests that race might play a role in AD. Only 5 studies were included in our meta-analysis; thus, more studies with Asians are needed to confirm our results. In the stratified analysis by
Carson et al. found that BCHE activity was associated with the amyloid and the neuritic component in neuritic plaques [33]. Guillozet et al. also found that BCHE activity increased in the AD brain [34]. The activity of serum BCHE-K to hydrolyze butyrylthiocholine was found to be reduced by 30% relative to BCHE-U [7]. Thus, BCHE K variant might be associated with a decreased AD risk. However, Lopez et al. reported that BCHE K variant carriers were refractory to cholinesterase inhibitor therapy [35]. Additionally, Podoly et al. found that BCHE K variant had an elevated AD risk due to inefficient interference with amyloidogenic processes [36]. Furthermore, Ballard et al. found that BuCh E may play a role in the phosphorylation of tau, relevant to therapeutic inhibition of the enzyme [37]. Alkalay et al. found no association between BChE activity and amyloid loads in the AD brain [38]. Thus, the pathological role of BCHE K variant was still controversial. Our meta-analysis confirmed that this polymorphism might be associated with AD risk. More studies are needed to investigate the mechanism by which BCHE K variant could impact the risk of AD [39,40].
This meta-analysis had several limitations. First, results of this meta-analysis were based on unadjusted OR, because not all studies offered the adjusted ORs. Second, although the number of included studies was relatively large, the sample size and statistical power was still limited. Third, we only included the published studies; thus, publication bias and selection bias might exist. Forth, lack of sufficient eligible data on BCHE K variant and AD limited our further stratified analyses.
Conclusions
In conclusion, this study shows that BCHE K variant is associated with AD risk. More well-conducted studies with larger sample size are warranted to confirm our results.
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