Association of BDNF and BCHE with Alzheimer's disease: Meta‑analysis based on 56 genetic case‑control studies of 12,563 cases and 12,622 controls
- Authors:
- Published online on: March 3, 2015 https://doi.org/10.3892/etm.2015.2327
- Pages: 1831-1840
Abstract
Introduction
Alzheimer's disease (AD) is a common neurodegenerative disorder that is the main cause of dementia. The clinical presentation of AD is characterized by progressive memory disorder and cognitive dysfunction (1). The worldwide prevalence of AD was 26.6 million in 2006, and this number is predicted to quadruple by 2050. The rapidly increased AD incidence is likely lead to a significant burden on family and society (2).
AD is a complex disease involving the interaction of genetic and environmental factors. It has been shown that AD development is contributed to by several elements, such as senile plaques, neurofibrillary tangles (NFTs), abnormally aggregated ‘reactive’ proteins like β-amyloid (Aβ) and tau, exposure to aluminum and brain inflammation (3). A genome-wide association study revealed that multiple mutations in candidate genes greatly increase the chance of developing AD (4). Genes such as brain-derived neurotrophic factor (BDNF) and butyrylcholinesterase (BCHE) are believed to play a significant role in AD progression (5–7).
BDNF is a member of the neurotrophic factor family and is encoded by a gene located on chromosome 11p13 (8). A previous study demonstrated that the levels of BDNF and its receptor, tyrosine receptor kinase B, were decreased in the frontal cortex and hippocampus of patients with AD (9). BDNF is known to protect against the neurotoxicity of the Aβ peptide and neural cell death by the aggregation of Aβ and tau proteins (10,11). Several single nucleotide polymorphisms (SNPs), such as Val66Met and C270T (rs2030324), in BDNF have been reported to be associated with AD (12–19).
BCHE is located on chromosome 3q26 (20), spanning over 73 kb with four exons and three large introns (21). The protein, BCHE, is an acetylcholine-hydrolyzing enzyme. BCHE is considered to be relevant to the progressive memory disorder and dementia in AD (22,23) and has been associated with NFTs and Aβ in the pathology of AD (24). In addition, BCHE has been found to play an important role in AD plaque maturation (25).
Inconsistent results have been reported in the previous studies on the association of BDNF and BCHE polymorphisms with AD. For BDNF Val66Met, there have been five positive results in Europeans (12–15) and Asians (16), and 21 negative results (among 18 studies) in Europeans (26–37), Asians (19,38–42) and Africans (29). For BDNF C270T, there have been four positive results in Europeans (13,17) and Asians (18,19) and 14 negative results in Europeans (28–31,34–37,43–45), Asians (40,41) and Africans (29). For BCHE-K variants, there have been six positive results in Europeans (46–51) and 22 negative results in Europeans (5,52–67) and Asians (68–72). Discrepancies among the previous association studies may have been the result of limited power, different ethnic backgrounds or the different processes and status in patients with AD. Meta-analysis can strengthen the power by combining data from different studies and can draw a more comprehensive conclusion by analyzing studies in different ethnicities (73–75). The aim of the current meta-analysis was to assess the association between the three polymorphisms and AD.
Materials and methods
Article retrieval
Articles were retrieved in January 2014 by searching PubMed without time or language restrictions. The following keywords were used: ‘Alzheimer disease BCHE association or Alzheimer disease BCHE polymorphism’ and ‘Alzheimer disease BDNF association or Alzheimer disease BDNF polymorphism’. The current meta-analysis included studies that met the following criteria: i) An original case-control study assessing the association of BDNF and BDHE with AD in humans; ii) a study containing sufficient information for the odds ratios (ORs) and 95% confidence intervals (CIs) to be obtained; iii) a study in which the genotype distribution of each polymorphism in controls met the Hardy-Weinberg equilibrium (HWE); iv) a study in the cumulative number of stages for one genetic locus was at least three. From each study, the following data were extracted or calculated: First author, publication year, country, ethnicity, number of cases and controls, HWE for controls, reported association results and the power of each study.
Data analysis
Arlequin software (76) was used to test whether the genotyping distribution in the controls was in HWE. The power of each study was calculated by a Power and Sample Size Calculation program (77). Cochran's Q statistic and I2 test (78) were used to evaluate the statistical heterogeneity. A fixed-effect model was used for the studies with minimal to moderate heterogeneity (I2<50%), and the random-effect model was used for the studies with significant heterogeneity (I2≥50%), with the exception of the allelic analysis. Subgroup analyses were performed in different inheritable models that contained dominant, recessive and additive models. Review Manager 5 (The Nordic Cochrane Center, The Cochrane Collaboration, Copenhagen, Denmark) was used to estimate the combined ORs and CIs (79). Funnel plots were drawn to observe the potential publication bias. P<0.05 was considered to indicate a statistically significant difference.
Results
Article retrieval
As shown in Fig. 1, 104 articles were obtained from the two searches. Two non-human studies were excluded, as were five non-AD studies, three reviews, 35 studies that only focused on patients and nine case-control studies without genotyping information. In addition, six studies were included from the references. The genotypes in the controls of the case-control studies met the HWE. Finally, 56 articles (5,12–19,26–72) with 12,563 cases and 12,622 controls among 72 stages were involved in the present meta-analysis. The characteristics of the included studies are shown in Table I.
BDNF Val66Met
A total of 23 articles with 26 stages involving 6,504 patients with AD and 6,636 controls were included for the meta-analysis of BDNF Val66Met. Significant statistical heterogeneity was found at the allelic level (I2=58%), under the dominant model (I2=56%) and the additive model (I2=53%). The major allele frequency of BDNF Val66Met was 0.805 in Europeans [International Haplotype Mapping Project panel derived from Utah residents with Northern and Western European ancestry (HapMap-CEU)], higher than the frequency in Asians [HapMap-Han Chinese in Beijing, China (HCB), 0.733; HapMap-Japanese in Tokyo Japan (JPT), 0.682] and Africans [HapMap-Yoruba in Ibadan, Nigeria (YRI), 0.004]. The ethnic differences for BDNF Val66Met were low between different populations [Fixation index (Fst)=0.1006]; therefore, the meta-analysis was also performed by ethnicity. No significant association was found in the meta-analysis on allelic analysis (P=0.99; OR, 1.00; 95% CI, 0.91–1.10; Table II) or under the other models for combined and stratified populations (P>0.05, Table II).
 | Table II.Meta-analysis of the association of the BDNF Val66Met, BDNF C270T and BCHE-K polymorphisms with Alzheimer's disease. |
BDNF C270T
A total of 17 articles with 18 stages involving 4,216 patients with AD and 4,370 controls were included for the meta-analysis of the BDNF C270T polymorphism. Significant heterogeneity was observed in the meta-analysis at the allelic level (I2=63%) and under the dominant model (I2=62%). The frequency of the BDNF C270T allele was 0.667 in Chinese subjects (HapMap-HCB), higher than that in the Japanese group (HapMap-JPT, 0.455), Europeans (HapMap-CEU, 0.570) and Africans (HapMap-YRI, 0.550). Further analysis showed a low ethnic difference for BDNF C270T (Fst=0.0230). No significant association between BDNF C270T and AD was observed at the allelic level (P=0.30; OR, 1.12; 95% CI, 0.91–1.37; Table II). A further subgroup meta-analysis by ethnicity showed a significant association between BDNF C270T and AD in Asians under a dominant model (P=0.03; OR, 1.88; 95% CI, 1.08–3.27; Table II and Fig. 2).
BCHE-K
A total of 28 articles with 4,894 patients with AD and 4,367 controls were included for the meta-analysis of the BCHE-K variant. Although minimal ethnic differences were found in Europeans and Asians (Fst=0.0009), significant heterogeneity was found in the meta-analysis on the allelic level (I2=56%) and under the dominant model (I2=65%); however, no significant association was found at the allelic level (P=0.31; OR, 1.07; 95% CI, 0.94–1.21; Table II). Subgroup meta-analysis also did not yield any significant results (P>0.05, Table II).
Power analyses
The power analyses in this meta-analysis were calculated under a moderate risk of AD (OR, 1.2; Tables I and II). The power was 1.000 for BDNF Val66Met, 0.986 for BDNF C270T and 1.000 for the BCHE-K variant (Table II), which was considerably higher than that in each of the individual studies (Table I). No publication bias was found in the meta-analyses of the three SNPs (Fig. 3).
Discussion
In the present study, 56 studies (72 stages) among 12,563 cases and 12,622 controls were analyzed to assess the association of the BDNF Val66Met, BDNF C270T and BCHE-K variants with AD. The results showed a moderate association between BDNF C270T and AD in Asians (P=0.03; OR, 1.88; 95% CI, 1.08–3.27; Table II and Fig. 2) but no significant associations were observed in the other meta-analyses.
The BDNF Val66Met polymorphism has been shown to impair the secretion of BDNF (80), and to be able to change brain morphology and cognitive function (81). Previous studies have reported five positive results (12–16) and 21 negative results (19,26–42) between the BDNF Val66Met polymorphism and AD. In the present meta-analysis, no significant association was found between BDNF Val66Met and AD (P>0.05, Table II). This was consistent with a former meta-analysis (82). The current meta-analysis of BDNF Val66Met included 23 articles, seven more than the previous study. In addition, meta-analyses were performed under various genetic models, including dominant, recessive and additive models. Subgroup meta-analysis by ethnicity was also conducted, although no statistically significant results were obtained.
The BDNF C270T polymorphism is located in a non-coding region and may affect the BDNF expression in the neural soma, dendrites or axonal regions (83). Heterozygous carriers of the T-allele tend to have a higher risk of developing AD than non-carriers (36). There have been a total of four significant results (13,17–19) and 14 non-significant results (28–31,34–37,40,41,43–45) among the previous association studies between the BDNF C270T polymorphism and AD. In the present meta-analysis, the BDNF C270T polymorphism was found to increase the risk of AD by 88% in Asians under the dominant model. No significant association was found in the other analyses (P>0.05, Table II). A strong power was shown in the meta-analysis of BDNF C270T polymorphism (0.986). Compared with a former meta-analysis that showed no positive results (82), the current meta-analysis of BDNF C270T included 18 studies, more than the 12 in the previous study (82); the meta-analyses were performed under various genetic models, and subgroup meta-analyses by ethnicity were also conducted. With a larger sample size and more comprehensive analysis, the present study showed a more reliable conclusion than the previous study.
The K variant alone does not decrease BCHE activity, but acts in synergy with APOE4 polymorphism to increase the risk of AD (84). Additionally, the BCHE-K variant promotes fibril formation by participating in the transformation of Aβ from an initially benign form to an eventually malignant form. The BCHE-K variant acts as a general candidate risk factor of AD (84,85). Six significant results (46–51) and 22 non-significant results (5,52–72) were found in previous studies on the association between the BCHE-K variant and AD. The power of BCHE-K was 1.000, which was sufficiently strong for a precise conclusion to be drawn. The current study showed no significant association between the BCHE-K variant and AD; this was consistent with a previous meta-analysis (86). The present study involved 27 stages, six more than the former study. The studies involved in the present meta-analysis met the HWE and were performed under various genetic models with subgroup meta-analysis by ethnicity. With stricter inclusion criteria, a stronger power and more comprehensive analysis, the present meta-analysis of BCHE-K was an improvement on the former one.
There were certain limitations in the meta-analysis. Firstly, publication bias may exist, as the negative-result studies are less likely to be published and may be missed, which may influence the results. Secondly, the majority of studies investigating the association between the three polymorphisms and AD were carried out in the European and Asian populations. The number of studies in other populations, such as Africans, was limited. Future studies in other ethnic populations are warranted. Thirdly, AD is a complex disease. Different statuses in AD may affect the results of the study; however, no detailed information of the AD diagnostic criteria was available from previous studies. Future case-control studies with more comprehensive information are required. Fourthly, there are 5,724 polymorphisms in BDNF and 5,059 polymorphisms in BCHE. The current study only focused on two polymorphisms of BDNF and one polymorphism of BCHE, which may not fully show the function of those two genes. Studies investigating a wider range of polymorphisms are required to improve the representation of the two genes. Fifthly, APOE is a known pivotal gene in the AD pathogenesis but no APOE genotype was included in any of the studies. Thus, any hidden interaction of the APOE genotype with the tested three polymorphisms may have been missed in the current meta-analysis. Sixthly, although a moderate association of the BDNF C270T polymorphism with the risk of AD was observed in Asians under a dominant model (P=0.03; OR, 1.88; 95% CI, 1.08–3.27), the significance was not retained following correction by multiple testing. This result should therefore be taken with caution. Finally, there was high heterogeneity in the BDNF C270T variant under the dominant model in Asians (P=0.03, I2=53%, Table II). We speculated that the number of participants was the source of the heterogeneity, as the studies with limited samples tended to produce negative results (n<200, P>0.05) in contrast to significant results produced in the studies with sufficient samples (n>200, P<0.05).
In conclusion, the present comprehensive meta-analysis suggested a moderate association between the BDNF C270T polymorphism and AD in Asians under the dominant model. Further studies focusing on a wider range of ethnic populations are required to confirm the results of the study.
Acknowledgements
The study was supported by grants from the National Natural Science Foundation of China (nos. 31100919 and 81371469), the 973 program from the Ministry of Science and Technology of China (no. 2013CB835100), the Natural Science Foundation of Zhejiang Province (no. LR13H020003), the Disciplinary Project of Ningbo University (no. B01350104900), the KC Wong Magna Fund in Ningbo University, the Program for Professor of Special Appointment (Eastern Scholars) at Shanghai Institutions of Higher Learning and the Key Basic Research Foundation of Science and Technology Commission of Shanghai Municipality (no. 13JC1403700).
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