Association between apolipoprotein E gene polymorphism and depression

Association between apolipoprotein E gene polymorphism and depression

Journal of Clinical Neuroscience 22 (2015) 1232–1238 Contents lists available at ScienceDirect Journal of Clinical Neuroscience journal homepage: ww...

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Journal of Clinical Neuroscience 22 (2015) 1232–1238

Contents lists available at ScienceDirect

Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn

Review

Association between apolipoprotein E gene polymorphism and depression Fang Feng a,1, Shan-Shan Lu a,1, Cai-Yun Hu a, Feng-Feng Gong a, Zhen-Zhong Qian a, Hui-Yun Yang a, Yi-Le Wu a, Yuan-Yuan Zhao a, Peng Bi a,⇑, Ye-Huan Sun a,b,⇑ a b

Department of Epidemiology and Health Statistics, School of Public Health, Anhui Medical University, 81 Meishan Road, Hefei, Anhui 230032, China Centre for Evidence-Based Practice, Anhui Medical University, Hefei, Anhui, China

a r t i c l e

i n f o

Article history: Received 27 August 2014 Accepted 2 February 2015

Keywords: Apolipoprotein E ApoE Depression Polymorphism Meta-analysis

a b s t r a c t We performed an updated meta-analysis to obtain a more precise estimation of the relationship between apolipoprotein E (ApoE) gene polymorphism and susceptibility to depression, as previous reports have been inconsistent. Twenty studies with 2286 depression patients and 3845 controls were included. Odds ratios (OR) with 95% confidence intervals (CI) were calculated to assess the association between ApoE gene polymorphism and depression using a random effects model. Results showed a significant association between ApoE gene polymorphism and susceptibility to depression in the overall population (e2/e3 genotype versus e3/e3: OR 0.76, 95% CI 0.59–0.99). Subgroup analyses indicated an association in the Caucasian population (e2 allele versus e3: OR 0.75, 95% CI 0.58–0.97) as well as in late-life depression (LLD) patients (e3/e4 genotype versus e3/e3: OR 1.34, 95% CI 1.07–1.68, and e4 allele versus e3: OR 1.30, 95% CI 1.06–1.59). We concluded that the e2/e3 genotype likely provided a protective effect against depression in the overall population and the e2 allele acted as a protective factor for depression in the Caucasian population while the e4 allele and e3/e4 genotype were associated with an increased risk of depression in the LLD subjects. Ó 2015 Elsevier Ltd. All rights reserved.

1. Introduction Apolipoprotein E (ApoE) is a cholesterol transporter glycoprotein, synthesized mainly in the liver. ApoE is involved in myelin formation and regeneration after neuronal injury or during the development of neurons [1]. ApoE exists in three common isoforms designated E2, E3, and E4. Located on chromosome 19q13.2, the gene possesses three common alleles (e2, e3 and e4) which determine six different genotypes (e2/e2, e2/e3, e2/e4, e3/e3, e3/e4, and e4/e4); the e3 allele is the most prevalent in the general population. The ApoE e4 allele has been strongly associated with increased risk of Alzheimer’s disease (AD) in both familial and sporadic forms [2] while the presence of the e2 allele might be a protective factor for AD development [3]. In addition, evidence also supports the relationship between ApoE gene polymorphism and vascular and Lewy body dementia, indicating the importance of

⇑ Corresponding authors. Tel./fax: +86 551 65143334. E-mail addresses: [email protected] (P. Bi), [email protected] (Y.-H. Sun). 1 These authors have contributed equally to the manuscript. http://dx.doi.org/10.1016/j.jocn.2015.02.012 0967-5868/Ó 2015 Elsevier Ltd. All rights reserved.

the ApoE gene in the development of neuropsychiatric disorders [4,5]. Depression is a clinically heterogeneous group of mental disorders characterized by multiple symptoms reflecting alterations in cognitive, psychomotor and emotional processes. Various physiological factors may increase the risk of depression or depressive symptoms, including lipid metabolism and genetic variations related to lipids [6,7]. A potential genetic variant affecting lipid metabolism symptoms is the ApoE gene. In addition, depression is often accompanied by cognitive impairments similar to those occurring in AD [8]. Studies have found that a lifetime history of depression also increased the risk for AD [9], another indication that the ApoE gene polymorphism may be associated with depression. To date, numerous studies have been conducted to investigate the association between ApoE gene polymorphism and depression but the results from these studies have often been inconsistent [10– 14]. This could be due to different study designs and various study populations. Furthermore, the small sample sizes are lacking in ability to reveal statistically significant effects of these low-risk susceptibility genes [15]. A previous meta-analysis [16] showed that the ApoE e2 allele was a protective factor against the development of depression, however, this did not include enough studies for a

F. Feng et al. / Journal of Clinical Neuroscience 22 (2015) 1232–1238

subgroup meta-analysis of Asian origin studies. Given that previous meta-analyses were conducted 7 years ago, to better understand the association we performed an updated meta-analysis to identify whether the ApoE gene polymorphism had significant associations with depression. Furthermore, we considered the potential modifying effects of ethnicity and age.

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2.4. Statistical analyses

Electronic databases including PubMed, Springer Link, Elsevier, Wiley Online Library, OvidSP, Chinese Biomedical Database (CBM), China National Knowledge Infrastructure (CNKI), Chinese VIP database and Chinese WanFang database were searched for all eligible studies assessing the association of the ApoE gene polymorphism with depression. In addition, related literature searches online (www.baidu.com; Google Scholar) were also carried out. All included studies were published before the end of March 2014. We used various combinations of the search terms ‘‘apolipoprotein E’’, ‘‘ApoE’’ and ‘‘depression’’, ‘‘depressive disorder’’, ‘‘depressive symptom’’ and ‘‘polymorphism’’, ‘‘variant’’, ‘‘mutation’’. Furthermore, all references cited in these relevant publications were also reviewed to search for additional studies. All research was limited to English or Chinese language articles.

The strength of association between ApoE gene polymorphism and depression was assessed with odds ratios (OR) with 95% confidence intervals (CI). The combined OR were calculated for six genetic models (e2/e2 versus e3/e3, e2/e3 versus e3/e3, e3/e4 versus e3/e3, e4/e4 versus e3/e3, e2 allele versus e3 allele, and e4 allele versus e3 allele). HWE of genotypes in the control groups was tested by chi-squared analysis and a p value less than 0.05 was considered statistically significant. The random-effects model [17] was used in this meta-analysis because of the potential for between-study heterogeneity. Sensitivity analyses which reflect the influence of individual studies on the pooled OR were examined by means of sequentially omitting individual studies and recalculating the pooled OR and 95% CI on the remaining studies. In addition, sensitivity analyses were also conducted based on older patients without dementia or AD (for studies in which patients without dementia or AD were included). Potential publication bias was estimated by Begg’s and Egger’s tests [18]. Subgroup analyses were carried out based on ethnicity and age groups. Patients aged 50 years or over were defined as having late-life depression (LLD) in accordance with the Papassotiropoulos et al. study [19]. All statistical analyses were conducted using Stata (version 9.0; StataCorp, College Station, TX, USA). A p value less than 0.05 (two-tailed) was considered statistically significant.

2.2. Inclusion and exclusion criteria

3. Results

Inclusion criteria were as follows: (1) study of association between ApoE and depression; (2) case-control studies; (3) studies examining the three major isoforms (e2, e3, e4) of ApoE and providing complete data of alleles; (4) the distribution of the genotypes in control groups in the study was in Hardy–Weinberg equilibrium (HWE). Studies were excluded if one of the following existed: (1) a review or a case report; (2) a duplicated publication. If there were multiple publications on the same patients and/or controls, only the study comprising the larger sample size was included.

3.1. Study characteristics

2. Materials and methods 2.1. Literature search

2.3. Data extraction All data were extracted independently by two reviewers (FF and S-SL). Discrepancies were resolved through discussion. The following information was extracted from each eligible study: first author, year of publication, ethnicity of the study population and distribution of genotypes and alleles in all groups. Records identified through Chinese databases (n = 88)

Figure 1 summarizes the process for selecting eligible studies. In total, 20 articles [11–14,19–34] that consisted of 6131 subjects (2286 patients and 3845 controls) were included, of which two articles [33,34] reported the number of each allele. Of the 20 studies there were 12 from Asian populations and eight from Caucasian populations. Thirteen studies were conducted in LLD patients. Patients from all studies had no dementia or AD, except those in the study by Traykov et al. [13]. All control samples from these studies did not depart from HWE. Details of the included studies are listed in Table 1. 3.2. Quantitative synthesis As shown in Table 2, the results based on all studies showed significant associations between the ApoE gene polymorphism and Records identified through English databases (n = 202)

Total records identified (n = 290)

Articles requiring full-text review (n = 65) Additional articles identified by searching the references (n = 1). Articles meeting criteria for analysis (n = 20)

225 articles excluded: Duplicate records (n = 71); Reviews (n = 5); Other language (n = 2); Other topic (not depression or ApoE (n = 147).

46 articles excluded: No control group (n = 3); No target outcomes (n = 39); Case reports or letter (n = 4)

Fig. 1. Flow diagram of the article review and selection process for studies on apolipoprotein E (ApoE) gene polymorphism and depression.

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Table 1 Characteristics of eligible studies included in this meta-analysis on apolipoprotein E (ApoE) gene polymorphism and depression Study, first author (year)

Ethnicity

Patient

Control

ApoE Genotype

Wang (2001) [20] Shi (2001) [21] Yuan (2006) [22] Sun (2010) [23] Wang (2012) [24] Traykov (2007) [13] You (2009) [25] Garcia-Peña (2010) [26] Zubenko(1996) [11] Ohara (1999) [27] Jiao (2007) [14] Zhang (2012) [28] Zong (2012) [29] Huuhka (2005) [30] Fan (2006) [12] Papassotiropoulos (1999) [19] Hwang (2006) [31] Rigaud (2001) [32] Holmes (1998) [33] Butters (2003) [34]

ApoE Allele

ApoE Genotype

ApoE Allele

e2/ e2

e3/ e3

e4/ e4

e2/ e3

e2/ e4

e3/ e4

e2

e3

e4

e2/ e2

e3/ e3

e4/ e4

e2/ e3

e2/ e4

e3/ e4

e2

e3

e4

Asian Asian Asian Asian Asian Caucasian Asian Caucasian Caucasian Asian Asian Asian Asian Caucasian Asian Caucasian

3 2 1 0 2 0 3 6 0 2 1 4 2 0 1 0

56 27 35 21 61 8 76 194 31 96 62 147 74 71 233 88

0 0 0 1 1 0 1 1 0 3 1 2 4 4 0 6

7 2 5 4 14 2 22 2 4 8 10 48 16 7 1 25

0 0 4 3 5 2 11 0 0 4 2 24 4 3 0 4

7 11 15 11 14 12 31 23 10 21 16 54 20 34 38 37

13 6 11 7 23 4 39 14 4 16 14 80 24 10 3 29

126 67 90 57 150 30 205 413 76 221 150 396 184 183 505 238

7 11 19 16 21 14 44 25 10 31 20 82 32 45 38 53

0 11 2 1 1 0 2 42 0 0 0 2 2 3 8 0

61 69 41 26 26 77 55 1153 36 67 39 108 54 228 312 109

0 1 0 0 0 0 0 5 1 5 1 3 1 16 2 1

9 4 4 4 10 15 32 22 10 10 7 30 12 40 46 33

0 0 2 1 0 3 6 3 1 2 2 15 2 10 5 2

10 15 11 8 7 27 15 115 13 21 11 44 9 101 56 46

9 26 10 7 12 18 42 109 11 12 9 49 18 56 67 35

141 157 97 64 67 196 157 2443 95 165 96 290 129 597 726 297

10 17 13 9 7 30 21 128 16 33 15 65 13 143 65 50

Asian Caucasian Caucasian Caucasian

2 0 – –

80 28 – –

0 0 – –

9 4 – –

0 2 – –

20 15 – –

13 6 5 19

189 75 67 261

20 17 12 40

1 0 – –

105 34 – –

3 0 – –

16 4 – –

0 2 – –

19 9 – –

18 6 22 27

245 81 108 237

25 11 18 48

– = no data.

Table 2 Summary of pooled odds ratios (OR) with 95% confidence intervals (CI) in the meta-analysis on apolipoprotein E (ApoE) gene polymorphism and depression studies Studies

Comparison model*

M⁄

Association test OR (95% CI)

I2, %

p value (OR)

p value (publication bias test) Begg’s test

Egger’s test

All studies

e2/e3 versus e3/e3 e2/e2 versus e3/e3 e3/e4 versus e3/e3 e4/e4 versus e3/e3 e2 versus e3 e4 versus e3

0.76 0.87 1.14 0.88 0.80 1.12

(0.59–0.99) (0.52–1.44) (0.97–1.34) (0.50–1.57) (0.64–1.01) (0.96–1.31)

0.042 0.576 0.126 0.671 0.059 0.144

R R R R R R

21.1 0.0 3.2 0.0 46.3 25.2

1.00 0.74 0.10 0.58 0.58 0.23

0.30 0.50 0.06 0.64 0.16 0.08

Caucasian populations

e2/e3 versus e3/e3 e2/e2 versus e3/e3 e3/e4 versus e3/e3 e4/e4 versus e3/e3 e2 versus e3 e4 versus e3

0.78 0.81 2.02 1.28 0.75 1.17

(0.52–1.16) (0.35–1.86) (0.77–5.32) (0.43–3.75) (0.58–0.97) (0.90–1.52)

0.213 0.618 0.148 0.658 0.030 0.237

R R R R R R

0.0 0.0 40.6 21.8 0.0 43.0

0.71 1.00 0.26 1.00 0.27 1.00

0.81 – 0.18 0.75 0.65 0.41

Asian populations

e2/e3 versus e3/e3 e2/e2 versus e3/e3 e3/e4 versus e3/e3 e4/e4 versus e3/e3 e2 versus e3 e4 versus e3

0.75 (0.51–1.09) 0.90 (0.48–1.71) 1.07 (0.88–1.32) 0.71 0.33–1.52) 0.83(0.59–1.18) 1.08 (0.89–1.31)

0.133 0.747 0.496 0.376 0.229 0.428

R R R R R R

43.3 0.0 0.0 0.0 61.1 14.4

1.00 0.63 0.30 0.15 0.73 0.45

0.33 0.21 0.15 0.33 0.24 0.09

LLD

e2/e3 versus e3/e3 e2/e2 versus e3/e3 e3/e4 versus e3/e3 e4/e4 versus e3/e3 e2 versus e3 e4 versus e3

0.77 0.88 1.34 1.76 0.82 1.30

0.071 0.702 0.010 0.240 0.058 0.010

R R R R R R

0.0 0.0 0.0 0.0 0.0 23.0

0.53 0.37 0.16 0.54 0.76 0.58

0.38 0.99 0.14 0.25 0.83 0.19

(0.57–1.02) (0.47–1.67) (1.07–1.68) (0.69–4.49) (0.67–1.01) (1.06–1.59)

* e2, e3 and e4 are alleles of the ApoE gene. LLD = late-life depression (aged P50 years), M⁄ = model of meta-analysis, R = random effects model.

depression in the overall population (e2/e3 versus e3/e3: OR 0.76, 95% CI 0.59–0.99, p = 0.042). The subgroup analyses by ethnicity revealed an association between the ApoE gene polymorphism and depression in the Caucasian populations (e2 allele versus e3 allele: OR 0.75, 95% CI 0.58–0.97, p = 0.030). In the LLD subjects, this analysis found that the e3/e4 genotype and e4 allele were significantly associated with an increased risk of depression (e3/e4 versus e3/e3: OR 1.34, 95% CI 1.07–1.68, p = 0.010; e4 versus e3: OR 1.30, 95% CI 1.06–1.59, p = 0.010).

The sensitivity analyses we performed by sequentially omitting each study did not materially alter the pooled OR except for e2/e3 versus e3/e3 in the overall population and for e2 versus e3 allele in the Caucasian population (Supp. Fig. 1). The sensitivity analyses were also performed based on patients without dementia or AD and the corresponding pooled OR were not substantially altered for all comparisons. Neither the Begg’s test nor the Egger’s test showed any obvious evidence for publication bias in all genetic models. The main results of these analyses are shown in Table 2 and Figure 2, 3.

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(A)

ε2/ε3 vs.ε3/ε3 Study ID

OR (95% CI)

Wang (2001) Shi (2001) Yuan (2006) Sun (2010) Wang (2012) Traykov (2007) You (2009) García-Pe?a (2010) Zubenko(1996) Ohara (1999) Jiao (2007) Zhang (2012) Zong (2012) Huuhka (2005) Fan (2006) Papassotiropoulos (1999) Hwang (2006) Rigaud (2001) Overall (I-squared = 21.1%, p = 0.203)

0.85 1.28 1.46 1.24 0.60 1.28 0.50 0.54 0.46 0.56 0.90 1.18 0.97 0.56 0.03 0.94 0.74 1.21 0.76

% Weight

(0.30, 2.43) 5.06 (0.22, 7.39) 2.06 (0.36, 5.88) 3.14 (0.28, 5.55) 2.74 (0.23, 1.52) 6.14 (0.25, 6.65) 2.32 (0.26, 0.95) 10.39 (0.13, 2.32) 2.89 (0.13, 1.63) 3.76 (0.21, 1.49) 5.67 (0.32, 2.56) 5.11 (0.70, 1.98) 13.34 (0.43, 2.22) 7.38 (0.24, 1.31) 7.13 (0.00, 0.21) 1.63 (0.52, 1.69) 11.55 (0.31, 1.76) 6.87 (0.28, 5.30) 2.83 (0.59, 0.99) 100.00

NOTE: Weights are from random effects analysis .00399

(B)

251

1

ε2 vs.ε3 %

Study

Weight

ID

OR (95% CI)

Traykov (2007)

1.45 (0.46, 4.58) 5.14

García-Pe?a (2010)

0.76 (0.43, 1.34) 21.20

Zubenko(1996)

0.45 (0.14, 1.48) 4.85

Huuhka (2005)

0.58 (0.29, 1.16) 14.15

Papassotiropoulos (1999)

1.03 (0.61, 1.74) 25.05

Rigaud (2001)

1.08 (0.33, 3.49) 4.93

Holmes (1998)

0.37 (0.13, 1.01) 6.56

Butters (2003)

0.64 (0.35, 1.18) 18.10

Overall (I-squared = 0.0%, p = 0.484)

0.75 (0.58, 0.97) 100.00

NOTE: Weights are from random effects analysis .132

1

7.55

Fig. 2. Forest plots for apolipoprotein E gene polymorphism and depression for (A) e2/e3 genotype versus e3/e3 in the overall population and (B) e2 allele versus e3 in the Caucasian populations. CI = confidence interval, OR = odds ratio.

4. Discussion Derived from 2286 patients and 3845 control subjects from 20 case-control studies, this meta-analysis revealed a significant OR of 0.76 for e2/e3 versus e3/e3 in the overall population. Some other

studies have suggested positive associations between total cholesterol levels and depression, [35–37] and the ApoE e2 allele decreases the total cholesterol level [38]. Consequently, serum lipid may be an intermediary factor involved in the mechanism of ApoE gene polymorphism and depression. Given the potentially

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(A)

ε3/ε4 vs.ε3/ε3 Study

%

ID

OR (95% CI)

Weight

Yuan (2006)

1.60 (0.65, 3.93) 6.21

Sun (2010)

1.70 (0.58, 5.00) 4.33

Wang (2012)

0.85 (0.31, 2.36) 4.86

Traykov (2007)

4.28 (1.58, 11.58) 5.06

You (2009)

1.50 (0.74, 3.03) 10.04

García-Pe?a (2010)

1.19 (0.74, 1.91) 22.47

Zubenko(1996)

0.89 (0.34, 2.32) 5.52

Zong (2012)

1.62 (0.69, 3.84) 6.77

Papassotiropoulos (1999)

1.00 (0.59, 1.67) 18.87

Hwang (2006)

1.38 (0.69, 2.76) 10.49

Rigaud (2001)

2.02 (0.77, 5.32) 5.38

Overall (I-squared = 0.0%, p = 0.485)

1.34 (1.07, 1.68) 100.00

NOTE: Weights are from random effects analysis .0863

(B)

1

11.6

ε4 vs.ε3 Study

%

ID

OR (95% CI)

Yuan (2006)

1.58 (0.74, 3.37) 5.82

Sun (2010)

2.00 (0.82, 4.87) 4.45

Wang (2012)

1.34 (0.54, 3.30) 4.36

Traykov (2007)

3.05 (1.45, 6.40) 6.08

You (2009)

1.60 (0.92, 2.81) 9.43

García-Pe?a (2010)

1.16 (0.74, 1.80) 13.03

Zubenko(1996)

0.78 (0.34, 1.82) 4.88

Zong (2012)

1.73 (0.87, 3.42) 6.96

Papassotiropoulos (1999)

1.32 (0.87, 2.02) 13.74

Hwang (2006)

1.04 (0.56, 1.92) 8.14

Rigaud (2001)

1.67 (0.73, 3.79) 5.13

Holmes (1998)

1.07 (0.49, 2.37) 5.46

Butters (2003)

0.76 (0.48, 1.19) 12.53

Overall (I-squared = 23.0%, p = 0.211)

1.30 (1.06, 1.59) 100.00

Weight

NOTE: Weights are from random effects analysis .156

1

6.4

Fig. 3. Forest plot for apolipoprotein E gene polymorphism and depression for (A) e3/e4 genotype versus e3/e3 and (B) e4 allele versus e3 in late-life depression patients. CI = confidence interval, OR = odds ratio.

modifying effect of ethnicity, we also performed subgroup analyses. Results showed that the e2 allele provided protective effects against depression in the Caucasian population. However, in the Asian population, no association between ApoE gene

polymorphism and depression was been observed. Inconsistency in genetic effects across the ethnicities was detected for depression, suggesting that the Caucasian population and the Asian population might have different genetic risks for developing

F. Feng et al. / Journal of Clinical Neuroscience 22 (2015) 1232–1238

depression on account of genetic variation. Our meta-analysis results are not consistent with a previous meta-analysis [16] which found that ApoE gene polymorphism had a statistically significant association with the ApoE e2 allele alone (OR 0.51). These inconsistent results might be due to the smaller sample size from the previous meta-analysis which included only seven case-control studies. Furthermore, 12 of the studies included in our analysis were conducted in Asian populations while previous meta-analysis provided limited Asian population data. In addition, no association was found between the e4 allele and depression in the overall population, as well as in with subgroup analyses from different ethnicities which indicates that the ApoE e4 allele might not play a major role in depression risk, which is in agreement with findings from the previous meta-analysis [16]. To date there are a few studies that have examined the effects of ApoE gene polymorphism among elderly people. Considering that LLD serves as either a precursor or early indicator of AD, there may be common risk factors between AD and LLD, including the ApoE e4 allele [34]. Therefore, a subgroup analysis of LLD patients was performed. Significant associations between the e4 allele and e3/e4 genotype and risk of LLD were detected in this meta-analysis. This could be due to the ApoE e4 allele increasing total cholesterol level [38]. Elderly people are also more prone to high total cholesterol levels. Accordingly, the e4 allele and e3/e4 genotypes were seen to be risk factors for depression in the LLD patients. Given that the ApoE e4 allele is associated with an increased risk of AD, and as depression is a common symptom of AD [39], sensitivity analyses were performed to ascertain whether omission of dementia or AD patients from the study had affected the final results. The corresponding pooled OR were not substantially altered in all genetic models indicating that the results of this meta-analysis were statistically robust. There are previous, conflicting reports about the association between the e4 allele and the age of onset of depression [27,34]. Zubenko et al. [11] and Zong [29] have found inconsistent results regarding the association between the e4 allele and cognitive deficits of geriatric depression patients. However, there were insufficient data to test the association between ApoE gene polymorphism, age of depression onset and cognitive impairment in depressed subjects. Further studies are required to clarify these associations in the future. For better interpretation of our results, several limitations should be acknowledged. Firstly, the sensitivity analyses suggested that some positive effects were not statistically robust, therefore, more well-designed studies are needed to confirm the association. Secondly, only full text articles published in English or Chinese were included in this meta-analysis, missing some eligible studies which were unpublished or reported in other languages. Considering these limitations, our findings should be considered with caution. Despite these limitations, the strengths of this meta-analysis should also be highlighted. Firstly, this meta-analysis has much greater statistical power than those performed previously due to the larger sample size. Secondly, no publication bias was detected, indicating that the pooled results should be unbiased. Finally, this is the first meta-analysis to examine the association between ApoE gene polymorphism and LLD.

5. Conclusion In conclusion, this meta-analysis of 20 studies suggested that the e2/e3 genotype likely provided a protective effect for depression in the overall population. The ApoE e2 allele acted as a protective factor for depression in the Caucasian population. The e4 allele and e3/e4 genotype were associated with an increased risk of depression in the LLD patients. Further, well-designed studies with larger sample sizes are required to confirm our findings.

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Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. Acknowledgements This study was supported by grants from Ren Cai Xiang Mu Program of Anhui Provincial Higher Education Development Plan in 2013. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jocn.2015.02.012. References [1] Boyles JK, Zoellner CD, Anderson LJ, et al. A role for apolipoprotein E, apolipoprotein A-I, and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve. J Clin Invest 1989;83:1015–31. [2] Kamboh MI. Apolipoprotein E polymorphism and susceptibility to Alzheimer’s disease. Hum Biol 1995;67:195–215. [3] Smith AD, Johnston C, Sim E, et al. Protective effect of apo epsilon 2 in Alzheimer’s disease. Oxford Project to Investigate Memory and Ageing (OPTIMA). Lancet 1994;344:473–4. [4] Frisoni GB, Calabresi L, Geroldi C, et al. Apolipoprotein E epsilon4 allele in Alzheimer’s disease and vascular dementia. Dementia 1994;5:240–2. [5] Benjamin R, Leake A, Edwardson JA, et al. Apolipoprotein E genes in Lewy body and Parkinson’s disease. Lancet 1994;343:1565. [6] Elovainio M, Puttonen S, Heponiemi T, et al. Relationship between DRD4 polymorphism and lipid metabolism: what is the role of novelty seeking? Neuropsychobiology 2005;51:53–8. [7] Cardiovascular Risk in Young Finns Study, Elovainio M, Keltikangas-Jarvinen L, et al. Depressive symptoms and C-reactive protein: the Cardiovascular Risk in Young Finns Study. Psychol Med 2006;36:797–805. [8] Copeland JR, Davidson IA, Dewey ME, et al. Alzheimer’s disease, other dementias, depression and pseudodementia: prevalence, incidence and three-year outcome in Liverpool. Br J Psychiatry 1992;161:230–9. [9] Speck CE, Kukull WA, Brenner DE, et al. History of depression as a risk factor for Alzheimer’s disease. Epidemiology 1995;6:366–9. [10] Krishnan KR, Tupler LA, Ritchie JC, et al. Apolipoprotein E-epsilon4 frequency depression. Biol Psychiatry 1996;40:69–71. [11] Zubenko GS, Henderson R, Stiffler JS, et al. Association of the APOE epsilon4 allele with clinical subtypes of late life depression. Biol Psychiatry 1996;40: 1008–16. [12] Fan PL, Chen CD, Kao WT, et al. Protective effect of the apo epsilon2 allele in major depressive disorder in Taiwanese. Acta Psychiatr Scand 2006;113: 48–53. [13] Traykov L, Bayle AC, Latour F, et al. Apolipoprotein E e4 allele frequency in elderly depressed patients with and without cerebrovascular disease. J Neurol Sci 2007;257:280–3. [14] Yumei J, Lisheng S, Yan L, et al. Apolipoprotein E gene polymorphisms and serum lipid characteristics in depressive patients. Shanghai Mental Health Center 2007;19:326–39. [15] Lohmueller KE, Pearce CL, Pike M, et al. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 2003;33:177–82. [16] López-León S, Janssens AC, Gonzalez-Zuloeta Ladd AM, et al. Meta-analyses of genetic studies on major depressive disorder. Mol Psychiatry 2008;13:772–85. [17] DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177–88. [18] Egger M, Davey Smith G, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ 1997;315:629–34. [19] Papassotiropoulos A, Bagli M, Jessen F, et al. Early-onset and late-onset depression are independent of the genetic polymorphism of apolipoprotein E. Dement Geriatr Cogn Disord 1999;10:258–61. [20] Dongxiang W, Zheng L, Shenxun S, et al. A study of the association between unipolar depression and polymorphisms of APOE gene. Shanghai Mental Health Center 2001;13:77–9. [21] Shenxun S, Sanduo J, Dongxiang W, et al. An association of apolipoprotein E gene polymorphisms between depression and dementia. Shanghai Mental Health Center 2001;13:196–8. [22] Yuan YG, Ye Q, Chen Y, et al. A study of serum lipid concentrations and apolipoprotein E genotype among patients with senile depression and Alzheimer disease. Chin Gen Pract 2006;9:106–8. [23] Sun B. Serum levels of BDNF and apolipoprotein E genotype among patients with senile depressive and Alzheimer’s disease [Master’s thesis]. Suzhou University; 2010 [in Chinese].

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