Association between the CETP polymorphisms and the risk of Alzheimer's disease, carotid atherosclerosis, longevity, and the efficacy of statin therapy.

Neurobiology of Aging 35 (2014) 1513.e13e1513.e23

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Association between the CETP polymorphisms and the risk of Alzheimer’s disease, carotid atherosclerosis, longevity, and the efficacy of statin therapy Qing Li a, Ping Huang a, Qian-Chao He b, Quan-Zhen Lin a, Jian Wu a, Rui-Xing Yin a, * a Department of Cardiology, Institute of Cardiovascular Diseases, the First Affiliated Hospital, Guangxi Medical University, Nanning, Guangxi, People’s Republic of China b Department of Neurology, the First Affiliated Hospital, Guangxi Traditional Medical University, Nanning, Guangxi, People’s Republic of China

a r t i c l e i n f o

a b s t r a c t

Article history: Received 31 October 2013 Accepted 30 December 2013 Available online 3 January 2014

The purpose of this meta-analysis was to detect the association between the cholesteryl ester transfer protein gene polymorphisms and the risk of Alzheimer’s disease (AD), carotid atherosclerosis, longevity, and the efficacy of statin therapy. Databases of MEDLINE, EMBASE, BIOSIS, the Cochrane Library, and the Chinese National Knowledge Infrastructure were systematically searched. Thirty-two studies were included in this meta-analysis. There was no difference in the I405V, C629A, and Taq1B polymorphisms between AD and control groups. However, stratified analysis showed that AD group had higher B2B2 genotype frequency than control group in Asian populations with APOE4þ in Taq1B. I405V and Taq1B polymorphisms were not associated with the risk of carotid atherosclerosis and longevity. The efficacy of statin therapy was not associated with Taq1B polymorphism. In conclusion, there was no association between cholesteryl ester transfer protein gene polymorphisms and the risk of AD, carotid atherosclerosis, longevity, and the efficacy of statin therapy in the pooled effects of overall population. However, the B2B2 genotype of Taq1B was associated with increased risk of AD in the Asian populations with APOE4þ. Ó 2014 Elsevier Inc. All rights reserved.

Keywords: Cholesteryl ester transfer protein Polymorphisms Alzheimer’s disease Carotid atherosclerosis Longevity Efficacy of statin therapy Meta-analysis

1. Introduction Alzheimer’s disease (AD), carotid atherosclerosis, and dyslipidemia result in diminished quality of life, life-years lost, and enormous medical costs. Therefore, it is necessary to detect the association of genetic variants and these diseases. Recently, the association of cholesteryl ester transfer protein (CETP) gene and dyslipidemia, the risk of AD, carotid atherosclerosis, longevity, or the efficacy of statin therapy has been widely reported (Agerholm-Larsen et al., 2000; Al-Daghri et al., 2003; Bauerfeind et al., 2002; Bercovich et al., 2006; Fiegenbaum et al., 2005; Murphy et al., 2012; Parra et al., 2012; Qureischie et al., 2009; Soyal et al., 2011; Winkelmann et al., 2003; Yu et al., 2012). Plasma CETP is an extremely hydrophobic glycoprotein with a relative molecular mass of 74,000, and consists of 476 amino acids with 4 Nlinked glycosylation sites. The human CETP spans approximately 25 kb, encompasses 16 exons, and is found on chromosome 16q13.

* Corresponding author at: Department of Cardiology, Institute of Cardiovascular Diseases, the First Affiliated Hospital, Guangxi Medical University, 22 Shuangyong Road, Nanning 530021, Guangxi, People’s Republic of China. Tel.: þ86-7715326125; fax: þ86-771-5353342. E-mail address: [email protected] (R.-X. Yin). 0197-4580/$ e see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.neurobiolaging.2013.12.032

Several polymorphisms have been identified in the human CETP (Corbex et al., 2000). CETP regulates cholesterol homeostasis via the transfer of cholesteryl esters from high-density lipoprotein cholesterol (HDL-C) to low-density lipoprotein cholesterol (LDL-C) in exchange for triacylglycerol (TG) (Barter and Kastelein, 2006). Several single-nucleotide polymorphisms within CETP have been suggested to influence enzymatic activity or gene expression level. In particular, Taq1B (rs708272) is characterized by a silent base change affecting the 277th nucleotide in intron 1 of the gene and possesses a restriction site for the endonuclease Taq1. Mutant alleles of the polymorphism in the Taq1B intron 1 in the CETP have been associated with increased HDL-C concentrations (Fidani et al., 2004). The I405V (rs5882) located in exon 14 of the CETP is characterized by alteration in the primary structure of the protein. This polymorphism has been related to plasma CETP concentration and HDL-C concentrations and to the degree of carotid atherosclerosis (Kakko et al., 2000). C629A (rs1800775) within the gene promoter is associated with decreased expression (Dachet et al., 2000). Many studies have proved that dyslipidemia is correlated to the risk of AD, carotid atherosclerosis, and longevity, such as a low concentration of HDL-C have been associated with the risk of AD (Brewer, 2004), carotid atherosclerosis (Soyal et al., 2011), and longevity (Kolovou et al., 2010).

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Q. Li et al. / Neurobiology of Aging 35 (2014) 1513.e13e1513.e23

It is well established that the risk of AD is dependent on APOE genotype and the ε4 allele of APOE (APOE4þ) may be related to AD (Bertram et al., 2007). However, there probably are several other genes that increase the susceptibility for AD. Recent studies of the link between CETP polymorphisms and the susceptibility of AD, carotid atherosclerosis, longevity, or the efficacy of statin therapy have been published, respectively, but the results are equivocal (Arai et al., 2003; Arias-Vasquez et al., 2007; Cellini et al., 2005; Chen et al., 2008; Fidani et al., 2004; Kakko et al., 2000; Kuivenhoven et al., 1998; Rodriguez et al., 2006; Soyal et al., 2011; Winkelmann et al., 2003; Zhu et al., 2005). In many of these studies, the sample sizes were relatively small. Therefore, we performed a meta-analysis of the published studies to derive a more precise estimation of the association. 2. Methods 2.1. Search strategy We sought studies published between January 1970 and July 2013 on CETP I405V, C629A, and Taq1B polymorphisms associated with the risk of AD, carotid atherosclerosis, longevity, and the efficacy of statin therapy. Electronic searches, limited to the English language and the Chinese language, were performed by using MEDLINE via PubMed, EMBASE, BIOSIS, Science Citation Index, the Cochrane Library database, and the Chinese National Knowledge Infrastructure database, and supplemented by scanning reference lists of articles identified for all relevant studies and review articles. The computer-based searches combined search terms related to “cholesteryl ester transfer protein,” “CETP”, “I405V (rs5882)”, “C629A (rs1800775)” or “Taq1B (rs708272)”, “polymorphism”, “Alzheimer’s disease”, “longevity”, “carotid atherosclerosis”, and “efficacy of statin therapy”. The previously mentioned search strategy described was used to obtain titles and abstracts of studies

that may have been relevant to this review. The titles and abstracts were screened by 2 authors (Qing Li and Ping Huang), who discarded studies that were not applicable. When multiple reports from the same patients were found, only the study with the most complete data set was included in the meta-analysis. But duplicate patients of different articles that have different types of data of outcomes were included. Any disagreements were arbitrated by discussion with the other reviewer (Rui-Xing Yin). 2.2. Included and excluded studies The selection criteria for studies to be considered for this metaanalysis were as follows: (1) the studies published in peer-reviewed journals with full available text in English or in Chinese; (2) the CETP gene I405V, C629A, and Taq1B polymorphisms and the risk of AD, carotid atherosclerosis, longevity, or the efficacy of statin therapy; and (3) reporting at least 1 relevant outcome of association between genotype and the risk of AD, carotid atherosclerosis, longevity, or the efficacy of statin therapy. Excluded studies: studies in which it was not possible to extract data from the published results or from the authors as well as those studies that did not report appropriate outcomes were also excluded. 2.3. Types of outcome measures The types of outcome measures were as follows: (1) relationship between the risk of AD and genotypes; (2) relationship between longevity and genotypes; (3) relationship between carotid atherosclerosis and genotypes; and (4) relationship between efficacy of statin therapy on serum lipid levels (TC (cholesterol), TG, HDL-C, and LDL-C) and genotypes. The diagnosis of AD was made in accordance with accepted criteria for dementia (DSM-III-R) (Association, 1987) and Alzheimer’s disease (NINDS-ADRDA) (McKhann et al., 1984). Longevity included nonagenarian and

Fig. 1. Flow chart showing study selection process.


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Fig. 2. Forest plot of the association between I405V polymorphism and the risk of AD, (genetic model: VV vs. VV þ VI þ II). Abbreviations: AD, Alzheimer’s disease; CI, confidence interval.

centenarian groups. The structure measured of carotid atherosclerosis was intima-media thickness, which was defined as the distance between the mediaeadventitia interface and the lumeneintima interface. Statins included pravastatin, atorvastatin, simvastatin, and fluvastatin. 2.4. Data extraction and management The following data were extracted independently by 5 investigators (Qing Li, Ping Huang, Qian-Chao He, Quan-Zhen Lin, and Jian Wu): first author, year of publication, sample size, diagnostic criteria, study design, genotype information (number of genotypes, genotype distribution), relationship between genotypes, and the risk of AD, longevity, carotid atherosclerosis, or the effect of statin therapy. Discrepancies were resolved by discussion and by adjudication of the other reviewer (Rui-Xing Yin). When repeated publications of the same trial were identified, data were extracted from the repeated publications and reported as a single trial. 2.5. Quality assessment The Newcastle-Ottawa Scale (NOS) (Wells et al., 2000) was used to assess the quality of each included study of the AD and longevity group. Eight items were contained in the NOS (Supplementary Table 1). It was categorized into 3 dimensions including selection, comparability, and exposure for caseecontrol studies. Items (4, 1, and 3) were contained in the selection, comparability, and

exposure, respectively. A star system was used to allow a semiquantitative assessment of the study quality. A study can be awarded a maximum of 1 star for each numbered item within the selection and exposure categories. A maximum of 2 stars can be given for comparability. The NOS ranges from 0 up to 9 stars. High-, medium-, and poor-quality studies should be achieved for >7, 4 to 6, and 0.05). Allele frequencies of each study were determined by the allele counting method. We carried out statistical analysis by the Review Manager software 5.1.0 (updated in March 2011 by the Cochrane Collaboration). Dichotomous outcomes were expressed as odds ratio (OR) with 95% confidence intervals (CI). Continuous variables were expressed as mean difference (MD) or standardized mean difference (SMD) (when variables were measured by different units) with 95% CI. The pooled effects were calculated using random effects models when there was significant heterogeneity, but the fixed effects model was analyzed to ensure robustness of the model chosen and susceptibility to outliers, or using fixed effects models when there was no significant heterogeneity, but the random effects model was analyzed to ensure robustness of the model chosen and susceptibility to outliers. The point estimate of the OR was considered

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statistically significant at the 2-tailed p 0.05 level. For the sensitivity analyses, we performed stratified analysis by ethnicity of Asian and European, or analyzed another model chosen, or eliminated the study with fewer than 100 patients in each group. Heterogeneity was analyzed using a c2 test on N1 degrees of freedom. I2 values of 25%, 50%, and 75% correspond to low, medium, and high levels of heterogeneity, respectively. If enough studies were identified, funnel plots were to be used to investigate reporting biases.

Kolovou et al., 2013a; Kuivenhoven et al., 1998; Li et al., 2008; Miltiadous et al., 2005; Mohrschladt et al., 2005; Winkelmann et al., 2003; Zhang et al., 2008) (Figs. 2e7). The main characteristics of each study were shown in Table 1. The quality of all included studies that associated between the polymorphisms and the risk of AD, and longevity were assessed by NOS (Table 2). Most studies were of medium or high quality in terms of selection and exposure. However, as for comparability, the quality was relativity low, because some of confounders were not to be adjusted for in the analysis.

3. Results 3.1. Characteristics of included studies Thirty-two studies, 26 in English and 6 in Chinese with 19,973 patients met the included criteria for this meta-analysis (Fig. 1). Therefore, the meta-analyses in evaluation of the risk of AD included 12 eligible studies that contained 11,530 participants (Arias-Vasquez et al., 2007; Chen et al., 2008, 2012; Fidani et al., 2004; Murphy et al., 2012; Qureischie et al., 2008, 2009; Rodriguez et al., 2006; Shi et al., 2012b; Xiao et al., 2012; Yu et al., 2012; Zhu et al., 2005), the risk of carotid atherosclerosis included 3 eligible studies that contained 2338 participants (Kakko et al., 2000; Parra et al., 2012; Soyal et al., 2011), the longevity included 8 eligible studies that contained 4199 participants (Arai et al., 2003; Cellini et al., 2005; Kolovou et al., 2010, 2013b; Novelli et al., 2008; Pan et al., 2012; Sun et al., 2007; Zhang et al., 2011), and the relationship between genotypes and the efficacy of statin therapy included 9 eligible studies that contained 1906 participants (Bercovich et al., 2006; Fiegenbaum et al., 2005;

3.2. Frequencies of the genotype Frequencies of the genotypes of all the polymorphisms in each group and all p-values of HWE testing were shown in Supplementary Table 2. The genotype distributions of 2 polymorphisms in 2 eligible studies were not consistent with HWE (p < 0.05) (Xiao et al., 2012; Yu et al., 2012). 3.3. Outcomes of the risk of AD For I405V polymorphism, there was no difference in the subjects of APOE4þ (OR: 0.86, 95% CI: 0.62e1.20, p ¼ 0.38), APOE4 (OR: 1.18, 95% CI: 0.93e1.49, p ¼ 0.17), and their total effect (OR: 1.04, 95% CI: 0.89e1.21, p ¼ 0.64) in the VV/II þ IV þ VV value between AD and control groups (Fig. 2). For C629A polymorphism, there was no difference in the subjects of APOE4þ (OR: 0.56, 95% CI: 0.19e1.61, p ¼ 0.28), APOE4 (OR: 1.35, 95% CI: 0.76e2.42, p ¼ 0.31), and their

Fig. 3. Forest plot of the association between C629A polymorphism and the risk of AD (genetic model: AA vs. CC þ CA þ AA). Abbreviations: AD, Alzheimer’s disease; CI, confidence interval.


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Fig. 4. Forest plot of the association between Taq1B polymorphism and the risk of AD in the overall population (A) and in Asian population (B), (genetic model: B2B2 vs. B1B1 þ B1B2 þ B2B2). Abbreviations: AD, Alzheimer’s disease; CI, confidence interval.

total effect (OR: 1.05, 95% CI: 0.78e1.41, p ¼ 0.76) in the AA/CC þ CA þ AA value between AD and control groups (Fig. 3). For Taq1B polymorphism, there was no difference in the subjects of APOE4þ (OR: 1.67, 95% CI: 0.39e7.18, p ¼ 0.49), APOE4 (OR: 1.29, 95% CI:

0.84e1.79, p ¼ 0.24), and their total effect (OR: 1.20, 95% CI: 0.86e1.28, p ¼ 0.28) in the B2B2/B1B1 þ B1B2 þ B2B2 value between AD and control groups (Fig. 4A). However, in the stratified analysis by ethnicity of Asian and European, the pooled effects

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Fig. 5. Forest plot of the association between CEPT polymorphisms and carotid atherosclerosis (genetic model: AA vs. AGþ GG). Abbreviations: CI, confidence interval; SD, standard deviation.

indicated that AD group had higher B2B2 genotype frequency than control group in Asian populations with APOE4þ in Taq1B polymorphism (OR: 3.46, 95% CI: 1.57e7.60, p ¼ 0.002) (Fig. 4B).

(MD: 0.03, 95% CI: 0.01 to 0.07, p ¼ 0.15) and in Taq1B polymorphism between B1B2 þ B2B2 and B1B1 groups (MD: 0.01, 95% CI: 0.00 to 0.02, p ¼ 0.28).

3.4. Outcomes of the risk of carotid atherosclerosis

3.5. Outcomes of longevity

As shown in Fig. 5, there was no difference of intima-media thickness in I405V polymorphism between IV þ VV and II groups

As shown in Fig. 6, the pooled effects indicated that there was no difference in I405V polymorphism (OR: 0.87, 95% CI: 0.50e1.53,

Fig. 6. Forest plot of the association between CEPT polymorphisms and longevity. Abbreviation: CI, confidence interval.


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Fig. 7. Forest plot of the association between TaqB1 polymorphism and efficacy of statin therapy. Abbreviations: CI, confidence interval; SD, standard deviation.

p ¼ 0.63) and in Taq1B polymorphism (OR: 1.11, 95% CI: 0.80e1.53, p ¼ 0.53) between longevity and control groups. 3.6. Efficacy of statin therapy on serum lipid levels As shown in Fig. 7, the pooled effects indicated that there was no difference in TC (SMD: 0.00, 95% CI: 0.12 to 0.11, p ¼ 0.98), TG (SMD: 0.07, 95% CI: 0.04 to 0.18, p ¼ 0.24), HDL-C (SMD: 0.01, 95% CI: 0.10e0.12, p ¼ 0.79), and LDL-C (SMD: 0.06, 95% CI: 0.17e0.05, p ¼ 0.29) in the efficacy of statin therapy in TaqB1 polymorphism between B1B2 þ B2B2 and B1B1 groups. 3.7. Sensitivity analysis Sensitivity analyses of AD of Taq1B polymorphism: in the stratified analysis by ethnicity of Asian and European, we removed the study by Fidani et al. (2004) of European population, the corresponding pooled OR was altered in APOE4þ (OR: 3.46, 95% CI: 1.57e7.60, p ¼ 0.002). We removed the study by Yu et al. (2012) and Xiao et al. (2012) in the meta-analysis because of the genotype distribution in the control groups of the study deviating from HWE (in the overall population), we found that the corresponding pooled SMD was not substantially altered. In the stratified analysis of I405V and C629A of AD by ethnicity of Asian and European, the corresponding pooled OR was not substantially altered. Sensitivity analyses of longevity in I405V and Taq1B polymorphisms: in the stratified analysis by ethnicity of Asian and European, the corresponding pooled OR was not substantially altered. Sensitivity analyses of efficacy of statin therapy in Taq1B

polymorphism: in the stratified analysis by ethnicity of Asian and European, and eliminating the studies with more than 300 patients or 50%, and the p-values of heterogeneity test were 55

>55

Qureischie et al. Chen et al. Shi et al. Xiao et al. Kolovou et al.

2008 2012 2012 2012 2010

Germany China China China Greece

351/338 100/102 184/205 104/104 69/67

68/53.4 58.8/63.0 nr 45.2/46.2 nr

72.5 8.8 77.5 7.3 nr 77.8 6.74 nr

72.4 7.9 77.0 6.3 nr 76.5 6.14 nr

Arai et al.

2003

Japan

256/190

74.2/54.7

100.9 1.6

40.0 11.2

Novelli et al.

2008

Italy

749/355

64.5/53.8

99.8 9.5

27.4 7.6

Cellini et al.

2005

Italy

175/189

nr

99.6 2.6

69.2 8.3

Pan et al.

2012

China

523/498

64.8/49.2

93.38 3.06

53.12 8.86

Zhang et al. Kolovou et al.

2011 2013

China Greece

276/301 202/105

nr 61.0

>95 nr

nr nr

Sun et al. Parra et al.

2007 2012

China Brazil

191/53 d/207

31.4/45.3 d/75

97 3 d

67 3 49 15

Kakko et al.

2000

Finland

515

d/50.9

d

40e61

Soyal et al.

2011

Austria

d/38.9

d

40e70

Mohrschladt et al.

2001

Netherlands

300/d

52.3/d

15e72

d

Kolovou et al.

2012

Greece

586/d

30.7/d

57.2 13.1

d

Fiegenbaum et al. Winkelmann et al.

2005 2003

Brazil USA

99/d 98/d

74.6/d 28/d

59.2 10.7 63 10

d

Miltiadous et al. Kuivenhoven et al. Bercovich et al. Zhang et al. Li et al.

2005 1998 2006 2008 2008

Greece Netherlands Israel China China

49/d 411/d 76/d 140/d 147/d

63/d nr nr 46.4/d 29.3/d

44 15 56 7 nr 66.49 10.96 56.69 12.51

d/1616

d

Dementia and/or AD follows the NINCDS-ADRDA criteria AD or mild cognitive impairment subjects from the Alzheimer’s Disease Neuroimaging Initiative cohort . Vascular dementia diagnosed according to DSM-IV AD diagnosed according to the NINCDS-ADRDA criteria Sporadic AD patients met the NINCDS-ADRDA criteria AD diagnosed according to the NINCDS-ADRDA criteria AD was diagnosed according to the NINCDS-ADRDA criteria Dementia and/or AD was diagnosed according to the DSM-III-R and NINCDS-ADRDA criteria. AD was diagnosed according to DSM-IV criteria. AD diagnosed according to the NINCDS-ADRDA criteria AD diagnosed according to the NINCDS-ADRDA criteria AD diagnosed according to the NINCDS-ADRDA criteria Plasma HDL-C >70 mg/dL, at least 1 relative older than the age of 90 years old, no history of CVD disease. Using national registry of centenarians published by Ministry of Health, Welfare, and Labor. Longevity: proof of age according to a birth certificate, functional independence, and normal cognitive status. Good health long-lived individuals did not present the more common age-related pathologies. The ages were defined by dates of birth as stated on identity cards. All subjects were essentially healthy. Healthy long-lived individuals. The age 90e98 years in nonagenarians and 99 years in centenarians. Healthy long-lived individuals. Longitudinal measurements of segments of the common carotid arteries at the distal wall and 1 cm from the bifurcation were performed. IMT was defined as the distance between the media eadventitia interface and the lumeneintima interface. IMT of the common and internal carotid arteries and the bifurcations were measured. Simvastatin (20e40 mg/d), pravastatin (40 mg/d), or atorvastatin (20e40 mg/d) for at least 6e8 wk. Atorvastatin (10e40 mg/d) or simvastatin (10e40 mg/d) for at least 6 mo. Simvastatin 20 mg/d for 6 mo. A median of 5 wk of treatment with pravastatin, cerivastatin, or atorvastatin. Atorvastatin 20 mg/d for 12 wk. Pravastatin sodium at a dose of 40 mg/d for 2 y. Fluvastatin capsules at daily doses of 40 mg for 20 wk. Simvastatin 20 mg/d for 4 wk. Simvastatin 20 mg/d for 3 mo.

Key: AD, Alzheimer’s disease; CVD, cardiovascular disease; FH, familial hypercholesterolemia; HDL-C, high-density lipoprotein cholesterol; IMT, intima-media thickness; nr, no recorded; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, fourth edition; NINCDS-ADRDA, U.S. National Institute of Neurological, language barrier and Stroke Society Institute and a senile dementia-related diseases. a Reported for total cohort participants.

of statin therapy have been widely examined, including CETP, CR1, BIN1, and APOE (a well-known susceptibility locus related to AD) and so on (Combarros et al., 2009; Shi et al., 2012a). It may conclude that AD, carotid atherosclerosis and longevity are both multifactorial and polygenic in nature. HDL-C is essential in limiting the amount of cholesterol deposition and removing excess cholesterol load in the cell, and reduced levels of HDL have been associated with these diseases (Brewer, 2004). CETP regulates cholesterol homeostasis via the transfer of cholesteryl esters from HDL-C to LDL-C in exchange for TG (Barter and Kastelein, 2006). I405V, C629A, and Taq1B polymorphisms within CETP have been suggested to influence enzymatic activity or gene expression level. Many investigators carried out studies to determine the association between these polymorphisms and the risk of AD, carotid atherosclerosis, longevity, or the efficacy

of statin therapy on serum lipid levels, but the results are inconclusive. This may be because of a small sample size. The characteristic of a meta-analysis is to obtain a more competitive result by combining the comparable studies, increasing the sample size and statistical power. As our results showed, there was no difference in I405V, C629A, and Taq1B polymorphisms between control and AD groups. In the stratified analysis by ethnicity of Asian and European, the pooled effects indicated that AD group had higher B2B2 genotype frequency than control group in Asian populations with APOE4þ in Taq1B polymorphism. There was no difference in I405V and Taq1B polymorphisms between longevity and control groups. I405V and Taq1B polymorphisms were not associated with carotid atherosclerosis in pooled effects of the overall population or ethnicity of Asian and European. There was no difference

Q. Li et al. / Neurobiology of Aging 35 (2014) 1513.e13e1513.e23 Table 2 Quality assessment for all the included studies of AD and longevity First author

Publishing year

Selection

Comparability

Exposure

Yu et al. Murphy et al. Qureischie et al. Chen et al. Rodríguez et al. Fidani et al. Zhu et al. Arias-Vásquez et al. Qureischie et al. Chen et al. Shi et al. Xiao et al. Kolovou et al. Arai et al. Novelli et al. Cellini et al. Pan et al. Kolovou et al. Zhang et al. Sun et al.

2012 2012 2009 2008 2006 2004 2005 2007

qqqq

qq

qq

qqq

q

qqq

qqq

qq

qq

qqq

qq

qq

qqq

d

qq

qqq

q

qq

qqq

qq

qqq

qqq

d

qq

2008 2012 2012 2012 2010 2003 2008 2005 2012 2013 2011 2007

qqq

qq

qq

qqq

q

qq

qqq

d

qq

qqqq

q

qq

qqq

q

qqq

qqq

q

qqq

qqq

q

qq

qqq

q

qq

qqqq

d

qqq

qq

q

qq

qq

q

qq

qqqq

qq

qq

The NOS ranges from zero up to nine stars. High-, medium-, and poor-quality studies should be achieved more than seven, four to six, and less than four stars; respectively.

between efficacy of statin therapy and different genotypes in Taq1B polymorphism. In the present study, however, we included 32 studies with 19,973 participants, which greatly increased the amount of sample size so that the CI became smaller and the accuracy of results increased. Baseline characteristics of 2 comparison groups of included studies were substantially similar. The quality of all the included studies that associated between polymorphism and the risk of AD and longevity was assessed by NOS and most studies were of medium or high quality. In addition, most heterogeneities of pooled effects were low, such as AD in I405V polymorphism, longevity and carotid atherosclerosis in Taq1B polymorphism, the efficacy of statin therapy in 3 polymorphisms and AD of Asian populations in Taq1B polymorphism and so on. OR of the risk of AD in Asian populations of APOE4þ in Taq1B polymorphism was large effect. All these made our conclusion more robust. Heterogeneity analysis showed significant heterogeneity in the outcomes of AD in Taq1B and longevity in I405V. To explore the sources of heterogeneity, we performed subgroup analyses

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stratified by ethnicity of Asian and European, heterogeneity decrease. This may be because of different genetic background and environmental factors between Asian and European. In addition, AD, longevity, and the efficacy of statin treatment are affected by genetic and environmental factors, such as dietary patterns, lifestyle, obesity, and physical inactivity (Yin et al., 2012). Moreover, pharmaceuticals, age, gender, and hypertension are also associated with serum lipid levels. Some limitations of this meta-analysis should be discussed. First, this meta-analysis focused only on papers published in the English and Chinese languages and the ones that reported in other languages may bias the present results. Second, some metaanalyses of some outcomes in these polymorphisms included little eligible studies that contained small participants. In addition, geneegene and geneeenvironment interactions should also be considered in the analysis. Therefore, it is necessary to conduct larger sample studies using homogenous patients and well-matched controls. Moreover, geneegene and geneeenvironment interactions should also be considered in the analysis. Such studies taking these factors into account may eventually lead to better, more comprehensive understanding of the association between these polymorphisms and the risk of AD, carotid atherosclerosis, longevity, and the efficacy of statin treatment. In conclusion, there is an association between the Taq1B polymorphism and the risk of AD in the Asian populations with APOE4þ, and the B2B2 genotype is associated with increased risk of AD. There is no difference in the risk of AD, carotid atherosclerosis, longevity, and the efficacy of statin therapy in different genotypes of I405V, C629A, and Taq1B polymorphisms in the pooled effect of overall population.

Disclosure statement The authors have no actual or potential conflicts of interest. All the studies had been approved by the Ethics Committee of their institutions, in accordance with the Helsinki Declaration of 1975 as revised in 1983, and all subjects had given informed consent.

Acknowledgements This study was supported by the National Natural Science Foundation of China (no: 81200205 and no: 30960130).

Table 3 Sensitivity analysis Association

Taq1B The risk of AD Longevity Efficacy of statin therapy in TC Efficacy of statin therapy in TG Efficacy of statin therapy in HDL Efficacy of statin therapy in LDL I405V The risk of AD Longevity

Total

Asia

OR and/or SMD (95% CI)

p-value

1.20 (0.86, 0.68) 0.63 (0.80, 1.53) 0.02 (0.12, 0.11)

0.28 0.53 0.98

1.18 (0.04, 0.18)


Europe

Consistent with HWE

N > 100

p-value


p-value


p-value


p-value

1.38 (0.90, 2.12) 1.17 (0.83, 1.66) 0.05 (0.57, 0.68)

0.15 0.37 0.87

0.96 (0.56, 1.64) 1.14 (0.63, 2.06) 0.01 (0.14, 0.12)

0.24 0.67 0.88

1.07 (0.80, 1.43) NA NA

0.66 NA NA

NA NA 0.01 (0.13, 0.11)

NA NA 0.91

0.24

0.12 (0.14, 0.38)

0.36

0.04 (0.13, 0.20)

0.38

NA

NA

0.11 (0.01, 0.23)

0.07

0.26 (0.10, 0.12)

0.79

0.10 (0.16, 0.36)

0.47

0.05 (0.14, 0.23)

0.61

NA

NA

0.05 (0.17, 0.07)

0.41

1.06 (0.17, 0.05)

0.29

0.13 (0.84, 0.57)

0.71

0.04 (0.16, 0.08)

0.63

NA

NA

0.08 (0.20, 0.04)

0.18

1.04 (0.89, 1.21) 0.48 (0.50, 2.39)

0.64 0.30

1.10 (0.74, 1.64) 0.56 (0.19, 1.65)

0.63 0.30

1.03 (0.87, 1.22) 1.04 (0.75, 1.43)

0.77 0.82

1.03 (0.87, 1.21) NA

0.76 NA

NA NA

NA NA

Key: AD, Alzheimer’s disease; CI, confidence interval; HDL, high-density lipoprotein; HWE, Hardy-Weinberg equilibrium; LDL, low-density lipoprotein; NA, Not available; OR, odds ratio; SMD, standardized mean difference; TC, cholesterol; TG, triacylglycerol.

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