Open Access

Association between the APOB XbaI and EcoRI polymorphisms and lipids in Chinese: a meta-analysis

Lipids in Health and Disease201514:123

https://doi.org/10.1186/s12944-015-0125-z

Received: 3 September 2015

Accepted: 29 September 2015

Published: 7 October 2015

Abstract

Background

No previous meta-analysis was to report the association between the apolipoprotein B (APOB) XbaI and EcoRI polymorphisms and serum lipids in Chinese. We performed the study to investigate their potentially association.

Methods and Results

Studies in English and Chinese were found via a systematic search of Pubmed, Embase, CNKI and Wanfang databases. The dominant genetic model and random-effects model were used to pool data from individual studies. As a result, a total of 30 articles with 5611 subjects for XbaI and 2653 subjects for EcoRI were included in the current study. For the XbaI polymorphism, overall, subjects carrying X+ allele were significantly associated with higher TC,TG and LDL compared with X-X- genotype (Pvalue =0.0006, OR (95 %) = -0.55 (-0.86,-0.23); Pvalue = 0.0004, OR (95 %) = -0.30 (-0.47,-0.14); (Pvalue = 0.05, OR (95 %) = -0.23(-0.46,-0.00), respectively). Similar results were observed in the subgroups of Han, healthy individuals (HT), coronary heart disease (CHD), cerebral infarction (CI), and cholelithiasis. For HDL, positive association between X+ allele with Lower lipid value was found in CHD and CI subgroups. For EcoRI polymorphism, overall, the E- allele carriers were found to be obviously linked with elevated LDL and lower HDL compared with E + E+ genotype (Pvalue = 0.02,OR (95 %) = -0.27 (-0.49,-0.05); Pvalue = 0.01, OR (95 %) = 0.17 (0.03, 0.30), respectively). TC was significantly high in subjects carrying E- allele in the subgroup of hyperlipidemia. No evidence of publication bias was observed.

Conclusions

The two genetic variants of APOB may be associated with serum lipids in Chinese.

Keywords

Apolipoprotein B or APOBChineseLipidPolymorphism

Introduction

Many epidemiological studies have reported that metabolic disorders in serum lipids are considerable risk factors for premature coronary artery disease and atherosclerosis [1]. Serum lipids are multifactorial that emphasize the contribution of genetic as well as environmental factors. Genetically determined variation has been shown to have a close relationship with the metabolism abnormality of lipids and the pathogenesis of atherosclerosis [2, 3]. Although no convincing gene has been found to be of the importance for lipids, the obvious candidate genes are still necessary for a better understanding of lipid metabolism.

Apolipoprotein B (APOB) is an important protein component in contribution to intermediate density lipoprotein, the formation of very low density lipoprotein, low density lipoprotein particle, and is related to the clearance of LDL in serum. Beside these, it mediates cellular uptake of cholesterol and is the ligand that binds to the LDL receptor [4]. The gene coding for APOB has been cloned and is located on the short arm of chromosome 2 (q23q24). Many variants of the APOB gene has been found to be directly linked with lipid levels. In our study, among these variants, we paid particular attention to the most investigated XbaI (rs693 ) in exon 26 and EcoRI (rs1042031) in exon 29 single nucleotide polymorphisms in the APOB gene.

A meta-analysis by Boekholdt et al. [5] ten years ago had showed the relationship between the XbaI and EcoRI polymorphisms and lipids in Caucasian subjects. However, no meta-analysis about their association has concentrated on Chinese up to now. The ethnic difference in genetic background between Caucasian and Chinese may result in different findings. Moreover, the results of many published papers for the two polymorphisms in Chinese were inconclusive. Some of them showed strong associations between the XbaI and EcoRI polymorphisms in the APOB gene and serum lipids, whereas others had null association. Therefore, we performed a systematic meta-analysis of all eligible studies investigating the APOB XbaI and EcoRI polymorphisms and their association with serum lipids in Chinese.

Methods

Literature search and selection criteria

To identify the studies evaluating the relationship between the APOB XbaI and EcoRI polymorphisms and lipid profile in Chinese, a computerized literature search of PubMed, EMBASE, Wanfang and CNKI databases was carried out, applying the following keywords: ‘apolipoprotein B or APOB’, ‘polymorphism’, ‘lipid’, ‘Chinese or China or Taiwanese or Taiwan’ (up to September 1, 2015). The articles in English and Chinese would be included. References of the relevant articles were also examined. If multiple articles used the same data, only the more detailed one was selected. The included studies should be accordance with the later criteria: (i) studies evaluating the association of the APOB XbaI and EcoRI polymorphisms with lipids in Chinese, (ii) At least one of the lipid phenotypes was measured: total cholesterol (TC), triglyceride (TG), low density lipoprotein(LDL), and high density lipoprotein(HDL), (iii) Sufficient data involving genotype frequency as well as mean and standard deviation (SD) of lipids, (iv) If the article was a retrospective case-control study, each population (case/control groups) was treated as a single study and genotype frequency among control populations must be tested for Hardy-Weinberg equilibrium (HWE). If the genotype frequency was not supplied or calculated, the writers of these papers would be contacted by emails.

Data extraction

Two of the authors extracted the information from each study independently. Inconsistencies were discussed between the authors to reach an agreement. For each study, the following information would be collected: first author, year, ethnicity, resident region, detection method, sample size, character of participants, and lipid phenotypes of each study.

Statistical analysis

In our study, standardized mean difference (SMD) with their 95 % CIs were used to measure the strength of the association of the APOB XbaI and EcoRI polymorphisms with lipids. For the two polymorphisms, we tested the dominant genetic model (X-X- vs. X + X-/X + X+, E + E+ vs. E + E-/E-E-), because the low frequency of homozygosity for the mutant alleles would yield a large number of studies with zero cell counts, leading to the unreliable estimates, and the X + X-/X + X+ and E + E-/E-E- genotypes in most studies were combined into one group. The random-effects model was used to assess the pooled estimates and the significance of the pooled estimates was determined using a Z-test. Heterogeneity among studies was assessed by the X2-based Q-statistic test and considered significant for P < 0.10 [6]. Subsequently based on racial ground, subgroup analysis was undertaken for Han and non-Han minority in Chinese. In addition, subgroup analysis for the XbaI polymorphism was also planned for healthy individuals (HT), coronary heart disease (CHD), cerebral infarction(CI), hyperlipidemia and cholelithiasis. Subgroup analysis for the EcoRI polymorphism was performed for healthy individuals (HT), coronary heart disease (CHD) and hyperlipidemia. Each subgroup had at least three independent studies. Sensitivity analysis was carried out by removing a single study each time in order to find out whether any single study could bias the overall estimate. Sensitivity analysis were used to detect the cause of heterogeneity when the between-study heterogeneity would exist. Finally, we evaluated publication bias by funnel diagram. The funnel diagram asymmetry, suggesting publication bias, was precisely assessed by Egger’s linear regression test and Begg’s rank correlation test [7, 8] we re-calculated HWE using a web program (http://ihg.gsf.de/cgi-bin/hw/hwal.pl). All data were analyzed with Review Manager 5.0 (Oxford, UK) and STATA 12.0 (Stata Corp., TX, USA). All P values reported were two-sided, and a significance level of less than 0.05 was considered statistically significant.

Results

Inclusion and characteristics of studies

As a beginning analysis, 77 relevant articles were found after literature search and selection. Among these selected studies, 43 articles were removed because their data were overlapping or duplicated. One paper [9] was deleted due to meta-analysis and two [10, 11] were excluded due to lack of the available information. For the EcoRI polymorphism, the data from 3 studies [1214] was excluded as they deviated from HWE. Finally, the remaining 30 articles [1342] with 5611 subjects for XbaI and 2653 subjects for EcoRI were included in this meta-analysis. Among them, Fan et al. [18] was an unpublished theses from the dissertation database, that is, an open sub-database shared by Wanfang and CNKI. 14 articles [1416, 20, 22, 24, 27, 28, 3034, 36] provided the available data on case and controls, which would be respectively handled as the separate two studies for each analysis. For all eligible studies, HWE had been recounted and had to be obeyed. The characteristics of the included studies were showed in Table 1.
Table 1

Main characteristics of the included studies in the meta-analysis

First author,year

Ethnicity

Region

Sample size

SNPs

Character of subjects

Method

Lipid profile

Bai, [15]2008

Han

Ningxia

165

EcoRI

CA/HT

PCR-RFLP

TC,TG,LDL,HDL

Chai, [16] 1996

Han

Shanghai

82

XbaI

CI/HT

PCR-RFLP

TC,TG,LDL,HDL

Evans, [17] 1993

Han

Shanxi

143

XbaI

HT

PCR-RFLP

TG,LDL,HDL

Fan, [18] 2009

Han

Fujian

387

XbaI

Hyperlipidemia

PCR-RFLP

TC,TG,LDL,HDL

Guo, [19] 1996

Han

Liaoning

55

XbaI

CI

PCR-RFLP

TC,TG,LDL,HDL

Han, [20] 2000

Han

Shanghai

631

XbaI

Cholelithiasis/HT

PCR-RFLP

TC,TG,LDL,HDL

Hu, [21] 2008

Han

Guangxi

150

XbaI

PNS

PCR-RFLP

TC,TG,LDL,HDL

Hu, [13] 2009

Han

Guangxi

200

XbaI

HT

PCR-RFLP

TC,TG,LDL,HDL

Ji,[22] 2014

Han

Inner mongolian

120

EcoRI,XbaI

Cholelithiasis/HT

PCR-RFLP

TC,TG,LDL,HDL

Li, [23] 1997

Han

Tianjing

71

EcoRI,XbaI

CHD

PCR-RFLP

TC,TG,LDL,HDL

Liu, [24] 2008

Han

Hunan

230

EcoRI

CI/HT

PCR-RFLP

TC,TG,LDL,HDL

Liu, [25] 2010

Han

Shanghai

186

XbaI

Gastric cancer

PCR-RFLP

TC,LDL

Liu,[26] 2014

Li/Han

Hainan

351

XbaI

HT

PCR-RFLP

TC,TG,LDL,HDL

Ma, [27] 2012

Yao

Guangdong

500

EcoRI,XbaI

Hyperlipidemia/HT

PCR-RFLP

TC,TG,LDL,HDL

Pan, [28] 1995

Han

Taiwan

301

EcoRI,XbaI

CHD/HT

PCR-RFLP

TC,TG,LDL,HDL

Saha, [29] 1992

Han

Singapore

196

EcoRI,XbaI

HT

PCR-RFLP

TC,TG,LDL,HDL

Tan, [30] 2003

Han

Jiangsu

211

EcoRI,XbaI

Cholelithiasis/HT

PCR-RFLP

TC,TG,LDL,HDL

Wang, [31] 1999

Han

Beijing

377

XbaI

CI/HT

PCR-RFLP

TC,TG,LDL,HDL

Wei, [32] 2001

Han

Sichuan

169

XbaI

Cholelithiasis/HT

PCR-RFLP

TC,TG,LDL,HDL

Xie, [33] 2010

Han

Xinjiang

300

EcoRI,XbaI

Hyperlipidemia/HT

PCR-RFLP

TC,TG,LDL,HDL

Yan, [34] 2003

Han

Beijing

257

EcoRI

CHD/HT

PCR-RFLP

TC,TG,LDL,HDL

Yao, [14] 1999

Han

Jiangsu

141

XbaI

CI/HT

PCR-RFLP

TC,TG,LDL,HDL

Yao, [35] 2005

Han

Xinjiang

112

EcoRI,XbaI

fatty liver

DNA chips

TC,TG,LDL,HDL

Ye, [36] 1995

Han

Beijing

203

XbaI

CHD/HT

PCR-RFLP

TC,TG,LDL,HDL

Ye, [37] 2003

Han

Beijing

88

XbaI

Hyperlipidemia

PCR-RFLP

TC,TG,LDL

Zhang, [39] 2009

Han

Hunan

130

XbaI

CI

PCR-RFLP

TC,TG,LDL,HDL

Zhang,[38] 2010

Han

Xinjiang

154

EcoRI

CHD

PCR-RFLP

TC,TG,LDL,HDL

Zhang, [40] 2015

Han

Beijing

82

EcoRI,XbaI

Hyperlipidemia

PCR-RFLP

TC,TG,LDL,HDL

Zhao, [41] 1997

Han

Beijing

117

XbaI

CI

PCR-RFLP

TC,TG,LDL,HDL

Zhu, [42] 2001

Han

Beijing

308

XbaI

HT

PCR-RFLP

TC,TG,LDL,HDL

CA carotid atherosclerosis, HT healthy individuals, CI cerebral infarction, PNS primary nephrotic syndrome, CHD coronary heart disease, PCR-RFLP polymerase chain reaction-restriction fragment length polymorphism, TC total cholesterol, TG triglyceride, LDL low density lipoprotein, HDL high density lipoprotein

In our study, based on the available genotype and allele frequency, we observed that, the X+ allele frequency of XbaI was 7.0 % in the whole population, and the E- allele frequency of EcoRI was 8.0 %, which both obviously had a lower frequency of the mutant allele than the Caucasian population.

Association of the XbaI polymorphism with various lipids

The results of the relationship between the APOB XbaI ploymorphism and lipids in Chinese were shown in Table 2. In this analysis of TC, 5468 subjects (37 studies) were included. Overall, we observed that, TC was significantly high in subjects carrying X+ allele compared with X-X- genotype (P value = 0.0006, OR (95 %) = −0.55 (−0.86,−0.23)). Similar findings were seen in the subgroups of Han (P value = 0.001, OR (95 %) = −0.59 (−0.94,−0.24)), CI (P value = 0.007, OR (95 %) = −0.85 (−1.46,−0.24)) and cholelithiasis (P value = 0.004, OR (95 %) = −0.54 (−0.91,−0.18)). However, no positive association was obtained in the subgroups of non-Han minorities, HT, CHD, and hyperlipidemia. For the TG analysis, 5425 subjects (37 studies) were collected. In the whole population, X+ allele carriers were found to be obviously associated with higher TG value compared with X-X- genotype (P value =0.0004, OR (95 %) = −0.30 (−0.47,−0.14)). Similar results were observed in the subgroups of Han (P value = 0.0009, OR (95 %) = -0.32 (-0.50,-0.13)), HT (P value = 0.05, OR (95 %) = −0.31 (−0.62,0.00)) and CHD (P value = 0.009, OR (95 %) = −0.53 (−0.93,−0.13)). There was no evidence of correlation in the subgroup of non-Han minorities, CI, cholelithiasis and hyperlipidemia.
Table 2

Overall and subgroup associations of the APOB XbaI polymorphism and lipids

Lipids

Overall or subgroups

Studies

Subjects

OR (95 %)

P value

Pheterogenity

Pe

TC

Overall

37

5468

−0.55[−0.86,−0.23]

0.0006

<0.01

0.08

 

Han

34

4812

−0.59[−0.94,−0.24]

0.001

<0.01

 
 

Non-Han minorities

3

651

−0.25[−0.61, 0.10]

0.16

0.08

 
 

HT

16

2708

−0.61[−1.3, 0.07]

0.08

<0.01

 
 

CHD

3

322

0.02[−0.37, 0.42]

0.90

0.71

 
 

CI

6

577

−0.85[−1.46,−0.24]

0.007

<0.01

 
 

Hyperlipidemia

5

957

−0.24[−0.71, 0.22]

0.31

<0.01

 
 

Cholelithiasis

4

456

−0.54[−0.91,−0.18]

0.004

0.11

 

TG

Overall

37

5425

−0.30[−0.47,−0.14]

0.0004

<0.01

0.25

 

Han

34

4774

−0.32[−0.50,−0.13]

0.0009

<0.01

 
 

Non-Han minorities

3

651

−0.19[−0.41, 0.02]

0.08

0.98

 
 

HT

17

2851

−0.31[−0.62, 0.00]

0.05

<0.01

 
 

CHD

3

322

−0.53[−0.93,−0.13]

0.009

0.41

 
 

CI

6

577

−0.50[−1.02, 0.02]

0.06

0.0001

 
 

Hyperlipidemia

5

957

−0.29[−0.62, 0.04]

0.09

0.01

 
 

Cholelithiasis

4

456

−0.11[−0.34, 0.12]

0.36

0.86

 

LDL

Overall

38

5611

−0.23[−0.46,−0.00]

0.05

<0.01

0.80

 

Han

35

4960

−0.23[−0.49, 0.03]

0.09

<0.01

 
 

Non-Han minorities

3

651

−0.26[−0.47,−0.04]

0.02

0.5

 
 

HT

17

2851

−0.21[−0.60, 0.18]

0.29

<0.01

 
 

CHD

3

322

0.15[−0.25, 0.54]

0.47

0.6

 
 

CI

6

577

−0.52[−1.08, 0.05]

0.07

<0.01

 
 

Hyperlipidemia

5

957

0.15[−0.47, 0.78]

0.63

<0.01

 
 

Cholelithiasis

4

456

−0.4[−0.64,−0.17]

0.0007

0.46

 

HDL

Overall

36

5337

0.17[−0.08, 0.41]

0.18

<0.01

0.86

 

Han

33

4686

0.15[−0.12, 0.43]

0.27

<0.01

 
 

Non-Han minorities

3

651

0.24[0.01, 0.47]

0.04

0.33

 
 

HT

17

2851

0.11[−0.43, 0.64]

0.07

<0.01

 
 

CHD

3

322

0.50[0.11, 0.90]

0.01

0.78

 
 

CI

6

577

0.43[0.13, 0.74]

0.005

0.11

 
 

Hyperlipidemia

4

869

0.10[−0.08, 0.27]

0.27

0.97

 
 

Cholelithiasis

4

456

−0.10[−0.33, 0.13]

0.40

0.78

 

TC total cholesterol, TG triglyceride, LDL low density lipoprotein, HDL high density lipoprotein, HT healthy individuals, CHD coronary heart disease, CI cerebral infarction

P value: the significance of the pooled estimate (95 % confidence interval)

Pheterogeneity: the Q statistic for heterogeneity

Pe: Egger’s statistic for publication bias

All results were calculated under the dominant genetic model (X-X- vs. X + X-/X + X+)

For LDL, 5611 subjects (38 studies) were collected. Overall, a marginally positive association between X+ allele with higher lipid value was found (P value = 0.05, OR (95 %) = −0.23 (−0.46,−0.00), Fig. 1). In the subgroup analysis, we also observed the significant association in non-Han minorities (P value = 0.02, OR (95 %) = −0.26 (−0.47,−0.04)) and cholelithiasis (P value = 0.0007, OR (95 %) =−0.4 (−0.64,-0.17)). No statistically significant differences were found in the subgroups of Han, HT, CHD, CI and hyperlipidemia. Finally for HDL, 5337 subjects (36 studies) were analyzed. No significant association was observed in the overall and in the subgroups of Han, HT, hyperlipidemia and cholelithiasis. In the non-Han minorities, CHD and CI subgroups, subjects carrying X+ allele were associated with lower HDL value than X-X- (P value = 0.04, OR (95 %) = 0.24 (0.01, 0.47); P value = 0.01, OR (95 %) = 0.50 (0.11, 0.90; P value = 0.005, OR (95 %) = 0.43 (0.13, 0.74), respectively ).
Fig. 1

Association between the APOB XbaI polymorphism and LDL under the dominant genetic model (X-X- vs. X + X-/X + X+). “X-“ represents the X-X- genotype; X+ represents the X + X-/X + X+ genotypes

Association of the EcoRI polymorphism with various lipids

The results of the relationship between the APOB EcoRI ploymorphism and lipids in Chinese were shown in Table 3. For TC, 2653 subjects (21 studies) were included. A significant association of the E- allele with higher TC was detected in the subgroup of hyperlipidemia (P value < 0.01, OR (95 %) = −0.56 (−0.78,−0.35)). There was no difference in the whole population and in the subgroups of Han, HT and CHD. For TG, 2653 subjects (21studies) were assessed. We found no significant association between the EcoRI ploymorphism and TG in overall and even in the subgroup analysis. For LDL, 2653 subjects (21 studies) were found. Overall, subjects carrying the E- allele were found to be obviously linked with higher LDL compared with E + E+ genotype (P value = 0.02, OR (95 %) = −0.27 (−0.49,−0.05), Fig. 2). Similar result was also shown in the subgroup of Han (P value = 0.04, OR (95 %) = −0.28 (−0.53,−0.02)). In the subgroups of HT, CHD and hyperlipidemia, no significant association was found. For the HDL analysis, 2653 subjects (21studies) were included. Overall, HDL was significantly low in subjects carrying the E- allele compared with E + E+ genotype (P value = 0.01, OR (95 %) = 0.17 (0.03, 0.30)). However, in all the subgroups, there was no significant association.
Table 3

Overall and subgroup associations of the APOB EcoRI polymorphism and lipids

Lipids

Overall or subgroups

Studies

Subjects

OR (95 %)

P value

Pheterogenity

Pe

TC

Overall

21

2653

−0.28[−0.58,0.01]

0.06

<0.01

0.64

 

Han

19

2153

−0.27[−0.61,0.07]

0.11

<0.01

 
 

HT

9

1142

−0.19[−0.89,0.52]

0.61

<0.01

 
 

CHD

4

529

−0.25[−0.56,0.05]

0.1

0.29

 
 

Hyperlipidemia

3

482

−0.56[−0.78,−0.35]

<0.01

0.45

 

TG

Overall

21

2653

−0.14[−0.32,0.03]

0.11

0.003

0.62

 

Han

19

2153

−0.14[−0.34,0.07]

0.19

0.001

 
 

HT

9

1142

−0.01[−0.35,0.34]

0.97

0.002

 
 

CHD

4

529

−0.26[−0.55,0.04]

0.09

0.33

 
 

Hyperlipidemia

3

482

−0.15[−0.49,0.18]

0.37

0.11

 

LDL

Overall

21

2653

−0.27[−0.49,−0.05]

0.02

<0.01

0.51

 

Han

19

2153

−0.28[−0.53,−0.02]

0.04

<0.01

 
 

HT

9

1142

−0.26[−0.59,0.07]

0.13

0.005

 
 

CHD

4

529

−0.21[−0.73,0.31]

0.43

0.01

 
 

Hyperlipidemia

3

482

−0.36[−0.88,0.15]

0.17

0.006

 

HDL

Overall

21

2653

0.17[0.03, 0.30]

0.01

0.2

0.44

 

Han

19

2153

0.13[−0.02, 0.28]

0.09

0.2

 
 

HT

9

1142

0.13[−0.09, 0.35]

0.25

0.25

 
 

CHD

4

529

0.24[−0.03, 0.52]

0.08

0.5

 
 

Hyperlipidemia

3

482

−0.03[−0.44,0.38]

0.89

0.04

 

TC total cholesterol, TG triglyceride, LDL low density lipoprotein, HDL high density lipoprotein, HT healthy individuals, CHD coronary heart disease

Pvalue: the significance of the pooled estimate (95 % confidence interval)

Pheterogeneity: the Q statistic for heterogeneity

Pe: Egger’s statistic for publication bias

All results were calculated under the dominant genetic model (E + E+ vs. E + E-/E-E-)

Fig. 2

Association between the APOB EcoRI polymorphism and LDL under the dominant genetic model (E + E+ vs. E + E-/E-E-). “E + “ represents the E + E+ genotype; E- represents the E + E-/E-E- genotypes

Sensitivity analysis

In the sensitivity analysis, we deleted one study at a time and found whether there was a individual study affecting the pooled SMD and the between-study heterogeneity. For the XbaI polymorphism, the removal of any single study did not obviously affect the heterogeneity and it still exist. However, the overall pooled SMD of LDL was apparently changed with the elimination in turn of eight studies (Chai- HT et al. [16], Guo et al. [19], Li et al. [23], Saha et al. [29], Yao et al. [35], Ye-CHD et al. [36], Ye et al. [37], and Zhang et al. [40]) (data not shown). For the EcoRI polymorphism, no individual study had an obvious influence on the between-study heterogeneity. After removing Saha et al. [29] for TC as well as Pan-HT et al. [28] and Saha et al. [29] for TG, the related overall pooled SMDs were changed (data not shown).

Finally, no significant publication bias was revealed under the dominant genetic model for XbaI (P = 0.08 for TC, 0.25 for TG, 0.8 for LDL, 0.86 for HDL, Table 2) and for EcoRI (P = 0.64 for TC, 0.62 for TG, 0.51 for LDL, 0.44 for HDL, Table 3).

Discussion

Some discrepancies could be caused by differences in ethnic background. Thus, we restricted the analysis to the Chinese population and performed a meta-analysis containing 30 articles with 5611 participants for XbaI and 2653 participants for EcoRI to more precisely understand the relationship between these polymorphisms and lipids in Chinese. So far this meta-analysis was the largest one investigating the association of these two polymorphisms in the AOPB gene with lipid level in Chinese. In the present study, we found that, X+ allele of the XbaI polymorphism was significantly associated with higher TC,TG and LDL in all subject, and E- allele of the EcoRI polymorphism was obviously associated with higher LDL and lower HDL level. Our results involving XbaI were partially consistent with the findings of the previous meta [5]. The difference on the results about EcoRI may be due to the distinct genetic backgrounds of the included populations.

The XbaI polymorphism within the coding region of APOB mRNA is caused by a silent cytosine to thymine mutation in the third base of the threonine codon at residue 2488 in the mature APOB protein, and this site itself is of dubious functional significance. Nevertheless, this polymorphism may be a genetic indicator in linkage disequilibrium with other functional mutations in the APOB gene or a nearby-located gene [43, 44], which can affect the metabolism of serum lipids. Compared with X-allele, X+ allele carriers with higher LDL may be explained by differing clearance by the receptor-mediated pathway of LDL catabolism, and with higher TC/TG may be attributable to the production of a relatively receptor-inactive APOB in the mutational group [45]. As a matter of fact, many studies have reported that, compared with the wild-type genotype, subjects with X+ allele have apparently higher TC,TG, APOB and LDL levels [5, 46, 47]. The APOB EcoRI polymorphism in the coding sequence could result in an acidic basic amino acid substitution, which is non-conservative and has putative importance in APOB protein function [48]. E+ allele carriers in association with abnormal lipid parameters were observed in many studies compared with E- allele carriers [5, 13]. Taken together, APOB plays a critical role in the lipid transport. If the gene encoding APOB has mutational changes, APOB structure and function would be affected and finally lead to lipid metabolism disorder, such as increase of plasma ApoB and LDL, decrease of HDL, etc.

For the Han subgroup, owing to the largest ethnic in Chinese and most related studies included in our meta, the association between the XbaI and EcoRI polymorphism and lipids was largely consistent with the results in the whole population. Irregular results involving the non-Han minorities in Chinese was seemingly understandable in a complex genetic background and limited number of studies. Studies in a larger population based on a single minority are needed for a more clear observation. For the subgroups of HT, CHD, CI and cholelithiasis in the XbaI analysis, our finding were partially in accordance with the published four articles [5, 9, 49-50]. In addition, hyperlipidemia was diagnosed when one of the following four lipids (TC、LDL、HDL and TG ) was more than the normal serum level, and thus the statistical power of the single lipid (such as LDL) to detect differences may be limited due to the smaller involved sample size. For EcoRI, when considering the subgroup analysis of hyperlipidemia, the conclusion may be influenced and should be treated with caution, because sample size of the subgroup as well as study number were relatively small (482 and 3, respectively).

Future related studies in this area should consider several limitations in the present meta-analysis. Firstly, a significant heterogeneity was detected in the analysis, and its contributors may be population source, study design, etc. Secondly, due to the limited number of studies at this time, the subgroup analysis on non-Han minority populations (such as Yao) can not be well done. Thirdly, the analysis did not focus on the detailed functional research of the studied two polymorphisms. Finally, beside genetic influence, the relationship between APOB single nucleotide polymorphisms and lipid profile was also affected by many environmental factors that didn’t be fully conducted in this study, which possibly confounded the results.

In conclusion, our meta-analysis showed significant association between the APOB XbaI polymorphism and lipids (TC, TG and LDL) in Chinese. Similar conclusions were observed in the subgroups of Han, HT, CHD, CI and cholelithiasis. For the AOPB EcoRI polymorphism, the E- allele carriers may be a genetic factor for higher LDL and lower HDL levels in Chinese. Additional studies with larger sample size should be conducted in Chinese to make clear the association of APOB SNPs with lipids. Studies investigating their detailed function were equally needed.

Abbreviations

APOB: 

Apolipoprotein B

TC: 

Total cholesterol

TG: 

Triglycerides

LDL: 

Low-density lipoprotein

HDL: 

High-density lipoprotein

SD: 

Standard deviation

HWE: 

Hardy-Weinberg equilibrium

SMD: 

Standardized mean difference

HT: 

Healthy individuals

CHD: 

Coronary heart disease

CI: 

Cerebral infarction

SNP: 

Single-nucleotide polymorphism

CA: 

Carotid atherosclerosis

PNS: 

Primary nephrotic syndrome

Declarations

Acknowledgements

We are very grateful and thank all the participants in this study. This study was financially supported by the Beijing Natural Science Foundation of China (Grant No. 7120001, 7133232) and the National High-tech Research and Development Projects (863) (No. 2008AA02Z441).

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Hypertension Research, Beijing Anzhen Hospital, Capital Medical University and Beijing Institute of Heart Lung and Blood Vessel Diseases
(2)
Department of cardiology, Beijing Anzhen Hospital, Capital Medical University

References

  1. Burnett JR. Lipids, lipoproteins, atherosclerosis and cardiovascular disease. Clin Biochem Rev. 2004;25:2.PubMed CentralPubMedGoogle Scholar
  2. Heller DA, de Faire U, Pedersen NL, Dahlén G, McClearn GE. Genetic and environmental infuences on serum lipid levels in twins. N Engl J Med. 1993;328:1150–6.View ArticlePubMedGoogle Scholar
  3. Pollin TI, Hsueh WC, Steinle NI, Snitker S, Shuldiner AR, Mitchell BD. A genome-wide scan of serum lipid levels in the Old Order Amish. Atherosclerosis. 2004;173:89–96.View ArticlePubMedGoogle Scholar
  4. Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science. 1986;232:34–47.View ArticlePubMedGoogle Scholar
  5. Boekholdt SM, Peters RJ, Fountoulaki K, Kastelein JJ, Sijbrands EJ. Molecular variation at the apolipoprotein B gene locus in relation to lipids and cardiovascular disease: a systematic meta-analysis. Hum Genet. 2003;113:417–25.View ArticlePubMedGoogle Scholar
  6. Lau J, Ioannidis JP, Schmid CH. Quantitative synthesis in systematic reviews. Ann Intern Med. 1997;127:820–6.View ArticlePubMedGoogle Scholar
  7. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50:1088–101.View ArticlePubMedGoogle Scholar
  8. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.PubMed CentralView ArticlePubMedGoogle Scholar
  9. Gong Y, Zhang L, Bie P, Wang H. Roles of ApoB-100 gene polymorphisms and the risks of gallstones and gallbladder cancer: a meta-analysis. PLoS ONE. 2013;8, e61456.PubMed CentralView ArticlePubMedGoogle Scholar
  10. Saha N, Tong MC, Tay JS, Jeyaseelan K, Humphries SE. DNA polymorphisms of the apolipoprotein B gene in Chinese coronary artery disease patients. Clin Genet. 1992;42:164–70.View ArticlePubMedGoogle Scholar
  11. Su SG, Qin JR, Wei YL. Polymorphism of the apolipoprotein B gene in Zhuang nationality and Han nationality patients with coronary heart disease. Guangxi Yi Ke Da Xue Xue Bao. 2003;20:858–61.Google Scholar
  12. Ye P, Chen BS, Wang SW. Polymorphisms of apolipoprotein B gene in relation to coronary heart disease in Chinese Han nationality. Chin Med J (Engl). 1994;107:30–5.Google Scholar
  13. Hu P, Qin YH, Jing CX, Lu L, Hu B, Du PF. Effect of apolipoprotein B polymorphism on body mass index, serum protein and lipid profiles in children of Guangxi China. Ann Hum Biol. 2009;36:411–20.View ArticlePubMedGoogle Scholar
  14. Yao J, Wang Y, Wang ZZ, Li HJ, Ding XS, Cheng H, et al. Analysis of apoB gene polymorphisms and plasma lipid levels in Chinese patients with atherosclerotic cerebral infraction. Zhongguo Shen Jing Mian Yi Xue Yu Shen Jing Bing Xue Za Zhi. 1999;6:20–2.Google Scholar
  15. Bai YS, Zhou LP, Bai XD, Du QC. Study on the relationship between carotid atherosclerosis diseases and EcoRI & MspI polymorphisms of apolipoprotein B gene. Ningxia Yi Xue Yuan Xue Bao. 2008;30:157–60.Google Scholar
  16. Chai YH, Qin Z, Qin ZJ, Yao JL, Su MF. Xbal polymorphisms of apolipoprotein B gene in relation to atherosclerotic cerebral infarction. Lin Chuang Shen Jing Bing Xue Za Zhi. 1996;9:70–3.Google Scholar
  17. Evans AE, Zhang W, Moreel JF, Bard JM, Ricard S, Poirier O, et al. Polymorphisms of the apolipoprotein B and E genes and their relationship to plasma lipid variables in healthy Chinese men. Hum Genet. 1993;92:191–7.View ArticlePubMedGoogle Scholar
  18. Fan L. Correlation between ApoB and ApoC I gene polymorphisms and lipid-lowering efficacy of atorvastatin. MD. Thesis, Shenyang Yao Ke Da Xue. 2009.Google Scholar
  19. Guo Y, Guo JJ, Wang FW, Wang AH. The relation between apolipoprotein B gene polymorphism and level of plasma lipids in patients with ICVD by polymerase chain reaction. Zhong Feng Yu Shen Jing Ji Bing Za Zhi. 1996;13:339–41.Google Scholar
  20. Han T, Jiang Z, Suo G, Zhang S. Apolipoprotein B-100 gene Xba I polymorphism and cholesterol gallstone disease. Clin Genet. 2000;57:304–8.View ArticlePubMedGoogle Scholar
  21. Hu P, Qin TH, Jing CX, Lei FY, Li MF. Associations of the apoliproprotein E and B gene polymorphisms with hyperlipidemia subsequenced to primary nephrotic syndrome. Zhongguo Xian Dai Yi Xue Za Zhi. 2008;18:3110–9.Google Scholar
  22. Ji J, Liu Y, Yu YL, Shi JS. Relationship between apolipoprotein B gene Xba I and EcoR I polymorphisms and cholelithiasis. Zhonghua Xiao Hua Wai Ke Za Zhi. 2014;13:291–4.Google Scholar
  23. Li FX, Huang TG, Li ZY, Zhou LJ, Liu SY. Relationship between apolipoprotein B gene polymorphisms and lipids metabolism and coronary heart disease. Shi Yong Xin Nao Fei Xue Guan Bing Za Zhi. 1997;5:1–5.Google Scholar
  24. Liu BQ, Zhang L, Yang QD, Liu YH, Hu ZY, Xu HW, et al. The association of apolipoprotein B gene polymorphism with cerebral infarction with positive family history and its effect on plasma lipid levels. Zhonghua Yi Xue Za Zhi. 2008;88:3332–6.PubMedGoogle Scholar
  25. Liu FL, Lu WB, Niu WX. XbaI polymorphisms of apolipoprotein B gene: another risk factor of gallstone formation after radical gastrectomy. World J Gastroenterol. 2010;16:2549–53.PubMed CentralView ArticlePubMedGoogle Scholar
  26. Liu YL, Zhang YB, Li Y, Ma RL, Cai WW, Lin-Jiang L, et al. Correlation between the Xba I polymorphism of apoB gene and serum lipid profiles in Li ethnic group. Asian Pac J Trop Med. 2014;7:63–6.View ArticlePubMedGoogle Scholar
  27. Ma ZZ, Huang WB, He FP, Zhang SB. Relationship between apolipoprotein B gene polymorphisms and lipid levels in Yao population of Yuebei area. Fen Zi Zhen Duan Yu Zhi Liao Za zhi. 2012;4:333–5.Google Scholar
  28. Pan JP, Chiang AN, Tai JJ, Wang SP, Chang MS. Restriction fragment length polymorphisms of apolipoprotein B gene in Chinese population with coronary heart disease. Clin Chem. 1995;41:424–9.PubMedGoogle Scholar
  29. Saha N, Tay JS, Humphries SE. Apolipoprotein B-gene DNA polymorphisms (Xbal and EcoRI), serum lipids, and apolipoproteins in healthy Chinese. Genet Epidemiol. 1992;9:1–10.View ArticlePubMedGoogle Scholar
  30. Tan YF, Yang S, Yu RB, Shen C, Ding WL, Zhou WM, et al. Relationship among the Xba I and EcoR I locus polymorphisms of apolipoprotein B gene, serum lipid metabolism and gallstone disease. Zhonghua Yi Xue Za Zhi. 2003;83:844–7.PubMedGoogle Scholar
  31. Wang LY, Gu Y, Wu GX, Wang W, Liu J, Pan XD. The relation between polymorphisms of apolipoprotein B gene and atherosclerotic cerebral infarction. Zhonghua Yi Xue Za Zhi. 1999;79:603–6.PubMedGoogle Scholar
  32. Wei JB, Lin QY, Chen NS, Zhang MY, Xiao LJ. Relationship among the Xba I locus polymorphisms of apolipoprotein B gene and gallstone disease. Zhonghua Yi Xue Yi Chuan Xue Za Zhi. 2001;18:66–7.Google Scholar
  33. Xie YJ, Huang G, Chi YH. Association of EcoR I and Xba I polymorphisms of apolipoprotein B gene with dyslipidemia and lipid levels. Zhongguo Yi Shi Za Zhi. 2010;11:1452–6.Google Scholar
  34. Yan SK, Li XL, Xue H, Song YH, Yang SD, Chen BS. Relationship between coronary heart disease and EcoRI & MspI polymorphisms of apolipoprotein B gene in Han nationality. Zhonghua Jian Yan Yi Xue Za Zhi. 2003;26:148–52.Google Scholar
  35. Yao H, Xu FL, Zhu B, Zeng BF, Guo G, Zhang JR, et al. Study on the relationship between apolipoprotein B, CIII, E gene polymorphisms and lipids metabolism disorders of fatty liver patients. Xinjiang Yi Ke Da Xue Xue Bao. 2005;28:605–7.Google Scholar
  36. Ye P, Chen B, Wang S. Association of polymorphisms of the apolipoprotein B gene with coronary heart disease in Han Chinese. Atherosclerosis. 1995;117:43–50.View ArticlePubMedGoogle Scholar
  37. Ye P, Shang Y, Ding X. The influence of apolipoprotein B and E gene polymorphisms on the response to simvastatin therapy in patients with hyperlipidemia. Chin Med Sci J. 2003;18:9–13.PubMedGoogle Scholar
  38. Zhang CJ, Mao Y, He BX. Relationship between coronary heart disease with diabetes and EcoRI polymorphism of apolipoprotein B gene in Uygur and Han nationality. Zhongguo Dong Mai Ying Hua Za Zhi. 2010;18:146–50.Google Scholar
  39. Zhang L, Zeng Y, Ma M, Yang Q, Hu Z, Du X. Association study between C7673T polymorphism in apolipoprotein B gene and cerebral infarction with family history in a Chinese population. Neurol India. 2009;57:584–8.View ArticlePubMedGoogle Scholar
  40. Zhang PZ, Tian Y. Influence of apolipoprotein B gene polymorphisms over effect of exercise on blood lipid. Ti Yu Ke Xue. 2015;35:38–47.Google Scholar
  41. Zhao RZ, Liu CJ, Shen BZ. The Xba1 polymorphism of the apolipoprotein B gene in Chinese atherosclerotic cerebral infarction patients. Beijing Yi Ke Da Xue Xue Bao. 1997;29:522–4.Google Scholar
  42. Zhu WL, Feng NP, Wang Y, Ye GG. Gene polymorphism at apoB locus and the serum lipids profile in children. Wei Sheng Yan Jiu. 2011;30:280–2.Google Scholar
  43. Huang LS, Ripps ME, Breslow JL. Molecular basis of five apolipoprotein B gene polymorphisms in non-coding regions. J Lipid Res. 1990;31:71–7.PubMedGoogle Scholar
  44. Berg K, Powell LM, Wallis SC, Pease R, Knott TJ, Scott J. Genetic linkage between the antigenic group (Ag) variation and the apolipoprotein B gene: assignment of the Ag locus. Proc Natl Acad Sci U S A. 1986;83:7367–70.PubMed CentralView ArticlePubMedGoogle Scholar
  45. Demant T, Houlston RS, Caslake MJ, Series JJ, Shepherd J, Packard CJ, et al. Catabolic rate of low density lipoprotein is influenced by variation in the apolipoprotein B gene. J Clin Invest. 1988;82:797–802.PubMed CentralView ArticlePubMedGoogle Scholar
  46. Vrablik M, Ceska R, Horinek A. Major apolipoprotein B-100 mutations in lipoprotein metabolism and atherosclerosis. Physiol Res. 2001;50:337–43.PubMedGoogle Scholar
  47. Aalto-Setälä K, Tikkanen MJ, Taskinen MR, Nieminen M, Holmberg P, Kontula K. XbaI and c/g polymorphisms of the apolipoprotein B gene locus are associated with serum cholesterol and LDL-cholesterol levels in Finland. Atherosclerosis. 1988;74:47–54.View ArticlePubMedGoogle Scholar
  48. Bentzen J, Jørgensen T, Fenger M. The effect of six polymorphisms in the Apolipoprotein B gene on parameters of lipid metabolism in a Danish population. Clin Genet. 2002;61:126–34.View ArticlePubMedGoogle Scholar
  49. Cao Y, Fan X, Zhu W, Ni G, Qian Y, Han Y, et al. Association of C7673T polymorphism in apolipoprotein B gene with ischemic stroke in the Chinese population: a meta-analysis. Int J Neurosci. 2015;20:1–9.View ArticleGoogle Scholar
  50. Li YY. ApoB gene SpIns/Del, XbaI polymorphisms and myocardial infarction: a meta-analysis of 7169 participants. J Cardiovasc Med (Hagerstown). 2014;15:717–26.View ArticleGoogle Scholar

Copyright

© Gu et al. 2015

Advertisement