Association between apolipoprotein B gene polymorphisms and the risk of coronary heart disease (CHD): an update meta-analysis

Abstract

Objective:

Polymorphisms in the apolipoprotein B (apoB) gene have been reported to be associated with coronary heart disease (CHD). However, the results on this topic are conflicting. The present study aims to derive a more precise estimation of the relationship between CHD and apoB genetic polymorphisms by meta-analysis.

Methods:

We identified a total of 54 studies involving 7236, 10,912, and 14,102 individuals, respectively, for EcoRI, XbaI, and SpIns/Del polymorphisms by searching in PubMed, Web of Science, Google Scholar, the Cochrane Library, Wanfang Data, SinoMed, and CNKI. We utilized RevMan 5.0 software to perform the meta-analyses.

Results:

A significant statistical association between apoB EcoRI polymorphism and CHD was observed under an allelic (p = 0.001, odds ratio (OR) = 1.33, 95% confidence interval (CI) = 1.12–1.57), dominant (p = 0.005, OR = 1.22, 95% CI = 1.06–1.40), and recessive (p = 0.04, OR = 1.33, 95% CI = 1.01–1.74) model. We also found similar association of apoB SpIns/Del polymorphism with CHD. However, we did not find association between apoB XbaI polymorphism and CHD.

Conclusion:

The current meta-analysis found an association of EcoRI polymorphism and SpIns/Del polymorphism with an increased risk of CHD. No significant association between apoB XbaI polymorphism and CHD we observed in the present study.

Keywords

coronary heart disease meta-analysis

Introduction

Coronary heart disease (CHD) is one of the leading causes of death worldwide. Many studies have revealed that the interaction between various environmental factors and certain genetic polymorphisms may lead to CHD. Dyslipidemia have been documented as risk factors for CHD. Apolipoprotein B (apoB) is the sole protein component of low-density lipoprotein (LDL) which plays an important role in atherogenesis. The relationship between CHD and apoB gene polymorphisms has been a hotspot in recent years. The apoB gene is located on chromosome 2 and comprises 29 exons.¹ Numerous studies have focused on the correlation between the apoB gene polymorphism and CHD risk. However, these studies result in conflicting conclusions. Previous meta-analyses exploring the association between the apoB polymorphisms and CHD risk were also contradictory. Chiodini et al. found no evidence of increased risk emerged for XbaI polymorphism,² but positive associations were detected for EcoRI and SpIns/Del polymorphisms in CHD patients. Boekholdt et al. found that homozygotes for the XbaI C allele had significantly elevated levels of LDL cholesterol (LDL-C) and apoB,³ but a decreased risk of CHD in Caucasian populations. Homozygosity for the SpIns/Del D allele was associated with similarly increased levels of LDL-C and apoB, and with an increased risk of CHD. Homozygous subjects for the rare EcoRI allele had significantly decreased levels of total and LDL cholesterol. Chen et al. performed a study by collecting and sorting the previously published studies in Chinese individuals,⁴ providing evidence that EcoRI A allele and XbaI C allele polymorphisms were a risk factor for the development of CHD, respectively .

To derive a more precise estimation of the relationship between CHD and these polymorphisms, we conducted a meta-analysis between the three most frequently investigated polymorphisms (XbaI, EcoRI, and SpIns/Del) of all published studies from 1990 to 2013.

Materials and methods

Literature search

All studies that reported the association between the apoB polymorphisms and CHD were identified by comprehensive computer-based searches of PubMed, Web of Science, Google Scholar, the Cochrane Library, Wanfang Data, China Biological Medicine Database(SinoMed), and China National Knowledge Infrastructure (CNKI). These computer searches were limited to English and Chinese language articles before March 2014, but did not include reviews and editorials. The following keywords were used for searching: “apolipoprotein B” OR “apoB” AND “polymorphism” OR “mutation” OR “variant” OR “variation” OR “genotype” AND “coronary heart disease” OR “CHD” OR “coronary artery disease” OR “CAD” OR “myocardial Infarction” OR “MI” OR “ischemic cardiovascular disease” OR “ischemic heart disease” OR “IHD”.

Inclusion criteria

The diagnosis of CHD was fitted to the examination results of coronary arteriography, clinical symptoms combined with electrocardiogram, treadmill exercise test, echocardiography, and myocardial perfusion imaging in emission computed tomography. The inclusion criteria for identified articles were as follows: (1) studies are limited to three polymorphisms (XbaI, EcoRI, and SpIns/Del) of the apoB gene and CHD; (2) independent case-control studies using either a hospital-based or a population-based design; (3) similar to the literature research methods; (4) the literature has a comprehensive statistical index, sufficient data for estimating an odds ratio (OR) with 95% confidence interval (CI); (5) not republished data. Exclusion criteria were: (1) studies in which it was not possible to extract data from the published results; (2) studies that did not report appropriate outcomes were also excluded.

Data extraction

Two authors independently extracted data. Disagreement was resolved by consensus. If these two authors could not reach a consensus, the result was reviewed by a third author. The extracted data were consisted of the follow items: the first author’s name, publication year, eligible subjects, number of genotypes, allele frequency of case, population, selection criteria, sex, and age of cases and controls.

Quality assessment

To determine the methodological quality of each study, we used the Newcastle–Ottawa scale, which uses a “star” rating system to judge the quality of observational studies.⁵ The NOS ranges between zero (worst) up to nine stars (best). Studies with a score equal to or higher than seven were considered to be of high quality. Two investigators independently assessed the quality of included studies, and the result was reviewed by a third investigator. Disagreement was resolved by discussion.

Statistical analysis

The associations between XbaI, EcoRI, and SpIns/Del polymorphisms of apoB gene and CHD were compared by using the OR corresponding to 95% CI. Heterogeneity between studies was assessed by I² test, p < 0.10 and I² > 50% indicated evidence of heterogeneity.^6,7 If heterogeneity existed among the studies, the random effects model was used to estimate the pooled OR (the DerSimonian and Kacker method).⁸ Otherwise, the fixed effects model was adopted (the Mantel–Haenszel method).⁹ For the apoB gene polymorphisms, we investigated associations between the genetic variant and CHD risk in a recessive dominant genetic model and allelic contrast. Z test was used to determine the pooled OR and significance was set at p < 0.05. Hardy–Weinberg equilibrium (HWE) for each single nucleotide polymorphism was assessed for the controls in each study using χ2 test at a significant level of p < 0.05. The potential publication bias was investigated by using funnel plots and Egger’s test.¹⁰ The statistical analysis was conducted by using Review Manager 5.20 (Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen). In order to observe the association between numerous polymorphic sites of apoB gene polymorphisms and CHD risk in Chinese, studies of Chinese were considered in the meta-analysis independently.

Results

Study characteristics

All of the studies had been approved by the ethics committees of their affiliations. A total of 54 studies were included in the final meta-analysis according to the inclusion criteria,^11
–64 29 for EcoRI, 41 for XbaI, and 27 about SpIns/Del polymorphisms. Table 1 shows the studies identified and their main characteristics. Figure 1 shows the study selection process. These eligible studies were from all over the world. In all studies, the genotype frequencies in controls were consistent with HWE. There were five studies that did not follow the HWE.^{13,16,20,34,51} The NOS results indicated that the methodological quality was generally good.

Table 1.

Characteristics of studies reporting the distribution of three APOB polymorphisms in CHD cases and controls.

Number of studies	Reference	Year	Eligible subjects		Allele frequency (case)			Population	Selection criteria	Male		Age (years)
Number of studies			case	control	EcoRI	XbaI	SPIns/Del		Selection criteria	case	control	case	control
1	Al-Bustan et al.¹¹	2009	143	122			0.53	Kuwaiti	CHD	91	65	60.8±12.1	57.1±13.0
2	Anghebem-Oliveira et al.¹²	2009	254	148	0.64	0.63		Euro-Brazilians	CAD			53.5±12.4	53.5±12.4
3	Baroni et al.¹³	2003	102	104	0.54			Italy	CAD	96	89	50.1±5.3	47.5±3.7
4	Benes et al.¹⁴	2000	175	222			0.31	Czech Republic	CAD	175	222	49.5±4.5	48.4±7.8
5	Benes et al.¹⁵	2000	349	166			0.34	Czech Republic	MI	349	166	57.6±8.2	57.6±8.2
6	Bøhn et al.¹⁶	1993	238	621	0.51			Norway	MI			M<56, F<61
7	Bøhn et al.¹⁷	1994	238	547			0.36	Norway	MI			M<56, F<61
8	Corbo et al.¹⁸	1997	49	117	0.6	0.22	0.28	Italy	CAD	0	0	74.7±11.6	78.9±7.1
9	De Padua et al.¹⁹	2000	249	136	0.67		0.27	Brazil	CAD			59±12	58±12
10	Duman et al.²⁰	2005	150	100	0.66	0.6		Turkish	CAD	77	52	60.51±0.95	59.23±1.28
11	Gallegos-Arreola et al.²¹	2012	114	132	0.45			Mexico	CAD	80	59	M 55.3±5.8 F 54.8±5.8	M 64.0±9.5 F 62.6±10.8
12	Gardemann et al.²²	1998	2813	705			0.29	Germany	CAD,MI	2813	705	CAD 62.3±9.3 MI 62.2±9.5	58.5±10.6
13	Genest et al.²³	1990	111	121	0.53	0.21		US	CAD	111	121	49±7	73±6
14	Hegele et al.²⁴	1986	84	84	0.5	0.11		US	MI			57.1±9.8	57.7±9.5
15	Heng et al.²⁵	1995	221	253	0.94	0.06	0.15	China	CAD
15	Heng et al.²⁵	1995	84	164	0.83	0.06	0.12	India	CAD
16	Hong et al.²⁶	1997	235	216	0.95		0.38	Korea	CAD			53.2±9	51.1±9
17	Hong et al.²⁷	2001	235	216		0.73		Korea	CAD	164	162	53.2±9.3	51.1±9.1
18	Huang and Xie²⁸	2011	204	132	0.61	0.66		China	CHD	152	93	57.7±10.3	56.9±11.1
19	Huang et al.²⁹	1996	43	60	0.39			China	CHD	26	34	57.6±6.9	55.4±4.3
20	Huang et al.³⁰	2012	205	236	0.46			China	CHD	129	148	49.28±8.15	49.06±8.48
21	Kallel et al.³¹	2008	318	368			0.55	Tunisia	CAD	318	368	54.0±8.6	50.5±9.2
22	Lamia et al.³²	2012	212	104	0.67	0.64	0.76	Tunisia	CAD	141	58	60.6±10.6	59.4±11.9
23	Li and Xiong³³	2013	21	45	0.43	0.5		China	CHD		24	56-81	66.7±4.5
24	Li et al.³⁴	1998	103	100	0.5	0.78		China	CAD	79	68	54.93	54.93
25	Li and Li³⁵	2011	67	37		0.75		China	CHD	52	34	75.73±10.6	74.35±5.87
26	Machado et al.³⁷	2011	67	67	0.62	0.15	0.34	Brazil	CAD	43	43	65	58
27	Ma et al.³⁶	2011	89	78	0.27			China	CHD	62	44	60.01±12.40	64.27±11.28
28	Mansur et al.³⁸	2000	251	137	0.63		0.66	Brazil	CAD,MI	181	56	59.4±11.7	57.5±11.9
29	Marshall et al.³⁹	1994	444	404	0.49	0.18	0.33	US	CAD			M 56 F 59	M 52.8 F 57.3
30	Masana et al.⁴⁰	2001	98	112			0.28	Spain	CAD	98	112	48.7	47
31	Mendis et al.⁴¹	1991	95	95	0.8			Sri Lanka	CAD	95	95	37-65	37-65
32	Miettinen et al.⁴²	1994	82	50	0.6			Finland	CAD	78	42	40.8	38.7
33	Myant et al.⁴³	1989	124	146	0.47	0.15		UK	CAD	124	146	27-60	25-60
34	Paulweber et al.⁴⁴	1990	106	118	0.52	0.15		Austria	CAD	106	118	< 55	< 55
35	Peacock et al.⁴⁵	1996	87	91	0.44	0.19	0.3	Sweden	MI	87	91	40.35	40.51
36	Puri et al.⁴⁶	2003	100	100	0.48		0.22	India	CAD	90	90	50.74±9.7	50.41±12.23
37	Régis-Bailly et al.⁴⁷	1996	119	270	0.53		0.35	France	CAD	119	270	33-55	20-65
38	Rebhi et al.⁴⁸	2008	251	94			0.84	Tunisia	CAD			59.26±11.40	42.17±14.35
39	Rios et al.⁴⁹	2003	298	188	0.6		0.62	Brazil	CAD	180	92	59.0±11.2	55.0±9.9
40	Saha et al.⁵⁰	1992	138	154	0.91	0.07	0.2	China	CAD			56.7	44
41	Salazar et al.⁵¹	2000	50	100	0.39	0.25	0.36	Brazil	CAD	0	0	48±9	50±6
42	Scartezini et al.⁵²	2003	116	78	0.63	0.89		Brazil	CAD			< 56	< 56
43	Su et al.⁵³	2003	59	111	0.34	0.52		China	CHD	32	51	44-83	18-38
44	Tybjaerg-Hansen et al.⁵⁴	1991	50	38	0.43	0.18		Denmark	MI	50	38	48.2±0.7	48.5±0.6
45	Visvikis et al.⁵⁵	1990	197	168			0.33	UK	MI	197	168	25-63	25-63
46	Wu et al.⁵⁶	1994	58	319			0.19	China	CAD			58±10	34-69
47	Xu and Shi⁵⁷	1999	84	84	0.49	0.53		China	MI
48	Yan et al.⁵⁸	2003	137	120		0.58		China	CHD	104	64	61±10	60±9
49	Ye et al.⁵⁹	1995	103	100	0.98	0.04	0.24	China	CAD			56.3±9.2	54.8±11.3
50	Zang et al.⁶⁰	2001	65	60	0.5			China	MI	45	40	55.3±8.2	53.7±4.2
51	Zhang et al.⁶¹	2002	26	60	0.28	0.43		China	CHD
52	Zhang et al.⁶²	2004	97	90	0.5	0.47		China	CHD	58	57	52.3	43.2
53	Zhang and Zheng⁶³	2009	112	136		0.58		China	CHD	86	76	59.40±10.92	47.48±11.07
54	Zhu et al.⁶⁴	2001	43	116	0.22			China	MI	33	57	57.1±11.9	56.9±11.5

Meta-analysis

For the apoB EcoRI polymorphism, significant heterogeneity was found in the allelic model (I² = 56%, p<0.0001) and dominant genetic model (I² = 68%, p<0.00001). Therefore, the random-effects model (DerSimonian and Kacker) was applied. No significant heterogeneity was found under the recessive genetic model (I² = 0, p = 0.95), therefore, the Mantel–Haenszel fixed effects model was used. Significant statistical association was observed between the apoB EcoRI polymorphism and CHD under the allelic contrast (A vs. G, p = 0.001, OR = 1.33, 95% CI = 1.12–1.57) (Figure 2). Both the dominant genetic model (AA+GA vs. GG, p = 0.005, OR = 1.22, 95% CI = 1.06–1.40) and the recessive genetic model (AA vs. GA+GG, p = 0.04, OR = 1.33, 95% CI = 1.01–1.74) were also obtained similar results. For the apoB XbaI polymorphism, significant heterogeneity was found under the allelic contrast (I² = 69%, p < 0.00001), dominant genetic model (I² = 55%, p <0.0001) and the recessive genetic model (I² = 68%, p<0.00001). The random-effects model was applied to perform meta-analysis.

No significant statistical association was found under the allelic contrast (T vs. C, P=0.51, OR = 0.96, 95% CI = 0.84–1.09) (Figure 3), dominant genetic model (TT+TC vs. CC, p = 0.92, OR = 0.99, 95% CI = 0.80–1.23), and recessive genetic model (TT vs. TC+CC, p = 0.86, OR = 1.02, 95% CI = 0.85–1.22). As to the apoB SpIns/Del polymorphism, significant heterogeneity was found under the allelic contrast (I² = 84%, p < 0.00001) and dominant genetic model (I² = 57%, p = 0.0002). Therefore, the random-effects model was applied. No significant heterogeneity was found under the recessive genetic model (I² = 40%, p = 0.02), we utilized the fixed effects model. Significant statistical association was observed between the apoB SpIns/Del polymorphism and CHD under the allelic contrast (D vs. I, p = 0.01, OR = 1.20, 95% CI = 1.04–1.39) (Figure 4), dominant genetic model (DD+DI vs. II, p = 0.004, OR = 1.20, 95% CI = 1.06–1.35), and the recessive genetic model (DD vs. DI+II, p = 0.0002, OR = 1.25, 95% CI = 1.11–1.40). After restricting our analysis to the subgroup of Chinese individuals, apoB XbaI polymorphism was significantly associated with CHD under the allelic contrast (T vs. C, p = 0.0001, OR = 0.46, 95% CI = 0.31–0.68), dominant genetic model (TT+TC vs. CC, p = 0.0002, OR = 0.35, 95% CI = 0.20–0.61), and the recessive genetic model (TT vs. TC+CC, p = 0.0007, OR = 0.48, 95% CI = 0.32–0.73). apoB EcoRI polymorphism and risk of CHD were found under the allelic contrast (A vs. G, p = 0.0006, OR = 1.46, 95% CI = 1.18–1.82) and dominant genetic model (AA+GA vs. GG, P = 0.002, OR = 1.38, 95% CI = 1.13–1.68). However, we did not find any association under the recessive genetic model (AA vs. GA+GG, p = 0.14, OR = 1.88, 95% CI = 0.81–4.36). Furthermore, no significant statistical association was observed between the apoB SpIns/Del polymorphism and CHD under the allelic contrast (D vs. I, p = 0.07, OR = 1.21, 95% CI = 0.98–1.50), dominant genetic model (DD+DI vs. CC, p = 0.09, OR = 1.24, 95% CI = 0.96–1.58) and the recessive genetic model (DD vs. DI+II, p = 0.27, OR = 1.39, 95% CI = 0.77–2.49).

When stratified by status of HWE (the presence or absence of HWE in controls), no significant heterogeneity was found under the allelic contrast, dominant genetic model and recessive genetic model for EcoRI, XbaI, and SpIns/Del polymorphisms. Significant statistical association still existed in the whole group and subgroup of Chinese population.

The contribution of each study to the pooled estimate was performed in order to assess the sensitivity analyses. We excluded individual studies one at a time and recalculated the pooled p or OR for the remaining studies. Huang et al.’s study had an undue influence on the pooled p or OR estimation in SpIns/Del polymorphism.⁶⁵ This result showed the reliability of our results. What is more, conversion between the two models also did not substantially change the pooled point estimate.

Publication bias

No obvious publication bias was found in the present study. The publication bias of the individual studies was evaluated using a funnel plot and Egger’s test. No visual publication bias was found in the funnel plot for the EcoRI (Figure 5(a)), XbaI (Figure 5(b)), or SpIns/Del (Figure 5(c)) gene polymorphisms. We further used Egger’s test to assess the whole test publication bias. No statistically significant difference was detected in the Egger’s test by using the allelic contrast model for EcoRI (T = 0.29, p = 0.775), XbaI (T = 1.09, p = 0.283), and SpIns/Del (T = 1.43, p = 0.165) polymorphisms in all studies. In the subgroup no statistically significant difference was detected by using the Egger’s test.

Discussion

In the present study, we found an association of EcoRI polymorphism with an increased risk of CHD. No significant association between apoB XbaI polymorphism and CHD was observed in all studies. For SpIns/Del polymorphism, an association was observed in all studies. However, no significant statistical association was found in Chinese people.

CHD is a multi-factorial and polygenic disorder which is thought to be the result of interactions between complex factors of gene-gene and gene-environment. The association between apoB gene polymorphisms and the risk of CHD has been widely studied, but the results remain inconclusive.^11
–64 For example, Baroni et al. reported a significant difference in the development of CHD between genotype classes of the XbaI polymorphism in an Italian population.¹³ Duman et al. did not observe significant differences in the frequencies of apoB XbaI (CC, CT, TT) and EcoRI (AA, AG, GG) genotypes between case and control subjects in Turkish.²⁰ Gallegos-Arreola et al. detected that the apoB XbaI (CC) genotype is associated with CAD patients in the Mexican population.²¹ Kallel et al. found a significant but not independent association between the Ins/Del polymorphism of the apoB gene and MI in the Tunisian population.³¹ Marshall et al. found no evidence that the apoB Ins/Del polymorphism had a significant influence on the risk of angiographically defined CAD.³⁹ In contrast, Hong et al. observed that the Ins allele frequency was significantly higher in patients than in healthy controls in a Korean case control study with 216 controls and 235 CAD patients.²⁶

In order to generate robust data on apoB gene (EcoRI, XbaI, and SpIns/Del) polymorphisms and CAD risk, we carried out an update meta-analysis involving 54 studies and focusing on worldwide studies to provide the most comprehensive analysis on the relationship between apoB gene polymorphisms and CAD risk. The effects of the dominant model, the recessive genetic model, and allelic contrast were estimated.

This meta-analysis revealed that EcoRI and SpIns/Del polymorphisms of apoB gene significantly increased the susceptibility for CHD. No significant statistical association was observed under XbaI polymorphism. The results were the same as those of a previous meta-analysis performed by Chiodini et al. in 2003.² Another meta-analysis was performed by Boekholdt et al. in Caucasians.³ Subjects homozygous for the rare EcoRI allele had significantly decreased levels of total and LDL cholesterol, but unaltered risk of CHD. Homozygotes for the XbaI C allele had significantly elevated levels of LDL cholesterol (LDL-C) and apoB, but a decreased risk of CHD. Homozygosity for the SpIns/Del D allele was associated with similarly increased levels of LDL-C and apoB, and with an increased risk of CHD. In our meta-analysis, in Chinese individuals, the XbaI polymorphism decreased the risk of CHD. The results were in line with a meta-analysis carried out by Chen et al. in 2006.⁴ As to SpIns/Del polymorphism, no significant statistical association was observed.

However, only full text articles published in English and Chinese were included in this meta-analysis, missing some eligible studies which were unpublished or reported in other languages. In this case, some inevitable publication bias might exist, although the funnel plots did not indicate obvious publication bias in the present meta-analysis. It might influence the interpretation of our final results.

For better interpreting the results, some limitations of this meta-analysis should be acknowledged. First, heterogeneity may affect the results of the present meta-analysis in our analysis. Second, subgroup analysis was not performed by the factors such as gender, age and experimental method because insufficient data could be extracted from the primary article. Further studies with large sample size, especially in subgroup analysis of different minority, were needed to confirm our findings.

Despite these limitations or disadvantages, our meta-analysis still had some advantages. First, a systematic review of the association of apoB gene (EcoRI, XbaI, and SpIns/Del) polymorphisms with CHD risk is statistically more powerful than any single study. Second, the studies retrieved were the latest; many of them were published after the previous meta-analysis. Third, the quality of case–control studies included in our meta-analysis was satisfactory and met our inclusion criteria.

Conclusions

In summary, the present meta-analysis points to an association of EcoRI polymorphism with an increased risk of CHD. No significant association between apoB XbaI polymorphism and CHD we observed in all studies, but it is a reduced risk of CHD in Chinese people. For SpIns/Del polymorphism, an association was observed in all studies. However, no significant statistical association was found under Chinese individuals. On the other hand, Huang and Xie found that combined polymorphisms of apoB and APOAI gene are related with CHD.²⁸ Scartezini et al. observed that individuals with the TT/GG genotype presented a 6.1 higher chance of developing CHD than individuals with the other XbaI/EcoRI genotypes in Brazilian patients.⁵² We conclude that the TT/GG genotype may be in linkage disequilibrium with an unknown variation in the apoB gene or with a variation in another gene that affects the risk of CHD. Larger scale primary studies with the consideration of gene–gene and gene–environment interactions are still required to further evaluate the interaction of apoB gene polymorphisms with CHD susceptibility.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by Xinjiang Science and Technology Projects (201491181).

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