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The Journal of International Medical Research logoLink to The Journal of International Medical Research
. 2016 Jan 5;44(1):3–14. doi: 10.1177/0300060515611539

Apolipoprotein E ɛ2/ɛ3/ɛ4 variant in association with obstructive sleep apnoea and lipid profile: A meta-analysis

Zhuoqiang Lu 1,, Xuemei Wu 2, Xueqing Jin 3, Feng Peng 1, Jinxiu Lin 1
PMCID: PMC5536579  PMID: 26740500

Abstract

Objective

A meta-analysis of the association between haplotypical variants of the apolipoprotein E (APOE) gene (ɛ2/ɛ3/ɛ4) and obstructive sleep apnoea (OSA) risk and changes in lipid profile.

Methods

Electronic databases were searched to retrieve articles that provided data on APOE gene ɛ2/ɛ3/ɛ4 variants in patients with OSA and healthy controls. Data were extracted from eligible articles and statistical analyses were performed.

Results

The meta-analysis included 14 articles involving 19 study populations (3198 patients and 6031 controls). There was no significant association between the presence of the ɛ4 allele and OSA risk. The presence of ɛ4 was associated with significantly increased total cholesterol and decreased high-density lipoprotein cholesterol, compared with ɛ4 allele negative individuals. There was a low probability of publication bias but significant heterogeneity.

Conclusions

There was no association between APOE ɛ2/ɛ3/ɛ4 and OSA susceptibility. The presence of APOE ɛ4 was associated with changes in lipid profile.

Keywords: Obstructive sleep apnoea, apolipoprotein E, variant, meta-analysis

Introduction

Obstructive sleep apnoea (OSA) is the most common form of apnoea, and is characterized by snoring, periodic apnoea, hypoxemia during sleep and daytime hypersomnolence.1 Despite several well-established modifiable risk factors such as obesity, compelling evidence supports a genetic component underlying the pathogenesis of OSA.2 As documented by family studies, individuals who had affected first-degree relatives were more likely to be at risk of OSA compared with those without an affected first-degree relative, and the risk increased in proportion to the number of affected relatives.3,4 It is estimated that up to 35% of the variability in OSA severity (as measured by apnoea–hypopnea index [AHI]) may be due to genetic determinants.5 Thus far, 85 genes have been listed as candidate OSA-susceptibility genes (hugenavigator.net/), with the gene encoding apolipoprotein E (APOE) ranked in the top three. Over the past decade, several association studies have independently assessed the relationship between OSA risk and a well-characterized haplotypical variant of the APOE gene (ɛ2/ɛ3/ɛ4; defined by the loci rs429358 and rs7412).68 These studies had poor reproducibility, possibly due to genetic heterogeneity across ethnic groups, methodological divergences and other confounding factors such as the coexistence of hypertension. To fully address this issue, this meta-analysis updates the findings of these analyses68 in order to re-evaluate the association between OSA risk and APOE ɛ2/ɛ3/ɛ4 alleles. In addition, we analysed changes in lipid profile and explored potential sources of heterogeneity.

Materials and methods

The implementation of this meta-analysis adheres to the protocols outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (Supplementary PRISMA checklist).

Literature search

The electronic databases PubMed®, Web of Science™, Wanfang (Chinese) and CNKI (Chinese) were searched to retrieve potentially eligible articles that provided data on APOE ɛ2/ɛ3/ɛ4 in patients with OSA and healthy controls published up to and including 10 May 2015. The key words were ‘obstructive sleep apnoea’ or ‘sleep disorder’ or ‘breathing’ [Title] and ‘apolipoprotein E’ or ‘APOE’ or ‘APO E’ [Abstract], and ‘allele’ or ‘genotype’ or ‘polymorphism’ or ‘variant’ or ‘SNP’ [Abstract]. We additionally checked the reference list of each major article to ensure comprehensive coverage.

Eligibility criteria

Inclusion criteria were: (i) OSA as the clinical endpoint; (ii) case–control design; (iii) the genotype or allele counts of APOE gene ɛ2/ɛ3/ɛ4 or the counts of ɛ4 allele positive and negative individuals in patients and controls; (iv) effect-size estimates presented as odds ratio (OR) with 95% confidence interval (95% CI). In the case of sample duplication the study with the larger sample size and more complete information was retained. Articles written in languages other than English and/or Chinese were excluded.

The title and abstract of each article were assessed for primary eligibility by two investigators acting independently and in duplicate (Z.L. and X.W.). In the case of uncertainty, the full text was retrieved for further evaluation and disagreements were resolved by consensus.

Data retrieval

The following data were extracted independently and in duplicate by two investigators (Z.L. and X.W.): first author’s last name; year of publication; race; study design; source of controls; AHI; diagnostic method for OSA; sample size; genotype/allele counts/ORs and 95% CIs; mean body mass index (BMI); triglyceride; total cholesterol; high- and low-density lipoprotein cholesterol (HDLC and LDLC); age; sex; prevalence of smoking; duration of education; and prevalence of hypertension and diabetes mellitus. Any disagreements were resolved during data retrieval by consensus and review of the full text of the article in question.

Statistical analyses

The DerSimonian and Laird method and a random-effects model were used to pool individual effect-size estimates for the association between APOE ɛ2/ɛ3/ɛ4 and OSA susceptibility.9 Differences in BMI, triglyceride, total cholesterol, HDLC and LDLC between ɛ4 allele positive and negative carriers were expressed as weighted mean difference (WMD) with 95% CI.

Heterogeneity was judged by the inconsistency index (I2) statistic, with statistically significant heterogeneity indicated by I2 > 50%. Sources of heterogeneity were evaluated by stratified analysis of categorical variables (study design, source of controls, AHI cut off, sample size) and by meta-regression analysis of continuous variables (age, sex, BMI, smoking, education, hypertension and diabetes mellitus). The probability of publication bias was visually inspected using Begg’s funnel plots and statistically assessed with Egger’s test (significance level 10%), using the trim-and-fill method to impute the presence of missing studies to yield an unbiased pooled estimate.

All statistical analyses were completed with Stata® software version 12.0 (StataCorp, College Station, TX, USA) for Windows®. Unless otherwise indicated, P-values < 0.05 were considered statistically significant.

Results

The initial literature search identified 55 potential articles. After exclusions, data were extracted from 14 articles (12 in English and two in Chinese) that fulfilled the predetermined eligibility criteria.1023 Figure 1 presents a flow diagram of search strategy and study selection; Table 1 shows the characteristics of all study populations. A total of 19 study populations were available from the 14 included studies, with 3198 patients and 6031 controls. There were no statistically significant between-group differences in age, smoking, hypertension and diabetes mellitus. Patients were significantly more likely to be obese (P = 0.0009) and male (P = 0.0016) than controls (Table 1).

Figure 1.

Figure 1.

Flow diagram of search strategy and study selection for a meta-analysis evaluating the association between obstructive sleep apnoea (OSA) risk and the apolipoprotein gene (APOE) ɛ2/ɛ3/ɛ4 alleles.

Table 1.

Characteristics of studies included in a meta-analysis evaluating the association between obstructive sleep apnoea risk and the apolipoprotein gene (APOE) ɛ2/ɛ3/ɛ4 alleles.

n
Age, years Male sex, %
Author, year
Country Design Source AHI cut off Method Cases Controls Cases Controls Cases Controls
Uyrum, 201510 Turkey Pro Hosp ≥5 PSG 42 31 54 44 59.5 38.8
Tisko (mild), 201411 Slovakia Retro Hosp >5–<15 PSG 126 128 49.5 47.8 70.6 53.1
Tisko (moderate), 201411 Slovakia Retro Hosp > 15–<30 PSG 66 128 51.6 47.8 68.2 53.1
Tisko (severe), 201411 Slovakia Retro Hosp ≥30 PSG 199 128 51.2 47.8 83.9 53.1
Osorio (mild), 201412 USA Pro Pop >5–15 PSG 52 25 67.8 65.3 41.2 32.0
Osorio (moderate/ severe), 201412 USA Pro Pop ≥15 PSG 19 25 70.1 65.3 42.1 32.0
Nikodemova (mild), 201313 USA Pro Pop >5–<15 PSG 399 1146 56.4 52.1 62.2 54.1
Nikodemova (moderate/ severe), 201313 USA Pro Pop ≥15 PSG 298 1146 56.6 52.1 71.5 54.1
Cosentino, 200814 Italy Retro Pop ≥15 PSG 123 121 58.6 57.9 66.7 64.5
Sheng, 200815 China Retro Pop ≥5 PSG 84 106 48.6 49.8 86.9 86.8
Zheng, 200716 China Retro Hosp ≥5 PSG 50 40 39 44.5 100 100
Gozal, 200717 USA Retro Pop >1 PSG 112 146 6.3 6.4 54.1 55.4
Craig, 200618 UK Retro Hosp Other NPI-D 217 185 78 78 40.0 33.0
Larkin (white), 200619 USA Pro Pop ≥15 PSG 218 796 40 38.7 48.2 45.7
Larkin (black), 200619 USA Pro Pop ≥15 PSG 197 796 37.1 38.7 42.8 45.7
Gottlieb, 200420 USA Pro Pop ≥15 PSG 337 1438 71 71 45.0 45.0
Kadotani, 200121 USA Pro Pop ≥15 PSG 66 725 49 49 58.3 58.3
Foley, 200122 USA Pro Pop ≥15 PSG 302 416 NA NA 100 100
Saarelainen, 199823 Finland Retro Pop ≥5 PSG 291 728 53.3 53.7 90.7 77.6
BMI, kg/m2
Smoking, % Education, years AHI Hypertension, % Diabetes mellitus, %
Cases
Controls
Cases
Controls
Cases
Controls
Cases
Controls
Cases
Controls
Cases
Controls
OR; 95% CI
Adjusted
35 31.8 NA NA NA NA 31.3 2.2 NA NA NA NA 2.90; 0.56, 15.05 No
29.6 28.4 34.9 34.4 NA NA 9.4 2.3 33.3 45.3 6.3 3.1 0.71; 0.40, 1.24 No
31.1 28.4 30.3 34.4 NA NA 20.8 2.3 56.1 45.3 10.6 3.1 0.58; 0.28, 1.19 No
33.9 28.4 45.7 34.4 NA NA 60.4 2.3 62.3 45.3 17.6 3.1 0.77; 0.47, 1.27 No
25.5 24.2 NA NA 17.2 16.2 8.3 2.3 29.4 24.0 7.8 8.0 1.18; 0.41, 3.37 No
28.9 24.2 NA NA 16.3 16.2 30.7 2.3 31.6 24.0 5.3 8.0 1.19; 0.32, 4.37 No
32.5 28.9 12.0 14.5 14.2 14.7 8.7 1.4 34.8 20.5 NA NA 0.81; 0.62, 1.06 No
36.6 28.9 11.4 14.5 14.0 14.7 29.4 1.4 51.3 20.5 NA NA 1.14; 0.86, 1.50 No
36.1 30.2 45.5 20.0 8.1 7.4 NA NA 61.8 57.1 18.7 8.6 1.22; 0.64, 2.31 No
29.58 24.71 NA NA NA NA NA NA NA 0.0 NA 0.0 7.12; 3.41, 14.89 No
NA NA NA NA NA NA NA NA 0.0 0.0 0.0 0.0 3.50; 1.05, 11.66 No
17 16.9 NA NA NA NA 8.6 0.8 NA NA NA NA 4.47; 1.27, 15.75 No
NA NA NA NA NA NA NA NA NA NA NA NA 1.03; 0.69, 1.53 No
29.6 30.3 NA NA NA NA NA NA 23.6 28.7 NA NA 0.85; 0.56, 1.00 Yes
31.1 30.3 NA NA NA NA NA NA 35.0 28.7 NA NA 0.64; 0.42, 0.98 Yes
NA NA NA NA NA NA NA NA NA NA NA NA 1.41; 1.06, 1.87 Yes
30 30 16.4 16.4 NA NA NA NA 33.0 33.0 NA NA 2.00; 1.20, 3.50 Yes
NA NA NA NA NA NA NA NA NA NA NA NA 0.77; 0.52, 1.14 Yes
NA NA NA NA NA NA NA NA NA NA NA NA 1.00; 0.75, 1.33 No

AHI, apnoea–hypopnea index; BMI, body mass index; OR, odds ratio; 95% CI, 95% confidence interval. Pro, prospective; Retro, retrospective; Hosp, hospital; Pop, population; PSG, polysomnography; NPI-D, neuropsychiatric inventory with caregiver distress; NA, not available;

There was no significant association between APOE ɛ4-positivity and OSA risk in the pooled study population. There was significant heterogeneity (I2 = 72.2%; P < 0.0005; Figure 2) and a low probability of publication bias for this comparison, as illustrated by Begg’s funnel plot (Figure 3) and Egger’s test. Trim-and-fill analysis suggested that three studies were missing to general a symmetrical filled funnel plot (Figure 3). After adjusting for the three missing studies, the presence of ɛ4 allele was associated with a nonsignificant 2% reduction in OSA risk (95% CI 0.77, 1.25).

Figure 2.

Figure 2.

Forest plot of a meta-analysis of the association between obstructive sleep apnoea (OSA) risk and the apolipoprotein gene (APOE) ɛ4 allele.1023 The colour version of this figure is available at: http://imr.sagepub.com.

Figure 3.

Figure 3.

Begg’s and Filled funnel plots for a meta-analysis of the association between obstructive sleep apnoea (OSA) risk and the apolipoprotein gene (APOE) ɛ4 allele.1023

There was no significant association between APOE ɛ4-positivity and OSA risk in adults1017,1923 or when analysis was limited to study populations with adjusted effect-size estimates.1922

Data regarding APOE gene ɛ2/ɛ3/ɛ4 alleles were provided in 11 study populations.1012,1416,18,23 When using the ɛ3 allele as a reference, there was no significant association between either ɛ2 or ɛ4 and OSA risk. There was significant heterogeneity for this comparison (I2 = 66.2%; P = 0.001).

Data regarding BMI and lipid parameters were provided by four studies.15,16,20,21 Total cholesterol was significantly higher (P = 0.007) and HDLC was significantly lower (P = 0.040) in ɛ4-positive individuals than ɛ4-negative individuals (Table 2).

Table 2.

Body mass index and lipid parameters in apolipoprotein gene (APOE) ɛ4-positive and negative individuals.

Parameter Studies, n n
WMD 95% CI Statistical significance Heterogeneity
ɛ4+ ɛ4−
BMI, kg/m2 4 713 2017 0.027 −0.817, 0.871 NS I2 = 56.4%
TG, mmol/l 4 713 2017 0.203 −0.085, 0.491 NS I2 = 77.4%
TC, mmol/l 4 713 2017 0.342  0.095, 0.590 P = 0.007 I2 = 78.7%
HDLC, mmol/l 4 713 2017 −0.052 −0.103, −0.002 P = 0.040 I2 = 31.5%
LDLC, mmol/l 3 274 681 0.197 −0.097, 0.491 NS I2 = 64.4%

WMD, weighted mean difference; CI, confidence interval; BMI, body mass index; NS, not statistically significant (P ≥ 0.05; random effects model); TG, triglyceride; TC, total cholesterol; HDLC, high-density lipoprotein cholesterol; LDLC, low-density lipoprotein cholesterol.

Stratified analyses revealed no effect of study design (prospective vs retrospective), source of controls (population-based vs hospital-based), AHI cut off (≥15 vs >5–<15) and sample size (≥500 vs <500) on heterogeneity (Table 3). The presence of ɛ4 was significantly associated with OSA risk in studies including only Chinese individuals (OR 5.87; 95% CI 3.13, 11.00).15,16

Table 3.

Stratified analyses of the association between obstructive sleep apnoea (OSA) risk and the apolipoprotein gene (APOE) ɛ4 allele.

Subgroups Studies, n n
OR 95% CI Heterogeneity
Patients Controls
Study design
 Prospective 10 1930 6544 1.02 0.82, 1.28 I2 = 62.9%
 Retrospective 9 1268 1710 1.33 0.86, 2.05 I2 = 80.0%
Source of controls
 Population-based 13 2498 7614 1.20 0.93,1.55 I2 = 77.7%
 Hospital-based 6 700 640 0.64, 1.38 I2 = 48.7%
AHI cut off
  >5–<15 3 577 1299 0.88 0.64, 1.02 I2 = 0.0%
  ≥15 10 1825 5719 0.99 0.79, 1.24 I2 = 62.1%
 ≥5 4 467 905 2.82 0.84, 9.45 I2 = 88.9%
Total sample size
 <500 11 1090 1063 1.45 0.91, 2.31 I2 = 75.9%
 ≥500 8 2108 7191 1.00 0.81, 1.22 I2 = 68.8%
Chinese subjects 2 134 146 5.87 3.13, 11.00 I2= 0.0%

OR, odds ratio; CI, confidence interval; AHI, apnoea–hypopnea index.

Meta-regression analysis found that hypertension was significantly correlated with OSA risk in both patients (r = −0.64; P = 0.024) and controls (r = −0.68; P = 0.01; Figure 4). There was no significant association between OSA risk and age, sex, BMI, smoking, duration of education, or diabetes mellitus.

Figure 4.

Figure 4.

Meta-regression analysis of the association between hypertension and risk of obstructive sleep apnoea (OSA). The colour version of this figure is available at: http://imr.sagepub.com.

Discussion

In accordance with the findings of others,68 the present meta-analysis of 14 articles and 9229 study subjects found no association between OSA risk and APOE ɛ2/ɛ3/ɛ4 positivity. The presence of the ɛ4 allele was significantly correlated with increased total cholesterol and decreased HDLC, however.

There is a growing recognition that pathophysiological mechanisms involving dysregulated lipid metabolism underlie OSA.11,24 APOE is a lipid transport and signalling protein with a key role in lipid metabolism,25 and its function is determined by the presence of three common alleles (ɛ2, ɛ3, ɛ4).26 Generally, a particular genetic variant could alter disease risk through its effects on either circulating concentrations or physiological function of a particular protein. The present analysis confirms the observation of others68 that individuals with different APOE ɛ2/ɛ3/ɛ4 genotypes show statistically significant differences in their circulating total cholesterol and HDLC levels. The absence of an association between ɛ2/ɛ3/ɛ4 alleles and OSA risk in the present analysis suggest that the principal differences in lipid profile driven by these variants relate to protein concentrations rather than function. The ɛ2/ɛ3/ɛ4 alleles appear to play a significant role in cholesterol regulation, although this is not strong enough to predict individual differences in OSA susceptibility.

Genetic epidemiological studies have shown varying and often nonreproducible findings regarding the association between APOE ɛ2/ɛ3/ɛ4 alleles and OSA susceptibility across ethnic groups. For example, the presence of the ɛ4 allele conferred a reduced risk for OSA in one study from the USA19 but an increased risk in another,21 and seemed to be neutral in a UK population.18 This lack of significance may be due to heterogeneity of effect associated with the presence of hypertension, as reflected in our meta-regression analysis. It is worth noting that the presence of hypertension might neutralize the contributory role of the ɛ4 allele in the pathogenesis of OSA, since ɛ4 was strongly associated with OSA risk after restricting analysis to the two studies of Chinese ancestry with normotensive controls.15,16 This finding may be too underpowered to be generalizable to a general population and other ethnic groups. On the other hand, OSA is an established risk factor for arterial hypertension,27 and the severity of hypertension is reported to be in proportion to that of OSA.28 Analyses stratified by OSA severity were still not significant in this meta-analysis, however. In view of the lack of necessary information, we agree that further adjustment for the severity of hypertension is critical to quantify reliably the association between APOE ɛ2/ɛ3/ɛ4 and OSA susceptibility.

The present analysis has several limitations. First, OSA is a polygenic disease, and it is not possible to unravel its genetic underpinnings by evaluating APOE ɛ2/ɛ3/ɛ4 alone. Secondly, all studies included in this meta-analysis were case–control in design. Thirdly, there was a very high level of heterogeneity between studies, but the level of publication bias was low. Finally, the limited sample sizes (especially in some stratified analyses) underline the requirement for large-scale, prospective studies.

In conclusion, this meta-analysis of 14 articles and 9229 study subjects failed to identify any association between APOE ɛ2/ɛ3/ɛ4 and OSA susceptibility. The presence of APOE ɛ4 was associated with changes in lipid profile. Importantly, hypertension was identified as a plausible source of heterogeneity between studies, and further studies incorporating information on the severity of hypertension are required to elucidate its role in OSA.

Declaration of conflicting interest

The authors declare that there are no conflicts of interest.

Funding

This analysis was supported by a grant from the “Miao Pu” Scientific Research Foundation of Fujian Medical University (2014MP030).

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