Advertisement

BMC Medical Genetics

, 20:109 | Cite as

The association between apolipoprotein E and gallstone disease: an updated meta-analysis

  • Lizhuo Li
  • Xin Qiao
  • Xia Wang
  • Di Liu
  • Qingmu Xue
  • Lu Han
  • Fei Dai
  • Guomin Ma
  • Zhipeng Yang
  • Tao Zhang
  • Shuo Yang
  • Shikang Cai
  • Mingyue Gao
  • Jingyun YangEmail author
Open Access
Research article
  • 122 Downloads
Part of the following topical collections:
  1. Genetic epidemiology and genetic associations

Abstract

Background

Gallstone disease (GSD) is a common biliary tract disease worldwide. Previous studies have investigated the association of apolipoprotein E (APOE) E4 with GSD and reported inconsistent results.

Methods

In this paper, we conducted meta-analyses to examine whether APOE E4 is associated with the risk of GSD. A systematic literature search was performed in PubMed, Cochrane Library, EMBASE, and Google Scholar using the following inclusion criteria: 1) Studies on human subjects; 2) subjects in the control group must undergo ultrasound GSD screening, and presence of GSD in the experiment group can be clearly determined, e.g., diagnosis of GSD through ultrasound screening or a previous history of cholecystectomy or cholelithiasis; 3) the studies reported APOE genotype data (APOE E4+ vs. E4-) for subjects with and without GSD. In all the meta-analyses, we used random-effects models to calculate the odds ratios (ORs) as a measure of association as well as the corresponding confidence intervals (CIs).

Results

Our literature search found 13 publications with 14 studies, including a total of 1632 GSD patients and 5001 controls, that met the eligibility criteria and were included in the meta-analyses. We did not find a significant association between APOE E4 and risk of GSD (OR = 1.23, 95% CI: 0.89–1.68; p = 0.205). No significant associations were observed in subgroup analyses by gender and mean age. We obtained similar insignificant findings if an additive model was used, if subjects who had E2E4 genotype were excluded, or if low-quality studies were excluded.

Conclusion

Our meta-analysis found insufficient evidence for the effect of APOE E4 on GSD risk. Future studies with large sample sizes that control for important confounding/risk factors are needed to validate our findings and to explore other genetic loci that might affect GSD risk.

Keywords

APOE Gallstone disease Polymorphism Meta-analysis 

Abbreviations

ABCG8

ATP Binding Cassette Subfamily G Member 8

APOE

Apolipoprotein E

CI

Confidence interval

GSD

Gallstone disease

HLP III

Type III hyperlipoproteinemia

MUPCDH

Mucin-like protocadherin

OR

Odds ratio

VLDL

Very low-density lipoproteins

Background

Gallstone disease (GSD) is one of the most prevalent biliary tract diseases worldwide [1], affecting 10–15% of the adult population in the United State [2]. Among gastrointestinal problems, GSD is a leading cause for hospital admissions, with an estimated 1.8 million ambulatory care visits each year [3]. GSD constitutes a major burden to the health care systems, with an annual cost of around $6.5 billion in the USA [2].

There are two major types of gallstones: cholesterol stones, which mainly consistent of cholesterol monohydrate crystals and precipitates of amorphous calcium bilirubinate, and pigment stones, which mainly contain calcium bilirubinate. The exact pathogenesis of GSD remains to be determined, and efficient strategies for primary prevention and nonsurgical therapies are still under development.

The etiology of GSD is multifactorial and involves interaction of genetic and environmental factors. Previous research has identified multiple risk factors for the development of GSD, such as age [4, 5], female gender [6], obesity [7], and diabetes mellitus [8]. Twin research indicated that the heritability of GSD was approximately 25% [9]. Meanwhile, multiple genes have been reported to be associated with increased GSD risk, such as ATP Binding Cassette Subfamily G Member 8 (ABCG8) [10], mucin-like protocadherin (MUPCDH) [11] and apolipoprotein E (APOE) [12].

The APOE gene is located on chromosome 19. APOE is a major component of very low-density lipoproteins (VLDLs), which is critical for removing excessive blood cholesterol and maintaining normal cholesterol level. Defects in APOE gene in human can lead to familial type III hyperlipoproteinemia (HLP III) showing impaired clearance of chylomicron, VLDL, LDL and increased blood cholesterol [13]. APOE has 3 polymorphic alleles, E2 (cys112, cys158), E3 (cys112, arg158), and E4 (arg112, arg158). The E4 has been found to be implicated in multiples diseases/disorders, such as impaired cognition, late-onset Alzheimer’s Disease, and ischemic cerebrovascular disease [14, 15].

Human and mouse model studies have been conducted to examine the role of APOE in the development of GSD. Research with APOE-deficient mice showed decreased gallstone formation compared to the wild-type mice, suggesting a role of APOE in gallstone formation [16]. However, findings in the human regarding the role of APOE in GSD formation are inconsistent. For example, a positive association was found between APOE E4 genotype and cholesterol crystals in bile, fast cholesterol crystallization in gallbladder bile and a higher cholesterol content in gallstones [12, 17]. However, other studies failed to confirm the findings [18, 19]. Moreover, presence of E4 allele was found to be an independent factor enhancing gallstone clearance in patients undergoing extracorporeal shock-wave lithotripsy (ESWL), but E4 carriers showed a higher recurrence rate following ESWL [20].

Previous studies also examined the relationship between APOE polymorphisms and GSD risk, with inconsistent conclusions. To the best of our knowledge, two meta-analyses have been conducted to address the relationship between APOE and GSD risk [21, 22]. The former one was included in a paper published in 2013, focusing on the association of eight genetic variants with GSD using a Mendelian randomization approach. This meta-analysis included studies published up to 2012. Some publications were missed in the literature search. The latter one was published in 2012, and included 17 studies with a total of 1773 cases and 2751 controls. This meta-analysis suffers from several methodological concerns, as outlined in more detail in the discussion section. Moreover, new studies appeared after the two meta-analyses. Therefore, to better examine the association of APOE genotype with GSD risk, we performed this updated meta-analysis which adapted more stringent criteria regarding inclusion of eligible studies and included most recent publications.

Methods

As our study used a systematic review and meta-analysis, ethical approval of this study and informed consent statement are not required.

Eligibility criteria

The following inclusion criteria were used to determine study eligibility: 1) Studies on human subjects; 2) subjects in the control group must undergo ultrasound GSD screening, and presence of GSD in the experiment group can be clearly determined, e.g., diagnosis of GSD through ultrasound screening or a previous history of cholecystectomy or cholelithiasis; 3) the studies reported APOE genotype data (APOE E4+ vs. E4) for subjects with and without GSD. We chose the one with a larger sample size if multiple studies used overlapping data.

Search strategy

Two authors (LL and JY) performed an extensive literature search in PubMed, Cochrane Library, EMBASE and Google Scholar for papers published before July 18, 2017. The keywords used in the literature search are provided online (Additional file 1: Keywords used in the literature search).

We retrieved all potentially relevant publications to evaluate study eligibility. We also searched the references in all relevant studies for research that might have been missed during the literature search. The two authors performed the literature search independently. The search was limited to studies published in English. Any disagreement was resolved by group discussion (LL, XQ and JY).

Data extraction

Two authors (LL and JY) independently extracted the following data from the eligible studies, according to a pre-specified protocol for data extraction: name of the first author, year of publication, participants characteristics including sample size, mean age, distribution of gender, race/country of origin of the participants, diagnosis of GSD, and APOE genotype data for patients with and without GSD. Any discrepancies were resolved in a group meeting. Quality of the included studies were assessed by two authors (LL and JY) independently using Newcastle–Ottawa scale (NOS) [23]. Extracted data were entered into a computerized spreadsheet for analyses.

Data analysis

All studies satisfied Hardy–Weinberg equilibrium (HWE) regarding the genotype in the control group. Odds ratios (ORs) were used as a measure of association between the APOE genotype and GSD risk. We used random-effects models to calculate the ORs and the corresponding 95% confidence intervals (CIs) in all the meta-analyses. Between-study heterogeneity was assessed using I2, and publication bias was evaluated using a funnel plot and Egger’s test.

Sensitivity/additional analysis

We examined the association by gender, and repeated the analysis by excluding subjects who had E2E4 genotype, and subsequently examined the association using an additive model (e.g., carrying one or two E4 alleles vs. no E4 allele). Finally, we repeated the analysis by excluding studies of low quality (NOS < 6 stars).

All statistical analyses were performed using Stata 11.2 (StataCorp LP, College Station, TX, USA) and SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). A p < 0.05 was considered statistically significant. This study was reported according to the PRISMA guidelines [24].

Availability of data and materials

No additional data are available.

Results

Study selection and characteristics

Figure 1 shows the selection of eligible studies included in our meta-analyses. We identified a total of 53 potential publications through our initial search. After screening of the abstracts, 29 publications were excluded either because they were not about human subjects, were not in English, were case studies, were reviews or meta-analyses, or were irrelevant. This left 24 studies which were retrieved for more detailed evaluations. We excluded an additional 11 studies because there was no control group, or the studies did not specify GSD screening in the control group or did not provide sufficient data. This led to 13 potentially relevant publications for our analysis. We identified one more study through searching the references of the potential studies, and then excluded one more study because the outcome is not GSD. This led to 13 publications with 14 studies that met the eligibility criteria and were included in our analyses [12, 21, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36].
Fig. 1

Flow diagram of the selection process of the studies included in the meta-analyses. Note: Please see the Methods section for additional details

All included publications had been published since 1994. Basic characteristics of the included studies were presented in Table 1. Most of the studies are of good quality. The combined study included 1632 GSD patients and 5001 subjects without GSD.
Table 1

Basic characteristics of all the studies included in the meta-analyses

Study

Year of publication

Country/origin

GSD

Control

Diagnosis of GSD

NOS

n

Age

Male (%)

n

Age

Male (%)

Rollan et al. [25]

1994

Chile

109

48 ± 13

42.2

110

37 ± 12

43.6

US

5

Bertomeu et al. [12]

1996

Spain

160

59 ± 12.6

34.4

125

58 ± 11.2

34.4

CG/US

8

Niemi et al. [26]

1999

Finland

148

53

31.8

896

51.2

52.8

US

9

Ko et al. [27]

2000

USA

52

24.4 ± 4.4

0

104

25.2 ± 4.6

0

US

8

Abu et al. [28]

2002

Israel

10

124

US

7

Hasegawa et al. [29]

2003

Japan

79

55 ± 8.9

46.8

53

39 ± 7.3

60.4

VS/infrared

6

Jiang et al. [30]

2004

China

105

47.5 ± 11.0

74.3

274

47.9 ± 12.2

67.2

US

6

Dixit et al.a [31]

2006

India

207

44.7 ± 13.2

32.2

322

44.0 ± 11.5

36.0

US

7

Mella et al. [32]

2007

Chile

117

49 ± 12

122

40 ± 13

US

7

Mella et al. [32]

2007

Germany

184

63 ± 13

184

63 ± 13

US

7

Jaime et al. [33]

2010

Mexico

101

51.9 ± 11.2

13.9

101

51.7 ± 11.0

13.9

US

7

Pinheiro-Júnior et al.b [34]

2012

Brazil

107

46.6 ± 11.2

17.5

104

40.6 ± 9.7

20

US

7

Martinez-Lopez et al. [35]

2015

Mexico

90

40.6 ± 13.8

8

371

37.1 ± 11.5

US

7

Shabanzadeh et al.c [36]

2017

Denmark

162

60

34.1

2112

40

52

US

7

Data for age were mainly presented as mean ± SD, or as median (range)

a Data for age and gender for the GSD group were based on 214 patients with GSD

b Data for age and gender were based on 114 subjects with cholelithiasis and 106 subjects without cholelithiasis

c Data for age and gender were based on 504 subjects with GSD and 4992 subjects without GSD. Data for age represent the median age of the GSD group and the control group, respectively

CG cholecystogram, Chole cholecystectomy, GSD gallstone disease, NDCD the National Danish Causes of Death, NDPR the National Danish Patient Registry, SD standard deviation, US ultrasound, VS visual inspection in cholecystectomy or liver transplantation

Assessment of publication Bias

We did not find evidence of a significant publication bias for the meta-analysis of the 14 included studies (p = 0.338; Fig. 2a), or for the meta-analysis excluding subjects who had E2E4 allele (p = 0.483). There was no evidence of publication bias in stratified meta-analysis by gender, or by mean age (all p > 0.190). We found evidence of a publication bias for the meta-analysis using an additive model (p = 0.005; Fig. 2b).
Fig. 2

Funnel plot for meta-analysis of the association of APOE E4 with GSD risk. a Funnel plot for meta-analysis if APOE E4 (yes vs. no); b) Funnel plot for meta-analysis of APOE E4 assuming an additive model. The x-axis is the standard error of the log-transformed odds ratio (log [OR]), and the y-axis is the log-transformed odds ratio. The horizontal line in the figure represents the overall estimated log-transformed odds ratio. The two diagonal lines represent the pseudo 95% confidence limits of the effect estimate. GSD, gallstone disease; OR, odds ratio

Association of APOE with GSD

We found no association of APOE E4 with the risk of GSD in the meta-analysis including all the 14 studies (OR = 1.23, 95% CI: 0.89–1.68; p = 0.205; Fig. 3). There was high heterogeneity among the included studies (I2 = 75.1%, p < 0.0001). We found no association in either the male (OR = 1.32, 95% CI: 0.77–2.27; p = 0.317; I2 = 20.3%, p for heterogeneity = 0.285), or the female subjects (OR = 1.17, 95% CI: 0.77–1.77; p = 0.474; I2 = 40.5%, p for heterogeneity = 0.169).
Fig. 3

Forest plot for meta-analysis of the association of APOE E4 with GSD risk. Each study is represented by a square whose area is proportional to the weight of the study. The overall effect from meta-analysis is represented by a diamond whose width represents the 95% CI for the estimated odds ratio (OR). GSD, gallstone disease; OR, odds ratio; CI, confidence interval

We then excluded subjects who had E2E4 genotype, and found no significant association of APOE E4 with GSD risk (OR = 1.30, 95% CI: 0.90–1.88; p = 0.156; I2 = 75.2%, p for heterogeneity< 0.0001). We then assessed the association assuming an additive genetic model, and found no statistically significant dosage effect of APOE E4 allele on the risk of GSD (OR = 0.63, 95% CI: 0.36–1.12; p = 0.114; I2 = 94.7%, p for heterogeneity< 0.0001).

We also divided the included studies into two subgroups based on the mean age in the control group: > 50 and ≤ 50 years, and conducted corresponding subgroup analysis. We found no statistically significant association of APOE E4 in both the > 50 age group (OR = 1.13, 95% CI: 0.68–1.88; p = 0.630; I2 = 71.7%, p for heterogeneity = 0.014), and in the ≤50 age group (OR = 1.14, 95% CI: 0.77–1.69; p = 0.521; I2 = 75.3%, p for heterogeneity < 0.0001). We repeated the analysis by excluding studies of low quality (NOS < 6 stars). Our findings remain essentially unchanged (OR = 1.21, 95% CI: 0.87–1.70; p = 0.257; I2 = 76.8%, p for heterogeneity< 0.0001). Finally, five studies (four publications) provided data regarding association of APOE genotype with cholesterol GSD [29, 32, 33, 34]. We performed meta-analysis using data from these five studies, and got similar non-significant results (OR = 0.84, 95% CI: 0.56–1.27; p = 0.418; I2 = 47.8%, p for heterogeneity = 0.105).

Discussion

In this paper, we performed a systematic literature search and conducted meta-analyses to examine the association of APOE with GSD. In the pooled analysis of 1632 GSD patients and 5001 subjects without GSD, we did not find evidence for significant association of APOE with GSD risk. Similar non-significance was observed in subgroup analysis by gender and mean age, and in other sensitivity analyses.

A previous meta-analysis published in 2012 of 17 studies from 16 publications examined the association of APOE E2/E3/E4 polymorphisms with GSD risk [22]. However, the main findings of this study are misleading due to the several methodological issues. The authors claimed that comparison of alleles E4 with E3 yielded a 25% increased risk that was statistically significant (p = 0.0003). However, based on the forest plot and the 95% CI (0.97–1.61), this increased risk should not be statistically significant (actual p = 0.084 based on the CI). Similar mistakes (wrong calculation of the p-values) can be found in the other findings throughout the publication. This meta-analysis also included one study which provided genotype frequency for cholesterol gallstone patients and pigment stone patients [37]. Out of the 16 publications included in the study, seven were based on Chinese subjects. After excluding these seven studies, no significant association was found between APOE E4 and GSD risk in non-Chinese studies. Our updated meta-analysis included publications missed by the previous meta-analysis, and we only retained studies in which presence/absence of GSD can be relatively accurately determined. We did not include two studies despite their relative samples sizes because in one study, the existence of GSD at baseline was determined according to a phone interview of medical history [38], and in the other study, subjects in the control group did not undergo GSD screening [21]. Including such studies could bias the results as subjects may have asymptomatic GSD. Nonetheless, we performed a sensitivity analysis by including the two studies in the meta-analysis, and obtained similar findings (OR = 1.10, 95% CI: 0.89–1.38; p = 0.376; I2 = 78.6%, p for heterogeneity< 0.0001; Fig. 4).
Fig. 4

Forest plot for meta-analysis of the association of APOE E4 with GSD risk after including the study by Boland et al. Each study is represented by a square whose area is proportional to the weight of the study. The overall effect from meta-analysis is represented by a diamond whose width represents the 95% CI for the estimated odds ratio (OR). GSD, gallstone disease; OR, odds ratio; CI, confidence interval

Out of the 14 studies included for meta-analyses in this paper, only three studies reported a significantly increased risk of GSD in APOE E4 carriers [12, 28, 35]. while other studies reported no significant association. It is also interesting to note that some studies seemed to indicate a trend of protective effect of APOE E4 on GSD risk. For example, the study by Jaime et al. [33] found that the risk of GSD decreased by 45% among APOE E4 carriers, compared to non-carriers (OR = 0.55, 95% CI: 0.28–1.06; p = 0.073). Similar findings held when we excluded E2E4 carriers. Selection bias may be underlying the inconsistent findings. In the three studies reporting a positive association, the APOE E4 allele frequency is relatively low in the control group (4–8%) compared to the general population [39].

Our study had several limitations: Although efforts were made in the systematic literature search in an attempt to include as many eligible studies as possible, the pooled sample size is still small. We had to exclude two large studies because the presence/absence of GSD cannot be clearly determined. More studies with larger samples are needed to further validate our findings. The heterogeneity was high for many of the meta-analyses in this study. Additional data of participants for each individual study were limited, and were only available for some of the included studies, making it hard to identify the real sources of heterogeneity. To explore the possible sources of heterogeneity, we performed a random-effects meta-regression analysis by including age, gender and race. However, none of the three variables were statistically significant, and there were 59.4% remaining residual variation due to heterogeneity. Interestingly, we obtained acceptable heterogeneity in a sensitivity analysis including 5 studies on the association of APOE with risk of cholesterol GSD. We got a similar non-significant finding, further supporting that there was no association between cholesterol gallstones and APOE E4 genotype. As in other meta-analyses that only utilized published data, we could not control for potential confounding/risk factors, such as age, sex [40], ethnicity and dietary pattern [41]. The estimated effect of APOE on GSD risk might be greatly confounded by such factors, and therefore could influence the validity of any meta-analysis that uses unadjusted results. Therefore, such important confounding factors should be taken into account in future studies on the relationship between APOE and the GSD risk.

Conclusions

We performed meta-analyses to examine the association of APOE E4 with GSD. We found no significant effect of APOE E4 on GSD risk. Future studies with large sample sizes that control for important confounding risk factors are needed to validate our findings and to explore additional genetic loci that might affect GSD risk. Prospective studies that take into account important comorbid factors, such as hypertension, diabetes, and coronary artery disease, are also needed to fully elucidate the relationship between APOE E4 and GSD risk.

Notes

Acknowledgements

We would like to thank the participants in the included studies for their contributions.

Authors’ contributions

JY is the guarantor. LL, QX, XW and JY drafted the manuscript. QX, LH, GM, ZY, TZ and SC contributed to the development of the selection criteria, the risk of bias assessment strategy and data extraction criteria. LL and JY developed the search strategy. DL, SY, MG and JY provided statistical expertise. LL and FD provided expertise on gallstone disease. All authors read, provided feedback and approved the final manuscript.

Funding

This study was supported by the National Natural Science Foundation of China (Grant No. 81660329 and No. 81771493), Key Science and Technology Program of Shaanxi Province, China (2015SF011), College Student Innovation & Entrepreneurship Project of Liaoning Province awarded to Dr. Lu Han (201410164000016), and College Student Innovation & Entrepreneurship Training Program of Hainan Medical University (HYCX2015054) awarded to Mr. Shikang Cai. Dr. Jingyun Yang’s research was also supported by NIH/NIA grant R01AG036042 and the Illinois Department of Public Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Ethics approval and consent to participate

Ethics approval and consent to participate is not needed because this is a study of published data.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Supplementary material

12881_2019_843_MOESM1_ESM.docx (15 kb)
Additional file 1: Keywords used in the literature search. Combination of keywords used in the literature search of potential publications in PubMed, Cochrane Library, EMBASE and Google Scholar (DOCX 14 kb)

References

  1. 1.
    Marschall HU, Einarsson C. Gallstone disease. J Intern Med. 2007;261:529–42.CrossRefGoogle Scholar
  2. 2.
    Shaffer EA. Gallstone disease: epidemiology of gallbladder stone disease. Best Pract Res Clin Gastroenterol. 2006;20:981–96.CrossRefGoogle Scholar
  3. 3.
    Shaheen NJ, Hansen RA, Morgan DR, et al. The burden of gastrointestinal and liver diseases, 2006. Am J Gastroenterol. 2006;101:2128–38.CrossRefGoogle Scholar
  4. 4.
    Chen CY, Lu CL, Huang YS, et al. Age is one of the risk factors in developing gallstone disease in Taiwan. Age Ageing. 1998;27:437–41.CrossRefGoogle Scholar
  5. 5.
    Volzke H, Baumeister SE, Alte D, et al. Independent risk factors for gallstone formation in a region with high cholelithiasis prevalence. Digestion. 2005;71:97–105.CrossRefGoogle Scholar
  6. 6.
    Shaffer EA. Epidemiology and risk factors for gallstone disease: has the paradigm changed in the 21st century? Curr Gastroenterol Rep. 2005;7:132–40.CrossRefGoogle Scholar
  7. 7.
    Everhart JE. Contributions of obesity and weight loss to gallstone disease. Ann Intern Med. 1993;119:1029–35.CrossRefGoogle Scholar
  8. 8.
    Wang W, Li N. The association of gallstone disease and diabetes mellitus. A meta-analysis. Saudi Med J. 2014;35:1005–12.PubMedGoogle Scholar
  9. 9.
    Katsika D, Grjibovski A, Einarsson C, Lammert F, Lichtenstein P, Marschall HU. Genetic and environmental influences on symptomatic gallstone disease: a Swedish study of 43,141 twin pairs. Hepatology. 2005;41:1138–43.CrossRefGoogle Scholar
  10. 10.
    Katsika D, Magnusson P, Krawczyk M, et al. Gallstone disease in Swedish twins: risk is associated with ABCG8 D19H genotype. J Intern Med. 2010;268:279–85.CrossRefGoogle Scholar
  11. 11.
    Chuang SC, Hsi E, Wang SN, Yu ML, Lee KT, Juo SH. Polymorphism at the mucin-like protocadherin gene influences susceptibility to gallstone disease. Clin Chim Acta. 2011;412:2089–93.CrossRefGoogle Scholar
  12. 12.
    Bertomeu A, Ros E, Zambon D, et al. Apolipoprotein E polymorphism and gallstones. Gastroenterology. 1996;111:1603–10.CrossRefGoogle Scholar
  13. 13.
    Mabuchi H, Itoh H, Takeda M, et al. A young type III hyperlipoproteinemic patient associated with apolipoprotein E deficiency. Metabolism. 1989;38:115–9.CrossRefGoogle Scholar
  14. 14.
    Namboori PK, Vineeth KV, Rohith V, et al. The ApoE gene of Alzheimer's disease (AD). Funct Integr Genomics. 2011;11:519–22.CrossRefGoogle Scholar
  15. 15.
    McCarron MO, Delong D, Alberts MJ. APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis. Neurology. 1999;53:1308–11.CrossRefGoogle Scholar
  16. 16.
    Sehayek E, Shefer S, Nguyen LB, Ono JG, Merkel M, Breslow JL. Apolipoprotein E regulates dietary cholesterol absorption and biliary cholesterol excretion: studies in C57BL/6 apolipoprotein E knockout mice. Proc Natl Acad Sci U S A. 2000;97:3433–7.CrossRefGoogle Scholar
  17. 17.
    Juvonen T, Kervinen K, Kairaluoma MI, Lajunen LH, Kesaniemi YA. Gallstone cholesterol content is related to apolipoprotein E polymorphism. Gastroenterology. 1993;104:1806–13.CrossRefGoogle Scholar
  18. 18.
    Van Erpecum KJ, Van Berge-henegouwen GP, Eckhardt ER, et al. Cholesterol crystallization in human gallbladder bile: relation to gallstone number, bile composition, and apolipoprotein E4 isoform. Hepatology. 1998;27:1508–16.CrossRefGoogle Scholar
  19. 19.
    Fischer S, Dolu MH, Zundt B, Meyer G, Geisler S, Jungst D. Apolipoprotein E polymorphism and lithogenic factors in gallbladder bile. Eur J Clin Investig. 2001;31:789–95.CrossRefGoogle Scholar
  20. 20.
    Portincasa P, van Erpecum KJ, van De Meeberg PC, Dallinga-Thie GM, de Bruin TW, van Berge-Henegouwen GP. Apolipoprotein E4 genotype and gallbladder motility influence speed of gallstone clearance and risk of recurrence after extracorporeal shock-wave lithotripsy. Hepatology. 1996;24:580–7.CrossRefGoogle Scholar
  21. 21.
    Stender S, Frikke-Schmidt R, Benn M, Nordestgaard BG, Tybjaerg-Hansen A. Low-density lipoprotein cholesterol and risk of gallstone disease: a Mendelian randomization study and meta-analyses. J Hepatol. 2013;58:126–33.CrossRefGoogle Scholar
  22. 22.
    Xue P, Niu WQ, Jiang ZY, Zheng MH, Fei J. A meta-analysis of apolipoprotein E gene epsilon2/epsilon3/epsilon4 polymorphism for gallbladder stone disease. PLoS One. 2012;7:e45849.CrossRefGoogle Scholar
  23. 23.
    Wells GA, Shea B, O'Connell D, et al. The Newcastle-Ottawa scale (NOS) for assessing the quality of nonrandomised studies in metaanalyses. 1999; http://www.ohri.ca/programs/clinical_epidemiology/oxford.htm. Accessed 20 July 2017.
  24. 24.
    Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097.CrossRefGoogle Scholar
  25. 25.
    Rollan A, Loyola G, Covarrubias C, Giancaspero R, Acevedo K, Nervi F. Apolipoprotein E polymorphism in patients with acute pancreatitis. Pancreas. 1994;9:349–53.CrossRefGoogle Scholar
  26. 26.
    Niemi M, Kervinen K, Rantala A, et al. The role of apolipoprotein E and glucose intolerance in gallstone disease in middle aged subjects. Gut. 1999;44:557–62.CrossRefGoogle Scholar
  27. 27.
    Ko CW, Beresford SA, Alderman B, et al. Apolipoprotein E genotype and the risk of gallbladder disease in pregnancy. Hepatology. 2000;31:18–23.CrossRefGoogle Scholar
  28. 28.
    Abu Abeid S, Szold A, Gavert N, et al. Apolipoprotein-E genotype and the risk of developing cholelithiasis following bariatric surgery: a clue to prevention of routine prophylactic cholecystectomy. Obes Surg. 2002;12:354–7.CrossRefGoogle Scholar
  29. 29.
    Hasegawa K, Terada S, Kubota K, et al. Effect of apolipoprotein E polymorphism on bile lipid composition and the formation of cholesterol gallstone. Am J Gastroenterol. 2003;98:1605–9.CrossRefGoogle Scholar
  30. 30.
    Jiang ZY, Han TQ, Suo GJ, et al. Polymorphisms at cholesterol 7alpha-hydroxylase, apolipoproteins B and E and low density lipoprotein receptor genes in patients with gallbladder stone disease. World J Gastroenterol. 2004;10:1508–12.CrossRefGoogle Scholar
  31. 31.
    Dixit M, Choudhuri G, Mittal B. Association of APOE-C1 gene cluster polymorphisms with gallstone disease. Dig Liver Dis. 2006;38:397–403.CrossRefGoogle Scholar
  32. 32.
    Mella JG, Schirin-Sokhan R, Rigotti A, et al. Genetic evidence that apolipoprotein E4 is not a relevant susceptibility factor for cholelithiasis in two high-risk populations. J Lipid Res. 2007;48:1378–85.CrossRefGoogle Scholar
  33. 33.
    Jaime S-C, Maribel A-M, Eliakym A-M, et al. ApoB-100, ApoE and CYP7A1 gene polymorphisms in Mexican patients with cholesterol gallstone disease. World J Gastroenterol. 2010;16:4685–90.CrossRefGoogle Scholar
  34. 34.
    Pinheiro-Junior S, Pinhel MA, Nakazone MA, et al. Effect of genetic variants related to lipid metabolism as risk factors for cholelithiasis after bariatric surgery in Brazilian population. Obes Surg. 2012;22:623–33.CrossRefGoogle Scholar
  35. 35.
    Martinez-Lopez E, Curiel-Lopez F, Hernandez-Nazara A, et al. Influence of ApoE and FABP2 polymorphisms and environmental factors in the susceptibility to gallstone disease. Ann Hepatol. 2015;14:515–23.PubMedGoogle Scholar
  36. 36.
    Shabanzadeh DM, Skaaby T, Sorensen LT, Jorgensen T. Screen-detected gallstone disease and cardiovascular disease. Eur J Epidemiol. 2017;32(6):501–10.CrossRefGoogle Scholar
  37. 37.
    van Erpecum KJ, Portincasa P, Dohlu MH, van Berge-Henegouwen GP, Jungst D. Biliary pronucleating proteins and apolipoprotein E in cholesterol and pigment stone patients. J Hepatol. 2003;39:7–11.CrossRefGoogle Scholar
  38. 38.
    Boland LL, Folsom AR, Boerwinkle E. Atherosclerosis risk in communities study I. Apolipoprotein E genotype and gallbladder disease risk in a large population-based cohort. Ann Epidemiol. 2006;16:763–9.CrossRefGoogle Scholar
  39. 39.
    Eisenberg DT, Kuzawa CW, Hayes MG. Worldwide allele frequencies of the human apolipoprotein E gene: climate, local adaptations, and evolutionary history. Am J Phys Anthropol. 2010;143:100–11.CrossRefGoogle Scholar
  40. 40.
    Nakeeb A, Comuzzie AG, Martin L, et al. Gallstones: genetics versus environment. Ann Surg. 2002;235:842–9.CrossRefGoogle Scholar
  41. 41.
    Jessri M, Rashidkhani B. Dietary patterns and risk of gallbladder disease: a hospital-based case-control study in adult women. J Health Popul Nutr. 2015;33:39–49.PubMedPubMedCentralGoogle Scholar

Copyright information

© The Author(s). 2019

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 and Affiliations

  • Lizhuo Li
    • 1
    • 2
  • Xin Qiao
    • 3
  • Xia Wang
    • 4
  • Di Liu
    • 5
  • Qingmu Xue
    • 2
  • Lu Han
    • 6
  • Fei Dai
    • 7
  • Guomin Ma
    • 8
  • Zhipeng Yang
    • 1
  • Tao Zhang
    • 9
  • Shuo Yang
    • 10
  • Shikang Cai
    • 11
  • Mingyue Gao
    • 10
  • Jingyun Yang
    • 12
    • 13
    • 14
    • 15
    Email author
  1. 1.Emergency DepartmentXuanwu Hospital, Capital Medical UniversityBeijingChina
  2. 2.Department of Critical Care and Emergency MedicineThe First Affiliated Hospital of Hainan Medical UniversityHaikouChina
  3. 3.Department of Animal Laboratory, School of Basic Medical SciencesCapital Medical UniversityBeijingChina
  4. 4.Department of Physiology and Pathophysiology, School of Basic Medical SciencesCapital Medical UniversityBeijingChina
  5. 5.Beijing Key Laboratory of Clinical Epidemiology, School of Public HealthCapital Medical UniversityBeijingChina
  6. 6.School of Basic MedicineShenyang Medical CollegeShenyangChina
  7. 7.Division of GastroenterologyThe Second Affiliated Hospital of Xi’an Jiaotong UniversityXi’anChina
  8. 8.Department of RadiologyLiaoning Provincial People’s HospitalShenyangChina
  9. 9.The First Research Institute, Ministry of the Public SecurityBeijingChina
  10. 10.Department of Epidemiology and Health StatisticsShenyang Medical CollegeShenyangChina
  11. 11.Hainan Medical UniversityHaikouChina
  12. 12.Division of Statistics, School of EconomicsShanghai UniversityShanghaiChina
  13. 13.Research Center of Financial InformationShanghai UniversityShanghaiChina
  14. 14.Rush Alzheimer’s Disease CenterRush University Medical CenterChicagoUSA
  15. 15.Department of Neurological SciencesRush University Medical CenterChicagoUSA

Personalised recommendations