Apolipoprotein E gene polymorphism and the risk of intracerebral hemorrhage: a meta-analysis of epidemiologic studies

  • Rongjun Zhang1,

    Affiliated with

    • Xiaofeng Wang1Email author,

      Affiliated with

      • Zongchun Tang1,

        Affiliated with

        • Jianxin Liu1,

          Affiliated with

          • Shuzhen Yang1,

            Affiliated with

            • Youbing Zhang1,

              Affiliated with

              • Yijun Wei1,

                Affiliated with

                • Wenyin Luo1,

                  Affiliated with

                  • Jun Wang1,

                    Affiliated with

                    • Jialong Li1,

                      Affiliated with

                      • Bobo Chen1 and

                        Affiliated with

                        • Kunhu Zhang1

                          Affiliated with

                          Lipids in Health and Disease201413:47

                          DOI: 10.1186/1476-511X-13-47

                          Received: 12 September 2013

                          Accepted: 20 September 2013

                          Published: 12 March 2014

                          Abstract

                          Background

                          Studies investigating the association between the apolipoprotein E (APOE) gene polymorphism and the risk of intracerebral hemorrhage (ICH) have reported conflicting results. We here performed a meta-analysis based on the evidence currently available from the literature to make a more precise estimation of this relationship.

                          Methods

                          Published literature from the National Library of Medline and Embase databases were retrieved. Odds ratio (OR) and 95% confidence interval (CI) were calculated in fixed- or random-effects models when appropriate. Subgroup analyses were performed by race.

                          Results

                          This meta-analysis included 11 case–control studies, which included 1,238 ICH cases and 3,575 controls. The combined results based on all studies showed that ICH cases had a significantly higher frequency of APOE ϵ4 allele (OR= 1.42, 95% CI= 1.21,1.67, P<0.001). In the subgroup analysis by race, we also found that ICH cases had a significantly higher frequency of APOE ϵ4 allele in Asians (OR= 1.52, 95% CI= 1.20,1.93, P<0.001) and in Caucasians (OR= 1.34, 95% CI= 1.07,1.66, P=0.009). There was no significant relationship between APOE ϵ2 allele and the risk of ICH.

                          Conclusion

                          Our meta-analysis suggested that APOE ϵ4 allele was associated with a higher risk of ICH.

                          Keywords

                          Apolipoprotein E Intracerebral hemorrhage Gene polymorphism Meta-analysis

                          Introduction

                          Intracerebral hemorrhage (ICH) occurs at an annual incidence rate of 15 to 19 per 100,000 [1]. ICH accounts for approximately 15% of acute strokes in the United States and 22–35% in Asian populations [25]. ICH can be a devastating type of stroke, and the 30-day case mortality rate of ICH is 40% to 50%. [2, 6]. A pooled prospective study found that the risk factors for ICH were older age, African-American ethnicity, hypertension, lower LDL-C, and lower triglycerides [7]. ICH has been shown to have important genetic and environmental risk factors.

                          Apolipoprotein E (APOE) gene, located on the long arm of chromosome 19, codes for a 299-amino acid protein (apoE). ApoE is a polymorphic glycoprotein involved in cholesterol transport and cell membrane maintenance and repair [8, 9]. APOE has three common alleles: epsilon 2 (ϵ2), ϵ3, and ϵ4 that encode the three major isoforms of apoE: E2, E3, and E4, which performs isoform-dependent neurotrophic and antioxidant functions [8, 1012]. Each person has 2 alleles that together compose that person’s APOE genotype (e.g., ϵ2/ϵ3 or ϵ3/ϵ3). APOE is one of the most widely studied genes in vascular and neurodegenerative diseases [13].

                          Recently, some studies have been conducted to clarify the association between APOE gene polymorphisms and the risk of ICH [1424]. However, previous studies investigating the association have reported conflicting results [25, 26]. We here performed a meta-analysis based on the evidence currently available from the literature to make a more precise estimation of this relationship.

                          Materials and methods

                          Literature search strategy

                          We used a detailed electronic search strategy in Medline and Embase from 1950 to the end of March 2013. Two authors independently searched the databases using following key words in all relevant combinations: ‘cerebral’ or ‘intracerebral’ or ‘intracranial’, ‘hemorrhage’, ‘apolipoprotein E*’ or ‘ApoE*’, ‘polymorphism’ or ‘allele’ or ‘genotype’ or ‘variant’. The search was conducted without limitation on language. The reference lists of all retrieved publications were scrutinized for additional studies. If studies had partially overlapping subjects, the smaller dataset was excluded. If necessary, we attempted to contact the principal investigators of retrieved articles to require additional data.

                          Inclusion and exclusion criteria

                          The following criteria were used to include published studies: (i) independent epidemiological studies (for humans only); (ii) a clear description of APOE allele in ICH cases and controls; (iii) sufficient allele data were presented to calculate the odds ratio (OR) and 95% confidence interval (CI); Major reasons for exclusion of studies were (i) no control; (ii) not an original paper (e.g. review or letter etc.); (iii) duplicate publications.

                          Data extraction

                          Data were extracted by two authors independently, and disagreements were resolved by consensus. When a study did not explicitly report one or more of the requested data, we contacted the author of the study for additional details. The following data were extracted: the last name of the first author, publication year, country, study design, genotyping method, sample size and the results of studies.

                          Statistical analysis

                          All analyses were performed using STATA 11.0 (Stata-Corp LP, College Station, TX, USA). The Mantel-Haenszel method for fixed effects and the Der-Simonian-Laird method for random effects were used to estimate pooled OR and corresponding 95% CI. Meta-analysis heterogeneity was quantified by computing Cochrane’s Q and corresponding P-value and I2 (percent of effect size attributable to heterogeneity). We used fixed-effects methods if the result of the Q test was not significant. Otherwise, we calculated pooled estimates and confidence intervals assuming a random-effects model. Also, subgroup analyses were performed on the basis of race. In this study, P < 0.05 was considered statistically significant. Publication bias was assessed by visual inspection of funnel plots, the Begg's rank correlation method and the Egger's weighted regression method.

                          Results

                          Study characteristics

                          Characteristics of studies included in the meta-analysis are summarized in Table 1. Our initial search identified 108 studies according to the search words. Through the step of screening the title, abstracts, 85 articles were excluded, leaving 23 articles for full publication review. Of these, 12 were excluded [2536]. Finally, a total of 11 studies were included in our meta-analysis [1424], which included 1,238 ICH cases and 3,575 controls. Of those, three studies were population-based case–control studies, and eight studies were hospital-based case–control studies. Studies were conducted in USA, United Kingdom, Portugal, Japan, India and China. The frequencies of apolipoprotein E alleles of studies included in the meta-analysis were shown in Table 2.
                          Table 1

                          Characteristics of studies included in the meta-analysis

                          Study (author, year)

                          Design

                          Study period

                          Population (country)

                          Genotyping method

                          No. of cases

                          No. of controls

                          Nakata 1997

                          HCC

                          1992-1995

                          Asians (Japan)

                          PCR

                          38

                          38

                          McCarron 1998

                          HCC

                          DNR

                          Caucasians (United Kingdom)

                          PCR

                          71

                          406

                          Garcia 1999

                          PCC

                          DNR

                          Caucasians (Portugal)

                          PCR-RFLP

                          48

                          173

                          Kokubo 2000

                          PCC

                          1997-1999

                          Asians (Japan)

                          PCR-RFLP

                          84

                          1126

                          Catto 2000

                          HCC

                          1997

                          Caucasians (United Kingdom)

                          PCR

                          60

                          289

                          Chowdhury 2001

                          HCC

                          1998-1999

                          Asians (Japan)

                          PCR-RFLP

                          80

                          190

                          Woo 2002

                          PCC

                          1997-2000

                          Caucasians (USA)

                          PCR

                          188

                          366

                          Woo 2005

                          HCC

                          1997-2002

                          Caucasians (USA)

                          TaqMan

                          172

                          339

                          Chen 2009

                          HCC

                          DNR

                          Asians (China)

                          PCR

                          217

                          280

                          Zhang 2012

                          HCC

                          2008-2010

                          Asians (China)

                          PCR-RFLP

                          180

                          180

                          Misra 2012

                          HCC

                          DNR

                          Asians (India)

                          PCR

                          100

                          188

                          Abbreviations: HCC Hospital-based case–control, PCC Population-based case–control, DNR Data not reported, PCR Polymerase chain reaction, RFLP Restriction fragment length polymorphism.

                          Table 2

                          Frequencies of apolipoprotein E alleles of studies included in the meta-analysis

                          Study (author, year)

                          ϵ2 of cases

                          ϵ3 of cases

                          ϵ4 of cases

                          ϵ2 of controls

                          ϵ3 of controls

                          ϵ4 of controls

                          Nakata 1997

                          3

                          32

                          3

                          2

                          32

                          4

                          McCarron 1998

                          18

                          89

                          35

                          66

                          599

                          147

                          Garcia 1999

                          4

                          84

                          8

                          14

                          298

                          34

                          Kokubo 2000

                          14

                          131

                          23

                          103

                          1913

                          236

                          Catto 2000

                          5

                          95

                          20

                          44

                          446

                          88

                          Chowdhury 2001

                          2

                          146

                          12

                          13

                          333

                          34

                          Woo 2002

                          39

                          96

                          53

                          64

                          206

                          96

                          Woo 2005

                          15

                          118

                          39

                          25

                          266

                          48

                          Chen 2009

                          33

                          359

                          42

                          44

                          479

                          37

                          Zhang 2012

                          26

                          280

                          54

                          26

                          314

                          20

                          Misra 2012

                          7

                          183

                          10

                          15

                          343

                          18

                          Quantitative synthesis

                          The combined results based on all studies showed that ICH cases had a significantly higher frequency of APOE ϵ4 allele (OR= 1.42, 95% CI= 1.21,1.67, P<0.001) (Figure 1) (Table 3). In the subgroup analysis by race, we also found that ICH cases had a significantly higher frequency of APOE ϵ4 allele in Asians (OR= 1.52, 95% CI= 1.20,1.93, P<0.001) and in Caucasians (OR= 1.34, 95% CI= 1.07,1.66, P=0.009) (Figure 1) (Table 3). There was no significant relationship between APOE ϵ2 allele and the risk of ICH (Figure 2) (Table 3).
                          http://static-content.springer.com/image/art%3A10.1186%2F1476-511X-13-47/MediaObjects/12944_2013_Article_1197_Fig1_HTML.jpg
                          Figure 1

                          Meta-analysis of APOE alleles and ICH (ϵ4 versus ϵ3).

                          Table 3

                          Meta-analysis of apolipoprotein E alleles and intracerebral hemorrhage risk

                           

                          No. of studies

                          OR (95% CI)

                          P of OR

                          P of heterogeneity

                          OR (95% CI)

                          P of OR

                          P of heterogeneity

                          ϵ4 versus ϵ3

                          ϵ2 versus ϵ3

                          All

                          11

                          1.42 (1.21,1.67)

                          <0.001

                          0.09

                          1.18 (0.96,1.44)

                          0.11

                          0.29

                          Asians

                          6

                          1.52 (1.20,1.93)

                          <0.001

                          0.05

                          1.11 (0.83,1.47)

                          0.47

                          0.25

                          Caucasians

                          5

                          1.34 (1.07,1.66)

                          0.009

                          0.32

                          1.26 (0.94,1.68)

                          0.12

                          0.28

                          Abbreviations: OR Odds ratio, CI Confidence interval.

                          http://static-content.springer.com/image/art%3A10.1186%2F1476-511X-13-47/MediaObjects/12944_2013_Article_1197_Fig2_HTML.jpg
                          Figure 2

                          Meta-analysis of APOE alleles and ICH (ϵ2 versus ϵ3).

                          Heterogeneity analysis and publication bias

                          Statistical heterogeneity was not found among studies in overall comparisons by using the Q statistic (Table 3). Publication bias was not found by the Begg's rank correlation method (Figure 3) or Egger weighted regression method (Figure 4).
                          http://static-content.springer.com/image/art%3A10.1186%2F1476-511X-13-47/MediaObjects/12944_2013_Article_1197_Fig3_HTML.jpg
                          Figure 3

                          Begg’s publication bias plot of APOE alleles and ICH.

                          http://static-content.springer.com/image/art%3A10.1186%2F1476-511X-13-47/MediaObjects/12944_2013_Article_1197_Fig4_HTML.jpg
                          Figure 4

                          Egger’s publication bias plot of APOE alleles and ICH.

                          Discussion

                          There is evidence for a role of genetic factors in the development of ICH. Studies investigating the association between genetic polymorphisms and ICH risk are being reported with rapidly increasing frequency. Endoglin gene polymorphism was a risk factor for sporadic ICH [37]. A comparative study that angiotensin converting enzyme (ACE) gene DD homozygosity of the I/D polymorphism in intron 16 is an independent risk factor for ICH in a Polish population [38]. A case–control study suggested that the beta1-tubulin Q43P polymorphism could be associated with ICH in men from southern Spain [39]. A population-based prospective nested case–control study found that estrogen receptor alpha gene polymorphisms were associated with first-ever ICH, particularly in combination with hypertension [40]. A case–control study found that glutathione peroxidase 1 C593T polymorphism was associated with lobar ICH in a Polish population [41]. A case–control study suggested that the rs2228048 of TGFBR2 gene may be associated with development of ICH in Korean population [42]. A study suggested that the rs17222919 of ALOX5AP may be associated with the development of ICH in Korean population [43].

                          The APOE gene polymorphisms are associated with many other diseases. A meta-analysis showed that APOE ϵ4 allele appeared to be associated with a higher prevalence of dementia in Parkinson disease [44]. A meta-analysis suggested that the APOE ϵ4 isoform was a genetic factor that might influence the age at onset of temporal lobe epilepsy [45]. A meta-analysis showed that the APOE ϵ4 allele was associated with an increased risk of developing hypertension [46]. A meta-analysis found that the APOE ϵ4 allele was associated with a moderately increased risk for progression from mild cognitive impairment to Alzheimer's disease-type dementia [47]. Prevalence of APOE ϵ4 alleles was significantly higher in patients with coronary artery disease than controls [48].

                          The exact mechanism of the association between APOE polymorphism and the risk of ICH remains unclear. APOE plays a critical role in redistributing lipids among central nervous system cells for normal lipid homeostasis [49], repairing injured neurons [50], maintaining synaptodendritic connections [51], neurite outgrowth [52], synaptic plasticity [53], mitochondrial resistance to oxidative stress [54], and glucose use by neurons and glial cells [25]. Compared with ϵ3/ϵ3, ϵ4 allele-containing genotypes are associated with increased total cholesterol levels [13]. It appears that the ϵ4 allele enhances amyloid deposition in blood vessels [55]. Thus, one might expect ϵ4 carriers to have increased susceptibility to ICH, especially in a lobar location. Furthermore, APOE ϵ4 allele was also associated with an increased risk of developing hypertension [46], which may be the reason that APOE ϵ4 allele was associated with a higher risk of ICH.

                          Several limitations of our meta-analysis should be noted. First of all, meta-analysis is powerful but also controversial-controversial because several conditions are critical to a sound meta-analysis, and small violations of those conditions can lead to misleading results [56]. Second, relatively small sample size of studies in overall comparisons was observed in this meta-analysis. The results of small meta-analyses should be regarded with caution, even if the P value shows extreme statistical significance [57]. Thirdly, because of the lack of individual patient data, we could not perform an adjustment estimate. In spite of these limitations, our meta-analysis also had some advantages. First, the major strengths of the meta-analysis are that we used a comprehensive searching strategy based on computer-assisted and manual searching which allowed the eligible studies to be included as far as possible. Second, no heterogeneity or publication bias was found, which leads to a possibly robust result.

                          In conclusion, our meta-analysis suggested that APOE ϵ4 allele was associated with a higher risk of ICH. Future studies will be required to clarify the biological implications of our findings.

                          Declarations

                          Acknowledgements

                          The study was supported by grants from the national key Technology R&D program for the 12th Five-year plan of P.R. China (2011BAI08B05).

                          Authors’ Affiliations

                          (1)
                          Department of Neurosurgery, Third Hospital of Chinese PLA

                          References

                          1. Broderick J, Brott T, Kothari R, Miller R, Khoury J, Pancioli A, Gebel J, Mills D, Minneci L, Shukla R: The greater Cincinnati/Northern Kentucky stroke study: preliminary first-ever and total incidence rates of stroke among blacks. Stroke. 1998, 29: 415-421. 10.1161/01.STR.29.2.415View ArticlePubMed
                          2. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF: Spontaneous intracerebral hemorrhage. N Engl J Med. 2001, 344: 1450-1460. 10.1056/NEJM200105103441907View ArticlePubMed
                          3. Mohr JP, Caplan LR, Melski JW, Goldstein RJ, Duncan GW, Kistler JP, Pessin MS, Bleich HL: The Harvard cooperative stroke registry: a prospective registry. Neurology. 1978, 28: 754-762. 10.1212/WNL.28.8.754View ArticlePubMed
                          4. Hu HH, Sheng WY, Chu FL, Lan CF, Chiang BN: Incidence of stroke in Taiwan. Stroke. 1992, 23: 1237-1241. 10.1161/01.STR.23.9.1237View ArticlePubMed
                          5. Zhang LF, Yang J, Hong Z, Yuan GG, Zhou BF, Zhao LC, Huang YN, Chen J, Wu YF, : Proportion of different subtypes of stroke in China. Stroke. 2003, 34: 2091-2096. 10.1161/01.STR.0000087149.42294.8CView ArticlePubMed
                          6. Broderick JP, Brott T, Tomsick T, Huster G, Miller R: The risk of subarachnoid and intracerebral hemorrhages in blacks as compared with whites. N Engl J Med. 1992, 326: 733-736. 10.1056/NEJM199203123261103View ArticlePubMed
                          7. Sturgeon JD, Folsom AR, Longstreth WT, Shahar E, Rosamond WD, Cushman M: Risk factors for intracerebral hemorrhage in a pooled prospective study. Stroke. 2007, 38: 2718-2725. 10.1161/STROKEAHA.107.487090View ArticlePubMed
                          8. Mahley RW: Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science. 1988, 240: 622-630. 10.1126/science.3283935View ArticlePubMed
                          9. Poirier J: Apolipoprotein E in animal models of CNS injury and in Alzheimer's disease. Trends Neurosci. 1994, 17: 525-530. 10.1016/0166-2236(94)90156-2View ArticlePubMed
                          10. Al-Khedhairy AA: Apolipoprotein E polymorphism in Saudis. Mol Biol Rep. 2004, 31: 257-260.View ArticlePubMed
                          11. Mahfouz RA, Sabbagh AS, Zahed LF, Mahfoud ZR, Kalmoni RF, Otrock ZK, Taher AT, Zaatari GS: Apolipoprotein E gene polymorphism and allele frequencies in the Lebanese population. Mol Biol Rep. 2006, 33: 145-149. 10.1007/s11033-006-6260-xView ArticlePubMed
                          12. Laskowitz DT, Horsburgh K, Roses AD: Apolipoprotein E and the CNS response to injury. J Cereb Blood Flow Metab. 1998, 18: 465-471.View ArticlePubMed
                          13. Eichner JE, Dunn ST, Perveen G, Thompson DM, Stewart KE, Stroehla BC: Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol. 2002, 155: 487-495. 10.1093/aje/155.6.487View ArticlePubMed
                          14. Zhang R, Wang X, Liu J, Yang S, Tang Z, Li S, Peng Y, Zhang H, Yang X, Zhou Y, Shao W: Apolipoprotein E gene polymorphism and the risk of intracerebral hemorrhage in the Chinese population. Genet Test Mol Biomarkers. 2012, 16: 63-66. 10.1089/gtmb.2011.0103View ArticlePubMed
                          15. Misra UK, Kalita J, Somarajan BI: Recurrent intracerebral hemorrhage in patients with hypertension is associated with APOE gene polymorphism: a preliminary study. J Stroke Cerebrovasc Dis. 2013, 22: 758-763. 10.1016/j.jstrokecerebrovasdis.2012.02.006View ArticlePubMed
                          16. Chen YC, Lee-Chen GJ, Wu YR, Hu FJ, Wu HC, Kuo HC, Chu CC, Ryu SJ, Chen ST, Chen CM: Analyses of interaction effect between apolipoprotein E polymorphism and alcohol use as well as cholesterol concentrations on spontaneous deep intracerebral hemorrhage in the Taiwan population. Clin Chim Acta. 2009, 408: 128-132. 10.1016/j.cca.2009.08.004View ArticlePubMed
                          17. Woo D, Kaushal R, Chakraborty R, Woo J, Haverbusch M, Sekar P, Kissela B, Pancioli A, Jauch E, Kleindorfer D, Flaherty M, Schneider A, Khatri P, Sauerbeck L, Khoury J, Deka R, Broderick J: Association of apolipoprotein E4 and haplotypes of the apolipoprotein E gene with lobar intracerebral hemorrhage. Stroke. 2005, 36: 1874-1879. 10.1161/01.STR.0000177891.15082.b9View ArticlePubMed
                          18. Woo D, Sauerbeck LR, Kissela BM, Khoury JC, Szaflarski JP, Gebel J, Shukla R, Pancioli AM, Jauch EC, Menon AG, Deka R, Carrozzella JA, Moomaw CJ, Fontaine RN, Broderick JP: Genetic and environmental risk factors for intracerebral hemorrhage: preliminary results of a population-based study. Stroke. 2002, 33: 1190-1195. 10.1161/01.STR.0000014774.88027.22View ArticlePubMed
                          19. Chowdhury AH, Yokoyama T, Kokubo Y, Zaman MM, Haque A, Tanaka H: Apolipoprotein E genetic polymorphism and stroke subtypes in a Bangladeshi hospital-based study. J Epidemiol. 2001, 11: 131-138. 10.2188/jea.11.131View ArticlePubMed
                          20. Catto AJ, McCormack LJ, Mansfield MW, Carter AM, Bamford JM, Robinson P, Grant PJ: Apolipoprotein E polymorphism in cerebrovascular disease. Acta Neurol Scand. 2000, 101: 399-404. 10.1034/j.1600-0404.2000.90308a.xView ArticlePubMed
                          21. Kokubo Y, Chowdhury AH, Date C, Yokoyama T, Sobue H, Tanaka H: Age-dependent association of apolipoprotein E genotypes with stroke subtypes in a Japanese rural population. Stroke. 2000, 31: 1299-1306. 10.1161/01.STR.31.6.1299View ArticlePubMed
                          22. Garcia C, Pinho e Melo T, Rocha L, Lechner MC: Cerebral hemorrhage and apoE. J Neurol. 1999, 246: 830-834. 10.1007/s004150050463View ArticlePubMed
                          23. McCarron MO, Nicoll JA: High frequency of apolipoprotein E epsilon 2 allele is specific for patients with cerebral amyloid angiopathy-related haemorrhage. Neurosci Lett. 1998, 247: 45-48. 10.1016/S0304-3940(98)00286-9View ArticlePubMed
                          24. Nakata Y, Katsuya T, Rakugi H, Takami S, Sato N, Kamide K, Ohishi M, Miki T, Higaki J, Ogihara T: Polymorphism of angiotensin converting enzyme, angiotensinogen, and apolipoprotein E genes in a Japanese population with cerebrovascular disease. Am J Hypertens. 1997, 10: 1391-1395. 10.1016/S0895-7061(97)00315-4View ArticlePubMed
                          25. Biffi A, Sonni A, Anderson CD, Kissela B, Jagiella JM, Schmidt H, Jimenez-Conde J, Hansen BM, Fernandez-Cadenas I, Cortellini L, Ayres A, Schwab K, Juchniewicz K, Urbanik A, Rost NS, Viswanathan A, Seifert-Held T, Stoegerer EM, Tomas M, Rabionet R, Estivill X, Brown DL, Silliman SL, Selim M, Worrall BB, Meschia JF, Montaner J, Lindgren A, Roquer J, Schmidt R: Variants at APOE influence risk of deep and lobar intracerebral hemorrhage. Ann Neurol. 2010, 68: 934-943. 10.1002/ana.22134PubMed CentralView ArticlePubMed
                          26. Sudlow C, Martinez Gonzalez NA, Kim J, Clark C: Does apolipoprotein E genotype influence the risk of ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage? Systematic review and meta-analyses of 31 studies among 5961 cases and 17, 965 controls. Stroke. 2006, 37: 364-370. 10.1161/01.STR.0000199065.12908.62PubMed CentralView ArticlePubMed
                          27. Fontanella M, Rainero I, Gallone S, Rubino E, Rivoiro C, Valfre W, Garbossa D, Nurisso C, Ducati A, Pinessi L: Lack of association between the apolipoprotein E gene and aneurysmal subarachnoid hemorrhage in an Italian population. J Neurosurg. 2007, 106: 245-249. 10.3171/jns.2007.106.2.245View ArticlePubMed
                          28. Tang J, Zhao J, Zhao Y, Wang S, Chen B, Zeng W: Apolipoprotein E epsilon4 and the risk of unfavorable outcome after aneurysmal subarachnoid hemorrhage. Surg Neurol. 2003, 60: 391-396. discussion 396–397, 10.1016/S0090-3019(03)00323-9View ArticlePubMed
                          29. Nicoll JA, McCarron MO: APOE gene polymorphism as a risk factor for cerebral amyloid angiopathy-related hemorrhage. Amyloid. 2001, 8 (Suppl 1): 51-55.PubMed
                          30. McCarron MO, Nicoll JA, Stewart J, Ironside JW, Mann DM, Love S, Graham DI, Dewar D: The apolipoprotein E epsilon2 allele and the pathological features in cerebral amyloid angiopathy-related hemorrhage. J Neuropathol Exp Neurol. 1999, 58: 711-718. 10.1097/00005072-199907000-00005View ArticlePubMed
                          31. McCarron MO, Nicoll JA, Ironside JW, Love S, Alberts MJ, Bone I: Cerebral amyloid angiopathy-related hemorrhage. Interaction of APOE epsilon2 with putative clinical risk factors. Stroke. 1999, 30: 1643-1646. 10.1161/01.STR.30.8.1643View ArticlePubMed
                          32. McCarron MO, Hoffmann KL, DeLong DM, Gray L, Saunders AM, Alberts MJ: Intracerebral hemorrhage outcome: apolipoprotein E genotype, hematoma, and edema volumes. Neurology. 1999, 53: 2176-2179. 10.1212/WNL.53.9.2176View ArticlePubMed
                          33. Nicoll JA, Burnett C, Love S, Graham DI, Dewar D, Ironside JW, Stewart J, Vinters HV: High frequency of apolipoprotein E epsilon 2 allele in hemorrhage due to cerebral amyloid angiopathy. Ann Neurol. 1997, 41: 716-721. 10.1002/ana.410410607View ArticlePubMed
                          34. Nicoll JA, Burnett C, Love S, Graham DI, Ironside JW, Vinters HV: High frequency of apolipoprotein E epsilon 2 in patients with cerebral hemorrhage due to cerebral amyloid angiopathy. Ann Neurol. 1996, 39: 682-683.View ArticlePubMed
                          35. Greenberg SM, Briggs ME, Hyman BT, Kokoris GJ, Takis C, Kanter DS, Kase CS, Pessin MS: Apolipoprotein E epsilon 4 is associated with the presence and earlier onset of hemorrhage in cerebral amyloid angiopathy. Stroke. 1996, 27: 1333-1337. 10.1161/01.STR.27.8.1333View ArticlePubMed
                          36. Greenberg SM, Rebeck GW, Vonsattel JP, Gomez-Isla T, Hyman BT: Apolipoprotein E epsilon 4 and cerebral hemorrhage associated with amyloid angiopathy. Ann Neurol. 1995, 38: 254-259. 10.1002/ana.410380219View ArticlePubMed
                          37. Alberts MJ, Davis JP, Graffagnino C, McClenny C, Delong D, Granger C, Herbstreith MH, Boteva K, Marchuk DA, Roses AD: Endoglin gene polymorphism as a risk factor for sporadic intracerebral hemorrhage. Ann Neurol. 1997, 41: 683-686. 10.1002/ana.410410519View ArticlePubMed
                          38. Slowik A, Turaj W, Dziedzic T, Haefele A, Pera J, Malecki MT, Glodzik-Sobanska L, Szermer P, Figlewicz DA, Szczudlik A: DD genotype of ACE gene is a risk factor for intracerebral hemorrhage. Neurology. 2004, 63: 359-361. 10.1212/01.WNL.0000130200.12993.0CView ArticlePubMed
                          39. Navarro-Nunez L, Lozano ML, Rivera J, Corral J, Roldan V, Gonzalez-Conejero R, Iniesta JA, Montaner J, Vicente V, Martinez C: The association of the beta1-tubulin Q43P polymorphism with intracerebral hemorrhage in men. Haematologica. 2007, 92: 513-518. 10.3324/haematol.10689View ArticlePubMed
                          40. Strand M, Soderstrom I, Wiklund PG, Hallmans G, Weinehall L, Soderberg S, Olsson T: Estrogen receptor alpha gene polymorphisms and first-ever intracerebral hemorrhage. Cerebrovasc Dis. 2007, 24: 500-508. 10.1159/000110419View ArticlePubMed
                          41. Pera J, Slowik A, Dziedzic T, Pulyk R, Wloch D, Szczudlik A: Glutathione peroxidase 1 C593T polymorphism is associated with lobar intracerebral hemorrhage. Cerebrovasc Dis. 2008, 25: 445-449. 10.1159/000126918View ArticlePubMed
                          42. Lim YH, Jeong YS, Kim SK, Kim DH, Yun DH, Yoo SD, Kim HS, Baik HH: Association between TGFBR2 gene polymorphism (rs2228048, Asn389Asn) and intracerebral hemorrhage in Korean population. Immunol Invest. 2011, 40: 569-580. 10.3109/08820139.2011.559498View ArticlePubMed
                          43. Kim DH, Ahn WY, Kim DK, Choe BK, Kim SK, Jo DJ, Kim JY, Chung JH, Jeong YS, Yun DH, Yoo SD, Kim HS, Baik HH: A Promoter polymorphism (rs17222919, -1316T/G) of ALOX5AP is associated with intracerebral hemorrhage in Korean population. Prostaglandins Leukot Essent Fatty Acids. 2011, 85: 115-120. 10.1016/j.plefa.2011.07.004View ArticlePubMed
                          44. Huang X, Chen P, Kaufer DI, Troster AI, Poole C: Apolipoprotein E and dementia in Parkinson disease: a meta-analysis. Arch Neurol. 2006, 63: 189-193. 10.1001/archneur.63.2.189View ArticlePubMed
                          45. Kauffman MA, Consalvo D, Moron DG, Lereis VP, Kochen S: ApoE epsilon4 genotype and the age at onset of temporal lobe epilepsy: a case–control study and meta-analysis. Epilepsy Res. 2010, 90: 234-239. 10.1016/j.eplepsyres.2010.05.007View ArticlePubMed
                          46. Niu W, Qi Y, Qian Y, Gao P, Zhu D: The relationship between apolipoprotein E epsilon2/epsilon3/epsilon4 polymorphisms and hypertension: a meta-analysis of six studies comprising 1812 cases and 1762 controls. Hypertens Res. 2009, 32: 1060-1066. 10.1038/hr.2009.164View ArticlePubMed
                          47. Elias-Sonnenschein LS, Viechtbauer W, Ramakers IH, Verhey FR, Visser PJ: Predictive value of APOE-epsilon 4 allele for progression from MCI to AD-type dementia: a meta-analysis. J Neurol Neurosurg Psychiatry. 2011, 82: 1149-1156. 10.1136/jnnp.2010.231555View ArticlePubMed
                          48. Rai TS, Khullar M, Sehrawat BS, Ahuja M, Sharma PK, Vijayvergiya R, Grover A: Synergistic effect between apolipoprotein E and apolipoprotein A1 gene polymorphisms in the risk for coronary artery disease. Mol Cell Biochem. 2008, 313: 139-146. 10.1007/s11010-008-9751-3View ArticlePubMed
                          49. Gong JS, Kobayashi M, Hayashi H, Zou K, Sawamura N, Fujita SC, Yanagisawa K, Michikawa M: Apolipoprotein E (ApoE) isoform-dependent lipid release from astrocytes prepared from human ApoE3 and ApoE4 knock-in mice. J Biol Chem. 2002, 277: 29919-29926. 10.1074/jbc.M203934200View ArticlePubMed
                          50. Buttini M, Orth M, Bellosta S, Akeefe H, Pitas RE, Wyss-Coray T, Mucke L, Mahley RW: Expression of human apolipoprotein E3 or E4 in the brains of Apoe-/- mice: isoform-specific effects on neurodegeneration. J Neurosci. 1999, 19: 4867-4880.PubMed
                          51. Nathan BP, Bellosta S, Sanan DA, Weisgraber KH, Mahley RW, Pitas RE: Differential effects of apolipoproteins E3 and E4 on neuronal growth in vitro. Science. 1994, 264: 850-852. 10.1126/science.8171342View ArticlePubMed
                          52. Bellosta S, Nathan BP, Orth M, Dong LM, Mahley RW, Pitas RE: Stable expression and secretion of apolipoproteins E3 and E4 in mouse neuroblastoma cells produces differential effects on neurite outgrowth. J Biol Chem. 1995, 270: 27063-27071. 10.1074/jbc.270.45.27063View ArticlePubMed
                          53. Trommer BL, Shah C, Yun SH, Gamkrelidze G, Pasternak ES, Ye GL, Sotak M, Sullivan PM, Pasternak JF, LaDu MJ: ApoE isoform affects LTP in human targeted replacement mice. Neuroreport. 2004, 15: 2655-2658. 10.1097/00001756-200412030-00020View ArticlePubMed
                          54. Gibson GE, Haroutunian V, Zhang H, Park LC, Shi Q, Lesser M, Mohs RC, Sheu RK, Blass JP: Mitochondrial damage in Alzheimer's disease varies with apolipoprotein E genotype. Ann Neurol. 2000, 48: 297-303. 10.1002/1531-8249(200009)48:3<297::AID-ANA3>3.0.CO;2-ZView ArticlePubMed
                          55. McCarron MO, Nicoll JA: Apolipoprotein E genotype and cerebral amyloid angiopathy-related hemorrhage. Ann N Y Acad Sci. 2000, 903: 176-179. 10.1111/j.1749-6632.2000.tb06366.xView ArticlePubMed
                          56. Walker E, Hernandez AV, Kattan MW: Meta-analysis: Its strengths and limitations. Cleve Clin J Med. 2008, 75: 431-439. 10.3949/ccjm.75.6.431View ArticlePubMed
                          57. Flather MD, Farkouh ME, Pogue JM, Yusuf S: Strengths and limitations of meta-analysis: larger studies may be more reliable. Control Clin Trials. 1997, 18: 568-579. discussion 661–566, 10.1016/S0197-2456(97)00024-XView ArticlePubMed

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