Journal of Glaucoma:
Apolipoprotein E Genotypes in Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma
Krumbiegel, Mandy MSc*; Pasutto, Francesca PhD*; Mardin, Christian Y. MD†; Weisschuh, Nicole PhD‡; Paoli, Daniela MD§; Gramer, Eugen MD∥; Weber, Bernhard H.F. MD¶; Kruse, Friedrich E. MD†; Schlötzer-Schrehardt, Ursula MD†; Reis, André MD*
*Institute of Human Genetics, University of Erlangen-Nuremberg
†Department of Ophthalmology, University Eye Hospital, Erlangen
‡Molecular Genetics Laboratory, University Eye Hospital, Tuebingen
∥University Eye Hospital, Wuerzburg
¶Institute of Human Genetics, University of Regensburg, Regensburg, Germany
§Department of Ophthalmology, Hospital of Monfalcone-Gorizia, Monfalcone-Gorizia, Italy
Supported by Grant SFB 539 from the German Research Foundation.
Reprints: André Reis, MD, Institute of Human Genetics, University of Erlangen-Nuremberg, Schwabachanlage 10, 91054 Erlangen, Germany (e-mail: firstname.lastname@example.org).
Received April 22, 2009
Accepted November 10, 2009
Purpose: Pseudoexfoliation (PEX) syndrome, an age-related, systemic, elastic microfibrillopathy, is characterized by fibrillar-granular deposits in the anterior segment of the eye. Although not representing a true amyloidosis, PEX syndrome shares some features with amyloid disorders, such as Alzheimer disease. It has been shown that amyloid-associated proteins also occur in association with PEX fibrils. Apolipoprotein E (Apo-E) is directly involved in these amyloid deposition and fibrils formation. The ε4 allele of APOE gene was shown to be associated both with an increased risk for coronary heart disease and late-onset Alzheimer disease. In this study, we therefore investigated whether APOE alleles are associated with PEX syndrome and/or PEX glaucoma (PEXG) in 2 large cohorts of German and Italian origin.
Methods: The 3 common APOE alleles ε2, ε3, and ε4 were genotyped in 661 unrelated patients (459 PEXG and 202 PEX patients) and 342 healthy individuals of German origin and furthermore in 209 unrelated patients (133 PEXG and 76 PEX patients) and 190 healthy individuals of Italian origin using TaqMan assays for allelic discrimination. A genetic association study was then performed.
Results: The ε3 allele was found to be the most common in both populations (80% to 83%), whereas the ε2 allele was the rarest (6% to 9%). No significant differences in allele and genotype frequencies between both groups were observed in either population.
Conclusion: Our data show that APOE genotypes are not associated with PEX and PEXG in either Germans or Italians.
Pseudoexfoliation (PEX) syndrome represents a complex, late-onset, generalized disease of the extracellular matrix characterized by the progressive, stable deposition of abnormal fibrillar aggregates in various intraocular and extraocular tissues.1 Its clinical manifestations involve all tissues of the anterior segment of the eye resulting in marked intraocular changes. In fact, PEX is also one of the most common identifiable causes of open-angle glaucoma accounting for about 25% of all open-angle glaucoma worldwide.2 The characteristic pathologic changes are thought to occur as a consequence of a stress-induced elastosis, associated with the excessive production and abnormal aggregation of elastic fiber components, enzymatic cross-linking processes, and impaired protection mechanisms against oxidative and cellular stress.1,3,4 PEX syndrome affects approximately 10% to 20% of the general population above the age of 60 years worldwide but its prevalence markedly varies between geographic populations.5–7 The etiology of PEX is poorly understood, but it most likely represents a complex disease in which environmental factors impact on an individual's genetic background.5,6
A strong genetic risk factor for PEX syndrome and PEX glaucoma (PEXG) has been recently identified. Thorleifsson et.al8 established a significant association between 2 common single nucleotide polymorphisms (SNPs) of the lysyl oxidase-like 1 (LOXL1) gene and both forms of the disease in Northern European populations. This association has been subsequently confirmed in different populations worldwide.9–15 Further, experimental data provided evidence that LOXL1 is a major component of PEX fibers in clear colocalization with elastic fiber components and suggested an involvement of LOXL1 in the initial stages of the abnormal fibrogenesis.16
Although not representing true amyloidosis,the PEX syndrome has been reported to share some features with amyloid disorders, such as Alzheimer disease (AD).1 Congo Red-positive material and amyloid-β peptide were found to be present in the aqueous humor of PEX patients.17,18 Amyloid-associated proteins, such as amyloid P component and apolipoproteins, also occur in association with PEX fibrils.19,20 These analogies suggested that PEX may be a conformational disorder, such as AD, which is characterized by the accumulation of a host protein that undergoes structural changes.1
It is known that apolipoprotein E (Apo-E) promotes the aggregation of amyloidogenic proteins into the β-pleated sheet conformation which is typical of all amyloid deposits. Thus Apo-E is directly involved in amyloid deposition and fibril formation.21,22 Mature Apo-E is a 34 kd glycosylated protein composed of 299 amino acids. The 3 major protein isoforms Apo-E2, E3, and E4, respectively, are coded by 3 alleles—ε2, ε3, and ε4. These 3 isoforms differ in amino acid sequence at 2 positions: amino acid residues 112 and 158 (respectively residues 130 and 176 considering the full-length amino acid sequence of the unprocessed protein).23,24 The SNP rs429358 results in a cysteine to arginine exchange at position 112 of the mature protein, the SNP rs7412 in an arginine to cysteine exchange at position 158. The ε3—ancestral allele—codes for cysteine/arginine, ε2 for cysteine/cysteine, and ε4 for arginine/arginine at positions 112/158. Allele ε4 of APOE has been shown to be associated with cerebral and systemic amyloid disorders such as late-onset AD and prion disorders, but also with an increased risk of cardiovascular disease.25,26 Different studies have also examined the association of APOE alleles and ocular diseases. The risk and protective role of the diverse APOE alleles have been widely established in age-related macular degeneration.27–32 In primary open-angle glaucoma, a number of studies showed association of APOE alleles to the disease,33–37 whereas others did not.38–41 An earlier study has also been suggested that APOE alleles may represent a risk factor for developing PEX syndrome. In fact, Yilmaz et al42 detected an association between APOE allele ε2 and the development of PEX in a Turkish population, whereas the allele ε3 was found to be protective. However, these results could not be replicated in another association study with PEX patients of Norwegian origin.43
In this study, we have therefore investigated whether APOE alleles are associated with PEX syndrome and/or PEXG in 2 large patients' cohorts of German and Italian origin.
The groups of patients consisted of 661 subjects of German origin (459 PEXG and 202 PEX patients) and 209 subjects of Italian origin (133 PEXG and 76 PEX patients). All individuals underwent standardized clinical examination for signs of PEX syndrome at the Ophthalmologic Department of the Universities of Erlangen-Nuremberg and Wuerzburg (Germany) or at the Ophthalmologic Department of the Monfalcone Hospital (Italy). All PEX patients had to have manifest PEX material on the anterior lens capsule and/or pupillary margin in mydriasis by slit-lamp biomicroscopy. Secondary open-angle glaucoma due to PEX syndrome was defined, if elevated intraocular pressure (>20 mm Hg), an open chamber angle, characteristic visual field defects in computed perimetry, and characteristic glaucomatous disc atrophy were found in the presence of manifest PEX deposits on the anterior lens capsule and/or pupillary margin.
A total of 342 healthy German subjects and 190 healthy Italian subjects were recruited from the same geographic regions as the patients. They underwent ophthalmologic examinations. Overall, healthy individuals had intraocular pressure levels below 20 mm Hg, no glaucomatous disc damage, no PEX material deposits on anterior lens capsule and/or pupillary margin, no clinical signs indicating early or suspect PEX (eg, atrophy of the iridal pigment epithelium at the pupillary margin, secondary melanin dispersion in the chamber angle and anterior chamber after dilation of the pupil, no dew-like condensation on the anterior lens capsule, and normal mydriasis), and no family history of PEX or glaucoma. Visual acuity was at least 0.8 and the optic media were clear for ophthalmologic examination. All subjects gave informed consent before entering the study. Age and sex distribution of the groups of patients and control subjects are shown in Table 1. Mean ages of the PEX patients and control subjects present respectively with a difference among groups (P=0.002 for German cohorts and P=0.015 for Italian cohorts). Sex distribution was not different among groups (P=0.520 for German cohorts and P=0.491 for Italian cohorts).
Genomic DNAs were extracted from peripheral blood leukocytes of patients and control individuals with automated techniques (AutoGenFlex 3000, MA) using Flexigene chemistry (QIAGEN, Hilden, Germany). The 2 SNPs rs429358 and rs7412 in APOE gene, which determine the APOE allele, were genotyped using predeveloped TaqMan genotyping assays (Applied Biosystems, Foster City, CA). Reactions were prepared according to manufacturers instructions and analyzed on an ABI Prism 7900 HT sequence detection system (Applied Biosystems) using standard thermal cycling conditions. Hardy-Weinberg equilibrium for the SNPs was confirmed and the genotyping rate was greater than 98%. Genotype data were verified by direct sequencing of 24 randomly chosen samples. The concordance between genotypes, obtained with TaqMan and sequencing assay, was 100%.
Statistical analysis was performed using the program Haploview version 4.0.44 The 6 APOE genotypes were reconstructed with the program PHASE version 2.145,46 and differences in genotype distributions between patients and controls were detected using χ2 statistics. A P value of ≤0.05 was considered statistically significant.
Calculations of samples size power to detect an association with PEX were performed using the program QUANTO version 1.2.447 (http://hydra.usc.edu/gxe). Considering a PEX prevalence of 4% in the German population, we have 75% power with our patients sample to detect effects with an odds ratio greater than 1.6 and more than 90% for effects with an odds ratio greater than 1.8 for the ε2 risk allele.
This study was approved by the ethical review board of the Medical Faculty of the University of Erlangen-Nuremberg (Germany) and that of the hospital in Monfalcone-Gorizia (Italy) and was in adherence to the tenets of the Declaration of Helsinki.
Genotyping of the 2 SNPs, rs429358 and rs7412, which determine the APOE alleles (TT=ε2, TC=ε3, and CC=ε4) was performed in 661 German and 209 Italian patients as well as in 342 German and 190 Italian control individuals. No significant difference in allele frequencies between PEX patients and healthy subjects was detected either in German or Italian populations. The same result was obtained after subclassification of the PEX patients in PEX syndrome and PEXG (Table 2).
Analysis of the 6 APOE genotypes (ε2/ε2, ε3/ε3, ε4/ε4, ε2/ε3, ε2/ε4, and ε3/ε4) was performed using the program PHASE version 2.145,46 (Table 3). An equal distribution of APOE genotypes was found between all patients and related control groups of both German and Italian origin. The ε3/ε3 represented the main genotype observed in all groups analyzed (63.5% to 70.7%). The other 2 homozygous genotypes ε2/ε2 and ε4/ε4 were very rare. Interestingly, genotype ε2/ε2, which was earlier shown to be associated with PEX disease,42 was not found at all in Italian patients but only in 1.6% of the Italian controls. Combination of the genotype data of the 2 patient groups, PEX and PEXG (Table 3), showed only for the heterozygous genotype ε2/ε3 an apparent nominally significant difference in frequency between PEX patients and control subjects in the Italian population (P=0.047, Table 3). Nevertheless, this difference did not remain statistically significant after correction for multiple testing as corrected P value is greater than 0.05.
We compared the allele frequencies of the 2 APOE polymorphisms conditioned on the presence of the identified LOXL1 common risk haplotype G-G, which is composed of the major alleles G of the 2 coding SNPs, rs1048661 and rs3825942. We stratified our German and Italian cohorts and control groups for carriers and noncarriers of the risk haplotype G-G. We did not find any significant differences in LOXL1 carriers and noncarriers suggesting no additive or interactive effects between LOXL1 and APOE.
PEX syndrome has been reported to share common features with amyloid disorders, such as AD, because Congo-Red positive material and amyloid-β peptide were found to be present in the aqueous humor of PEX patients17,18 and because amyloid-associated proteins, such as amyloid P component, were found to occur in association with PEX fibrils.1,19 In addition, clinical studies have provided evidence for an association between PEX and AD.48 Studies supported the concept that Apo-E is directly involved in amyloid formation and deposition and suggested a close association between one of the main isoforms of Apo-E encoded by the ε4 allele and both familial and sporadic late-onset AD.21,22 In addition, extracellular deposits in other forms of amyloidoses and prion diseases, such as Down syndrome, Creutzfeldt-Jakob disease, Lewy body dementia, and Parkinson disease, were shown to contain both biochemically and immunohistochemically detectable amounts of Apo-E.49–53 Thus, the molecular action of Apo-E seems to be not specific for AD but to represent a more common feature in the development of various amyloid-like fibrillar aggregates. Recently, the presence of Apo-E within extracellular PEX material has been determined,54 also other classes of apolipoproteins, such as clusterin (apolipoprotein J) and apolipoprotein D, have been shown to be associated with PEX material or to be upregulated in ocular tissues of PEX patients.3,20,55,56 However, our current study did not find evidence of a significant association between any APOE allele and PEX disease in either German or Italian populations. This result questions the positive association between PEX and the å2 allele found in the study by Yilmaz et al42 including 76 PEX patients of Turkish origin. Several factors, such as population-specific differences in disease-susceptibility loci or most probably insufficient statistical power in the earlier studies, could explain the discrepancy. However, on the basis of our considerably larger patient cohorts analyzed, we suggest that APOE alleles can not be considered as principal risk factors for the development of PEX syndrome or PEXG. In addition, the present data do not support previous observations that the distribution of APOE alleles is different between Northern European and Mediterranean countries such as Italy, Turkey, and Greece.57,58 At least in the German and Italian populations studied, we have observed an equal distribution of all APOE genotypes.
The lack of any association between APOE genetic polymorphisms and PEX syndrome/glaucoma indicates a distinct etiopathology between PEX and AD. PEX syndrome has been characterized as a generalized elastosis associated with the excessive production of elastic microfibrils and their abnormal aggregation into insoluble PEX material.1 The fibrillar core of this material has been shown to contain predominantly epitopes of elastic fibers, such as elastin, tropoelastin, vitronectin, and components of elastic microfibrils, such as fibrillin-1, fibulin-2, microfibril-associated glycoprotein-1, and latent TGF-β binding proteins-1 and 2.2,55 Despite certain analogies between PEX syndrome and amyloid disorders,17,18 the early suggestion that PEX material is a form of amyloid6 has never been confirmed and the amyloid theory on the pathogenesis of PEX syndrome could not be substantiated.59 Nevertheless, common pathogenetic steps, such as the formation of misfolded proteins stably accumulating in form of plaques and fibrils by aggregation, cross-linking processes, and posttranslational modifications, may be involved in both entities.
Future search for other genetic and external factors involved in this complex and multifactorial disease are now needed to understand its pathogenic mechanism.
The authors thank all patients and control individuals for participation in this study. They also thank Juliane Niedziella for invaluable help with patient recruitment and Olga Zwenger for technical support.
1. Schlotzer-Schrehardt U, Naumann GO. Ocular and systemic pseudoexfoliation syndrome. Am J Ophthalmol. 2006;141:921–937
2. Ritch R, Schlotzer-Schrehardt U. Exfoliation syndrome. Surv Ophthalmol. 2001;45:265–315
3. Zenkel M, Poschl E, Von der Mark K, et al. Differential gene expression in pseudoexfoliation syndrome. Invest Ophthalmol Vis Sci. 2005;46:3742–3752
4. Zenkel M, Kruse FE, Naumann GO, et al. Impaired cytoprotective mechanisms in eyes with pseudoexfoliation syndrome/glaucoma. Invest Ophthalmol Vis Sci. 2007;48:5558–5566
5. Forsius H, Forsman E, Fellman J, et al. Exfoliation syndrome: frequency, gender distribution and association with climatically induced alterations of the cornea and conjunctiva. Acta Ophthalmol Scand. 2002;80:478–484
6. Ringvold A. Epidemiology of the pseudo-exfoliation syndrome. Acta Ophthalmol Scand. 1999;77:371–375
7. Rao RQ, Arain TM, Ahad MA. The prevalence of pseudoexfoliation syndrome in Pakistan. Hospital based study. BMC Ophthalmol. 2006;6:27
8. Thorleifsson G, Magnusson KP, Sulem P, et al. Common sequence variants in the LOXL1 gene confer susceptibility to exfoliation glaucoma. Science. 2007;317:1397–1400
9. Pasutto F, Krumbiegel M, Mardin CY, et al. Association of LOXL1 common sequence variants in German and Italian patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma. Invest Ophthalmol Vis Sci. 2008;49:1459–1463
10. Ramprasad VL, George R, Soumittra N, et al. Association of non-synonymous single nucleotide polymorphisms in the LOXL1 gene with pseudoexfoliation syndrome in India. Mol Vis. 2008;14:318–322
11. Ozaki M, Lee KY, Vithana EN, et al. Association of LOXL1 gene polymorphisms with pseudoexfoliation in the Japanese. Invest Ophthalmol Vis Sci. 2008;49:3976–3980
12. Fan BJ, Pasquale L, Grosskreutz CL, et al. DNA sequence variants in the LOXL1 gene are associated with pseudoexfoliation glaucoma in a U.S. clinic-based population with broad ethnic diversity. BMC Med Genet. 2008;9:5
13. Aragon-Martin JA, Ritch R, Liebmann J, et al. Evaluation of LOXL1 gene polymorphisms in exfoliation syndrome and exfoliation glaucoma. Mol Vis. 2008;14:533–541
14. Hewitt AW, Sharma S, Burdon KP, et al. Ancestral LOXL1 variants are associated with pseudoexfoliation in Caucasian Australians but with markedly lower penetrance than in Nordic people. Hum Mol Genet. 2008;17:710–716
15. Fingert JH, Alward WL, Kwon YH, et al. LOXL1 mutations are associated with exfoliation syndrome in patients from the midwestern United States. Am J Ophthalmol. 2007;144:974–975
16. Schlotzer-Schrehardt U, Pasutto F, Sommer P, et al. Genotype-correlated expression of lysyl oxidase-like 1 in ocular tissues of patients with pseudoexfoliation syndrome/glaucoma and normal patients. Am J Pathol. 2008;173:1724–1735
17. Janciauskiene S, Krakau T. Alzheimer's peptide: a possible link between glaucoma, exfoliation syndrome and Alzheimer's disease. Acta Ophthalmol Scand. 2001;79:328–329
18. Berlau J, Lorenz P, Beck R, et al. Analysis of aqueous humour proteins of eyes with and without pseudoexfoliation syndrome. Graefes Arch Clin Exp Ophthalmol. 2001;239:743–746
19. Li ZY, Streeten BW, Yohai N. Amyloid P protein in pseudoexfoliative fibrillopathy. Curr Eye Res. 1989;8:217–227
20. Zenkel M, Kruse FE, Junemann AG, et al. Clusterin deficiency in eyes with pseudoexfoliation syndrome may be implicated in the aggregation and deposition of pseudoexfoliative material. Invest Ophthalmol Vis Sci. 2006;47:1982–1990
21. Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to beta-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A. 1993;90:1977–1981
22. Castano EM, Prelli FC, Frangione B. Apolipoprotein E and amyloidogenesis. Lab Invest. 1995;73:457–460
23. Weisgraber KH, Rall SC Jr, Mahley RW. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J Biol Chem. 1981;256:9077–9083
24. Rall SC Jr, Weisgraber KH, Innerarity TL, et al. Structural basis for receptor binding heterogeneity of apolipoprotein E from type III hyperlipoproteinemic subjects. Proc Natl Acad Sci U S A. 1982;79:4696–4700
25. Song Y, Stampfer MJ, Liu S. Meta-analysis: apolipoprotein E genotypes and risk for coronary heart disease. Ann Intern Med. 2004;141:137–147
26. Prasher VP, Sajith SG, Rees SD, et al. Significant effect of APOE epsilon 4 genotype on the risk of dementia in Alzheimer's disease and mortality in persons with Down syndrome. Int J Geriatr Psychiatry. 2008;23:1134–1140
27. Klaver CC, Kliffen M, Van Duijn CM, et al. Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet. 1998;63:200–206
28. Schmidt S, Saunders AM, De La Paz MA, et al. Association of the apolipoprotein E gene with age-related macular degeneration: possible effect modification by family history, age, and gender. Mol Vis. 2000;6:287–293
29. Schultz DW, Klein ML, Humpert A, et al. Lack of an association of apolipoprotein E gene polymorphisms with familial age-related macular degeneration. Arch Ophthalmol. 2003;121:679–683
30. Zareparsi S, Reddick AC, Branham KE, et al. Association of apolipoprotein E alleles with susceptibility to age-related macular degeneration in a large cohort from a single center. Invest Ophthalmol Vis Sci. 2004;45:1306–1310
31. Baird PN, Guida E, Chu DT, et al. The epsilon2 and epsilon4 alleles of the apolipoprotein gene are associated with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2004;45:1311–1315
32. Utheim OA, Ritland JS, Utheim TP, et al. Apolipoprotein E genotype and risk for development of cataract and age-related macular degeneration. Acta Ophthalmol. 2008;86:401–403
33. Al-Dabbagh NM, Al-Dohayan N, Arfin M, et al. Apolipoprotein E polymorphisms and primary glaucoma in Saudis. Mol Vis. 2009;15:912–919
34. Junemann A, Bleich S, Reulbach U, et al. Prospective case control study on genetic assocation of apolipoprotein epsilon2 with intraocular pressure. Br J Ophthalmol. 2004;88:581–582
35. Mabuchi F, Tang S, Ando D, et al. The apolipoprotein E gene polymorphism is associated with open angle glaucoma in the Japanese population. Mol Vis. 2005;11:609–612
36. Vickers JC, Craig JE, Stankovich J, et al. The apolipoprotein epsilon4 gene is associated with elevated risk of normal tension glaucoma. Mol Vis. 2002;8:389–393
37. Yuan HP, Xiao Z, Yang BB. A study on the association of apolipoprotein E genotypes with primary open-angle glaucoma and primary angle-closure glaucoma in northeast of China. Zhonghua Yan Ke Za Zhi. 2007;43:416–420
38. Jia LY, Tam PO, Chiang SW, et al. Multiple gene polymorphisms analysis revealed a different profile of genetic polymorphisms of primary open-angle glaucoma in northern Chinese. Mol Vis. 2009;15:89–98
39. Ressiniotis T, Griffiths PG, Birch M, et al. Apolipoprotein E promoter polymorphisms do not have a major influence on the risk of developing primary open angle glaucoma. Mol Vis. 2004;10:805–807
40. Saglar E, Yucel D, Bozkurt B, et al. Association of polymorphisms in APOE, p53, and p21 with primary open-angle glaucoma in Turkish patients. Mol Vis. 2009;15:1270–1276
41. Zetterberg M, Tasa G, Palmer MS, et al. Apolipoprotein E polymorphisms in patients with primary open-angle glaucoma. Am J Ophthalmol. 2007;143:1059–1060
42. Yilmaz A, Tamer L, Ates NA, et al. Effects of apolipoprotein E genotypes on the development of exfoliation syndrome. Exp Eye Res. 2005;80:871–875
43. Ritland JS, Utheim TP, Utheim OA, et al. Effects of APOE and CHRNA4 genotypes on retinal nerve fibre layer thickness at the optic disc and on risk for developing exfoliation syndrome. Acta Ophthalmol Scand. 2007;85:257–261
44. Barrett JC, Fry B, Maller J, et al. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–265
45. Stephens M, Smith NJ, Donnelly P. A new statistical method for haplotype reconstruction from population data. Am J Hum Genet. 2001;68:978–989
46. Stephens M, Scheet P. Accounting for decay of linkage disequilibrium in haplotype inference and missing-data imputation. Am J Hum Genet. 2005;76:449–462
47. Wang ZP, Li HQ. Sample size requirements for association studies on gene-gene interaction in case-control study. Zhonghua Liu Xing Bing Xue Za Zhi. 2004;25:623–626
48. Linner E, Popovic V, Gottfries CG, et al. The exfoliation syndrome in cognitive impairment of cerebrovascular or Alzheimer's type. Acta Ophthalmol Scand. 2001;79:283–285
49. Benjamin R, Leake A, Ince PG, et al. Effects of apolipoprotein E genotype on cortical neuropathology in senile dementia of the Lewy body and Alzheimer's disease. Neurodegeneration. 1995;4:443–448
50. Arai H, Higuchi S, Muramatsu T, et al. Apolipoprotein E gene in diffuse Lewy body disease with or without co-existing Alzheimer's disease. Lancet. 1994;344:1307
51. Arai H, Muramatsu T, Higuchi S, et al. Apolipoprotein E gene in Parkinson's disease with or without dementia. Lancet. 1994;344:889
52. Schupf N, Kapell D, Lee JH, et al. Onset of dementia is associated with apolipoprotein E epsilon4 in Down's syndrome. Ann Neurol. 1996;40:799–801
53. Wisniewski T, Frangione B. Apolipoprotein E: a pathological chaperone protein in patients with cerebral and systemic amyloid. Neurosci Lett. 1992;135:235–238
54. Sharma S, Chataway T, Burdon KP, et al. Identification of LOXL1 protein and Apolipoprotein E as components of surgically isolated pseudoexfoliation material by direct mass spectrometry. Exp Eye Res. 2009;89:479–485
55. Ovodenko B, Rostagno A, Neubert TA, et al. Proteomic analysis of exfoliation deposits. Invest Ophthalmol Vis Sci. 2007;48:1447–1457
56. Krumbiegel M, Pasutto F, Mardin CY, et al. Exploring functional candidate genes for genetic association in German patients with pseudoexfoliation syndrome and pseudoexfoliation glaucoma. Invest Ophthalmol Vis Sci. 2009;50:2796–2801
57. Corbo RM, Scacchi R, Mureddu L, et al. Apolipoprotein E polymorphism in Italy investigated in native plasma by a simple polyacrylamide gel isoelectric focusing technique. Comparison with frequency data of other European populations. Ann Hum Genet. 1995;59:197–209
58. Sklavounou E, Economou-Petersen E, Karadima G, et al. Apolipoprotein E polymorphism in the Greek population. Clin Genet. 1997;52:216–218
59. Morrison JC, Green WR. Light microscopy of the exfoliation syndrome. Acta Ophthalmol Suppl. 1988;184:5–27
pseudoexfoliation syndrome; association study; apolipoprotein E
This article has been cited 4 time(s).
British Journal of OphthalmologyPseudoexfoliation syndrome: don't brush it offBritish Journal of Ophthalmology
British Journal of OphthalmologyThe long-term psychosocial impact of correction surgery for adults with strabismusBritish Journal of Ophthalmology
Journal of ProteomicsMALDI MS imaging analysis of apolipoprotein E and lysyl oxidase-like 1 in human lens capsules affected by pseudoexfoliation syndromeJournal of Proteomics
OphthalmologyPseudoexfoliation: Normative Data and Associations The Beijing Eye Study 2011Ophthalmology
© 2010 Lippincott Williams & Wilkins, Inc.
Highlight selected keywords in the article text.