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Ophthalmic Molecular Genetics |

The Role of Apolipoprotein E Gene Polymorphisms in Primary Open-angleGlaucoma FREE

Thomas Ressiniotis, MRCOphth; Philip G. Griffiths, FRCOphth; Michael Birch, FRCOphth; Sharon Keers; Patrick F. Chinnery, PhD MRCP
[+] Author Affiliations

From the Department of Ophthalmology, Royal Victoria Infirmary (DrsRessiniotis, Griffiths, and Birch), and Department of Neurology, Medical School,University of Newcastle upon Tyne (Drs Ressiniotis and Chinnery and Ms Keers),Newcastle upon Tyne, England. The authors have no relevant financial interestin this article.


Section Editor: Edwin M. Stone, MD, PhD

More Author Information
Arch Ophthalmol. 2004;122(2):258-261. doi:10.1001/archopht.122.2.258.
Text Size: A A A
Published online

Objective  To test the hypothesis that genetic polymorphisms of the apolipoproteinE (APOE) gene are associated with primary open-angleglaucoma (POAG), based on the association between neurodegenerative diseasesand the APOE genotype.

Methods  Genomic DNA was examined from an unrelated cohort of 137 POAG patientsand 75 control subjects from the ophthalmology department of the Royal VictoriaInfirmary. The APOE allele frequency (ϵ2, ϵ3,and ϵ4 alleles) was studied by polymerase chain reaction amplificationof the related locus (19q13.2), enzymatic digestion of the products, gel electrophoresis,and imaging under UV illumination. For statistical analysis, we used a logisticregression model that included intraocular pressure as a continuous variableto study the possible correlation between POAG and APOE allele frequency.

Results  Logistic regression analysis showed no statistically significant associationbetween the frequency of the APOE allele and POAGfor the population studied, irrespective of the IOP (ϵ2 odds ratio, 0.82;95% confidence interval, 0.12-5.79 [P = .84]; ϵ3odds ratio, 0.39; 95% confidence interval, 0.10-1.49 [P = .17]; and ϵ4 odds ratio, 3.84; 95% confidence interval, 0.80-18.49[P = .09]).

Conclusion  In our cohort, the APOE genotype does not constitutea risk factor for developing POAG, even in patients with normal-tension glaucoma.

Clinical Relevance  Apolipoprotein E polymorphisms do not appear to be contributory to POAG.

Figures in this Article

Primary open-angle glaucoma (POAG) is one of the most common causesof blindness and affects approximately 70 million people worldwide.1 It is thought to be a neurodegenerative disease witha significant hereditary element.2 It is likelythat POAG is a complex trait with multiple genes contributing to the phenotype.3 Defining the genetic factors behind glaucoma willadvance our understanding of the pathogenesis of visual failure and may leadto the development of novel treatments.

Clinical studies4,5 haveshown an association between glaucoma and Alzheimer disease (AD), which isalso a complex trait. The most important identified genetic risk factor forthe neurodegeneration in sporadic AD is the apolipoprotein E (APOE) genotype.6 Apolipoprotein E isthe major apolipoprotein of the central nervous system, where it is synthesizedby glia, macrophages, and neurons.7 ApolipoproteinE exists in 3 common isoforms, E2, E3, and E4, encoded by the corresponding APOE gene alleles, ϵ2, ϵ3, and ϵ4.7,8 It is therefore possible that the APOE genotype is a common risk factor for neurodegenerationand explains the association between AD and glaucoma. This hypothesis wassupported by the results of a single study9 reportingan association between normal-tension glaucoma and the APOE ϵ4 allele. However, normal-tension glaucoma only accountsfor approximately 30% of glaucoma cases,10 andthe intraocular pressure (IOP) cutoff defining normal-tension glaucoma isin fact arbitrary. To clarify the role of APOE inglaucoma, we investigated the role of APOE polymorphismsas risk factors for POAG in a population in northeast England, using a statisticalapproach that controls for the effects of IOP without making a distinctionbetween low and high pressure.

Having obtained ethics approval from our local research ethics committee,blood samples were analyzed from an unrelated cohort of 137 POAG patientsand 75 control subjects, from the same population.

The definition for POAG included characteristic cupping of the opticdisc, open iridocorneal angle, and typical glaucomatous visual field defects.An experienced ophthalmologist (M.B.), specializing in glaucoma, clinicallyexamined the patients and controls. The highest pretreatment IOP and the cup-discratio were recorded and analyzed as variables. We excluded patients with IOPshigher than 30 mm Hg and secondary types of glaucoma (pseudoexfoliative, pigmentdispersion syndrome, and trauma- or corticosteroid-induced). Patients withIOPs higher than 30 mm Hg were excluded to maximize the chance of detectingpolymorphisms that exert their effect by increasing the vulnerability of theoptic nerve to damage. All controls were older than 65 years and had normalIOPs and optic discs.

GENOMIC DNA GENOTYPING

The genomic DNA was amplified by polymerase chain reaction of the relatedlocus (19q13.2). For each patient, 1 µL of DNA was mixed with 1 U of Taq DNA polymerase (Promega, Madison, Wis), 10× Promegabuffer, 2-mmol deoxyribonucleoside triphosphate, 10% dimethyl sulfoxide, 0.25µmol/L of each oligonucleotide (primer), and water to a total volumeof 50 µL. The primers used were forward (5'-TCC AAG GAG CTG CAG GCGGCG CA-3') and reverse (5'-ACA GAA TTC GCC CCG GCC TGG TAC ACT GCC A-3').Reactions were treated in a thermal cycle machine to incubation at 94°Cfor 2 minutes, followed by 40 cycles at 65°C for 1 minute, 72°C for1 minute, 94°C for 30 seconds, and a final incubation at 72°C for10 minutes.

The products were then digested separately per sample with 2 restrictionenzymes, Hae II and Afl III(New England Biolabs Inc, Beverly, Mass). The Hae IIdigestion mixture contained 20 µL of polymerase chain reaction product,5 U of enzyme, 0.3 µL of bovine serum albumin, and 3 µL of buffer(buffer 4, New England Biolabs Inc). The Afl IIIdigestion mixture contained 20 µL of polymerase chain reaction product,1 U of enzyme, 0.3 µL of bovine serum albumin, and 3 µL of buffer(buffer 3, New England Biolabs Inc). Water was added to create a total volumeof 30 µL per sample. Both reactions were allowed to proceed for at least12 hours at 37°C.

The resulting fragments were separated by electrophoresis on a 4% MicroSieveagarose gel (Flowgen; Ashby de la Zouch, Leicestershire, England) and visualizedby ethidium bromide staining with a digital camera.

APOE ϵ3 alleles were digested by bothenzymes (Afl III results in 50- and 177–basepair [bp] fragments, and Hae II results in 32- and195-bp fragments) where ϵ4 alleles lack the restriction site for Afl III and ϵ2 alleles lack the restriction site for Hae II. Therefore, the genotype was obtained by combiningthe band patterns for the 2 enzymes per sample.11

STATISTICAL ANALYSIS

To minimize the chance of detecting a spurious statistical association,we used a logistic regression model to simultaneously study the effect ofmultiple variables and their interactions when comparing POAG patients withcontrols.12 The model assumes that the logarithmof the odds ratio (OR) is a linear function of the variables included in themodel: Graphic Jump LocationImage not available.

where P indicates the probability of beingaffected; X1, X2, . . . ...Xn, the chosen predictor variables; B0, the intercept for the regression equation; and B1, B2, . . . ...Bn, the coefficients reflectingthe nature of each predictor. For the analysis, the predictor variables wereage, IOP, cup-disc ratio, and APOEgenotype. All the variables were added tothe model with stringent forward-selection criteria using Minitab version13.1 statistical package (Minitab Inc, State College, Pa).

Our cohort consisted of 137 POAG patients and 75 controls. The median± SD age was 73.0 ± 8.0 years (range, 51-87 years) for the POAGpatients and 78.0 ± 4.4 years (range, 68-90 years) for the controls.The mean ± SD IOP was 20.8 ± 2.6 mm Hg for the POAG patientsand 16.2 ± 3.4 mm Hg for the controls (Figure 1). The median cup-disc ratios were 0.8 and 0.3 for POAGpatients and controls, respectively (Figure2).

Place holder to copy figure label and caption
Figure 1.

Distribution of intraocular pressurein patients with primary open-angle glaucoma and control subjects.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Distribution of cup-disc ratioin patients with primary open-angle glaucoma and control subjects.

Graphic Jump Location

The frequency of ϵ2, ϵ3, and ϵ4 alleles in affected andunaffected individuals is shown in Table1. Logistic regression analysis confirmed that our patient and controlgroups were matched for age and sex but showed no evidence of an associationbetween ϵ2, ϵ3, and ϵ4 allele frequency and POAG (Table 2), irrespective of IOP (ϵ2OR, 0.82; 95% confidence interval, 0.12-5.79 [P =.84]; ϵ3 OR, 0.39; 95% confidence interval, 0.10-1.49 [P = .17]; and ϵ4 OR, 3.84; 95% confidence interval, 0.80-18.49[P = .09]).

Table Graphic Jump LocationTable 1. Frequency of APOE Alleles in Patientsand Control Subjects*
Table Graphic Jump LocationTable 2. Results of Logistic Regression Analysis Between Patients andControl Subjects

Apolipoprotein E, a 36-kDa glycoprotein, is the major apolipoproteinof the central nervous system, where it is synthesized by retinal Müllercells, glia, macrophages, and neurons.13,14 ApolipoproteinE plays an important role in neural function and is involved in neurite outgrowthand repair from injury.15 It is up-regulatedin response to oxidative stress and appears to act as an antioxidant. Apolipoproteinisoforms may affect the onset and severity of several neurodegenerative disorders,and the strongest association is with AD. The APOE ϵ4allele is associated with 40% to 50% of sporadic and familial AD, comparedwith a 30% frequency of the allele in the general population.8APOE alleles have been reported to have an effect on recoveryfrom head injury.8,15 There isalso association between the ϵ4 allele and severe progression of multiplesclerosis and reduced survival time in amyotrophic lateral sclerosis.7

Primary open-angle glaucoma can be considered a neurodegenerative disease16 with a significant hereditary element.2 Thestrongest risk factors for glaucomatous optic atrophy are raised IOP and age.However, it is clear that multiple risk factors operate, some of which areas yet undetermined.17 There is evidence fromtwin studies, case-control studies, and population studies of a heritableelement to POAG.2 The risk of glaucoma in first-degreerelatives is 2 to 4 times greater than that in the general population.18 Recently, several genes have been identified thatmay contribute to POAG,3,19 includingmyocilin,20OPA1,21 and OPTN.22 Itis likely that POAG is a complex trait with multiple genes contributing tothe phenotype, along with environmental factors.

There is evidence that the prevalence of POAG is higher in AD patients.A retrospective study4 of medical records ofpatients with POAG found that those with AD had more rapid progression oftheir disc cupping than those without AD. Another study5 showedthat AD and Parkinson disease occur more commonly in patients with POAG. Furthermore,at the cellular level, similar neurofilament triplet proteins susceptibleto neurofibrillary tangle formation were identified in AD and POAG.23 This raises the interesting possibility that the APOE genotype is a common genetic risk factor for the neurodegenerationin POAG and other neurodegenerative diseases.

This study showed no association between APOE genotypeand POAG. The frequency of the APOE ϵ4 allelein our control population was 13%. Power calculations indicate that we had87% power to detect an OR of 3.00 at the P = .05significance level. Our findings are in agreement with a previous study24 carried out on a French cohort with POAG, but theycontrast with those of a previous study9 thatreported an increased frequency of the APOE ϵ4allele in a Tasmanian population with normal-tension glaucoma. There are severalpossible explanations for this discrepancy. It is possible that APOE might have a more obvious effect in populations exposed to differentenvironmental factors or with a different genetic background. An alternativeexplanation is that our patients were defined differently compared with theprevious study. The choice of a normotensive cohort, which has also been usedby other authors,21 eliminates the strongestrisk factor (IOP) and may make a study more sensitive to underlying neurodegenerativerisk factors. However, the arbitrary division of POAG into normal- and high-tensiontypes may be unhelpful and misleading because POAG represents a spectrum ofphenotypes. Such a distinction based on a specific level of IOP, if wronglychosen, could conceal the true risk factors that operate in POAG or couldreveal spurious associations through artificial stratification.16 Toresolve these issues, we used a logistic regression model that controls forany effect of IOP during the analysis, without drawing an arbitrary cutoff,enabling a direct analysis of the effects of APOE genotypeirrespective of the IOP. This approach also minimizes the chance of detectinga false-positive result (type I error). This statistical approach may proveto be useful in further studies of POAG, as it allows for a more holisticview of the disease.

There is a strong rationale for pursuing further studies of apolipoproteinE as an etiological factor in glaucoma. Our study suggests that it is notthe isoform itself that is important, but the effect may be more subtle, possiblyinvolving different levels of APOE expression inthe optic nerve. This is supported by the recent finding of an associationbetween POAG and polymorphisms in the APOE promoterregion.24 Further investigations are requiredto confirm these findings in other populations.

Corresponding author: Thomas Ressiniotis, MRCOphth, Department ofOphthalmology, Royal Victoria Infirmary, Queen Victoria Road, Newcastle uponTyne NE1 4LZ, England (e-mail: tomres@doctors.org.uk).

Submitted for publication February 25, 2003; final revision receivedJuly 8, 2003; accepted October 1, 2003.

The study was funded by educational grants from Pharmacia Ltd, Buckinghamshire,England, and from the Special Trustees of the Newcastle upon Tyne HospitalsNHS Trust, Tyne and Wear, England.

The study was performed in partial fulfillment of requirements for amaster of philosophy degree for Dr Ressiniotis.

We thank Richard Andrews, FRCOphth, PhD, for his contribution to thework.

Quigley  HAVitale  S Models of open-angle glaucoma prevalence and incidence in the UnitedStates. Invest Ophthalmol Vis Sci. 1997;3883- 91
PubMed
WuDunn  D Genetic basis of glaucoma. Curr Opin Ophthalmol. 2002;1355- 60
PubMed Link to Article
Friedman  JSWalter  MA Glaucoma genetics, present and future. Clin Genet. 1999;5571- 79
PubMed Link to Article
Bayer  AUFerrari  F Severe progression of glaucomatous optic neuropathy in patients withAlzheimer's disease. Eye. 2002;16209- 212
PubMed Link to Article
Bayer  AUKeller  ONFerrari  FMaag  KP Association of glaucoma with neurodegenerative diseases with apoptoticcell death: Alzheimer's disease and Parkinson's disease. Am J Ophthalmol. 2002;133135- 137
PubMed Link to Article
Saunders  AMTrowers  MKShimkets  RA  et al.  The role of apolipoprotein E in Alzheimer's disease: pharmacogenomictarget selection. Biochim Biophys Acta. 2000;150285- 94
PubMed Link to Article
Bedlack  RSStrittmatter  WJMorgenlander  JC Apolipoprotein E and neuromuscular disease: a critical review of theliterature. Arch Neurol. 2000;571561- 1565
PubMed Link to Article
Horsburgh  KMcCarron  MOWhite  FNicoll  JA The role of apolipoprotein E in Alzheimer's disease, acute brain injuryand cerebrovascular disease: evidence of common mechanisms and utility ofanimal models. Neurobiol Aging. 2000;21245- 255
PubMed Link to Article
Vickers  JCCraig  JEStankovich  J  et al.  The apolipoprotein ϵ4 gene is associated with elevated risk ofnormal tension glaucoma. Mol Vis. 2002;8389- 393
PubMed
Klein  BEKlein  RSponsel  WE  et al.  Prevalence of glaucoma: the Beaver Dam Eye Study. Ophthalmology. 1992;991499- 1504
PubMed Link to Article
Chapman  JEstupinan  JAsherov  AGoldfarb  LG A simple and efficient method for apolipoprotein E genotype determination. Neurology. 1996;461484- 1485
PubMed Link to Article
Altman  D Practical Statistics for Medical Research.  New York, NY Chapman & Hall1997;
Shanmugaratnam  JBerg  EKimerer  L  et al.  Retinal Müller glia secrete apolipoproteins E and J which areefficiently assembled into lipoprotein particles. Brain Res Mol Brain Res. 1997;50113- 120
PubMed Link to Article
Amaratunga  AAbraham  CREdwards  RBSandell  JHSchreiber  BMFine  RE Apolipoprotein E is synthesized in the retina by Müller glialcells, secreted into the vitreous, and rapidly transported into the opticnerve by retinal ganglion cells. J Biol Chem. 1996;2715628- 5632
PubMed Link to Article
Teasdale  GMNicoll  JAMurray  GFiddes  M Association of apolipoprotein E polymorphism with outcome after headinjury. Lancet. 1997;3501069- 1071
PubMed Link to Article
Schumer  RAPodos  SM The nerve of glaucoma! Arch Ophthalmol. 1994;11237- 44
PubMed Link to Article
Sommer  A Intraocular pressure and glaucoma. Am J Ophthalmol. 1989;107186- 188
PubMed
Lichter  PR Genetic clues to glaucoma's secrets: the L Edward Jackson MemorialLecture: part 2. Am J Ophthalmol. 1994;117706- 727
PubMed
Craig  JEMackey  DA Glaucoma genetics: where are we? where will we go? Curr Opin Ophthalmol. 1999;10126- 134
PubMed Link to Article
Stone  EMFingert  JHAlward  WL  et al.  Identification of a gene that causes primary open angle glaucoma. Science. 1997;275668- 670
PubMed Link to Article
Aung  TOcaka  LEbenezer  ND  et al.  A major marker for normal tension glaucoma: association with polymorphismsin the OPA1 gene. Hum Genet. 2002;11052- 56
PubMed Link to Article
Rezaie  TChild  AHitchings  R  et al.  Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002;2951077- 1079
PubMed Link to Article
Vickers  JCSchumer  RAPodos  SMWang  RFRiederer  BMMorrison  JH Differential vulnerability of neurochemically identified subpopulationsof retinal neurons in a monkey model of glaucoma. Brain Res. 1995;68023- 35
PubMed Link to Article
Copin  BBrezin  APValtot  FDascotte  JCBechetoille  AGarchon  HJ Apolipoprotein E–promoter single-nucleotide polymorphisms affectthe phenotype of primary open-angle glaucoma and demonstrate interaction withthe myocilin gene. Am J Hum Genet. 2002;701575- 1581
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

Distribution of intraocular pressurein patients with primary open-angle glaucoma and control subjects.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Distribution of cup-disc ratioin patients with primary open-angle glaucoma and control subjects.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Frequency of APOE Alleles in Patientsand Control Subjects*
Table Graphic Jump LocationTable 2. Results of Logistic Regression Analysis Between Patients andControl Subjects

References

Quigley  HAVitale  S Models of open-angle glaucoma prevalence and incidence in the UnitedStates. Invest Ophthalmol Vis Sci. 1997;3883- 91
PubMed
WuDunn  D Genetic basis of glaucoma. Curr Opin Ophthalmol. 2002;1355- 60
PubMed Link to Article
Friedman  JSWalter  MA Glaucoma genetics, present and future. Clin Genet. 1999;5571- 79
PubMed Link to Article
Bayer  AUFerrari  F Severe progression of glaucomatous optic neuropathy in patients withAlzheimer's disease. Eye. 2002;16209- 212
PubMed Link to Article
Bayer  AUKeller  ONFerrari  FMaag  KP Association of glaucoma with neurodegenerative diseases with apoptoticcell death: Alzheimer's disease and Parkinson's disease. Am J Ophthalmol. 2002;133135- 137
PubMed Link to Article
Saunders  AMTrowers  MKShimkets  RA  et al.  The role of apolipoprotein E in Alzheimer's disease: pharmacogenomictarget selection. Biochim Biophys Acta. 2000;150285- 94
PubMed Link to Article
Bedlack  RSStrittmatter  WJMorgenlander  JC Apolipoprotein E and neuromuscular disease: a critical review of theliterature. Arch Neurol. 2000;571561- 1565
PubMed Link to Article
Horsburgh  KMcCarron  MOWhite  FNicoll  JA The role of apolipoprotein E in Alzheimer's disease, acute brain injuryand cerebrovascular disease: evidence of common mechanisms and utility ofanimal models. Neurobiol Aging. 2000;21245- 255
PubMed Link to Article
Vickers  JCCraig  JEStankovich  J  et al.  The apolipoprotein ϵ4 gene is associated with elevated risk ofnormal tension glaucoma. Mol Vis. 2002;8389- 393
PubMed
Klein  BEKlein  RSponsel  WE  et al.  Prevalence of glaucoma: the Beaver Dam Eye Study. Ophthalmology. 1992;991499- 1504
PubMed Link to Article
Chapman  JEstupinan  JAsherov  AGoldfarb  LG A simple and efficient method for apolipoprotein E genotype determination. Neurology. 1996;461484- 1485
PubMed Link to Article
Altman  D Practical Statistics for Medical Research.  New York, NY Chapman & Hall1997;
Shanmugaratnam  JBerg  EKimerer  L  et al.  Retinal Müller glia secrete apolipoproteins E and J which areefficiently assembled into lipoprotein particles. Brain Res Mol Brain Res. 1997;50113- 120
PubMed Link to Article
Amaratunga  AAbraham  CREdwards  RBSandell  JHSchreiber  BMFine  RE Apolipoprotein E is synthesized in the retina by Müller glialcells, secreted into the vitreous, and rapidly transported into the opticnerve by retinal ganglion cells. J Biol Chem. 1996;2715628- 5632
PubMed Link to Article
Teasdale  GMNicoll  JAMurray  GFiddes  M Association of apolipoprotein E polymorphism with outcome after headinjury. Lancet. 1997;3501069- 1071
PubMed Link to Article
Schumer  RAPodos  SM The nerve of glaucoma! Arch Ophthalmol. 1994;11237- 44
PubMed Link to Article
Sommer  A Intraocular pressure and glaucoma. Am J Ophthalmol. 1989;107186- 188
PubMed
Lichter  PR Genetic clues to glaucoma's secrets: the L Edward Jackson MemorialLecture: part 2. Am J Ophthalmol. 1994;117706- 727
PubMed
Craig  JEMackey  DA Glaucoma genetics: where are we? where will we go? Curr Opin Ophthalmol. 1999;10126- 134
PubMed Link to Article
Stone  EMFingert  JHAlward  WL  et al.  Identification of a gene that causes primary open angle glaucoma. Science. 1997;275668- 670
PubMed Link to Article
Aung  TOcaka  LEbenezer  ND  et al.  A major marker for normal tension glaucoma: association with polymorphismsin the OPA1 gene. Hum Genet. 2002;11052- 56
PubMed Link to Article
Rezaie  TChild  AHitchings  R  et al.  Adult-onset primary open-angle glaucoma caused by mutations in optineurin. Science. 2002;2951077- 1079
PubMed Link to Article
Vickers  JCSchumer  RAPodos  SMWang  RFRiederer  BMMorrison  JH Differential vulnerability of neurochemically identified subpopulationsof retinal neurons in a monkey model of glaucoma. Brain Res. 1995;68023- 35
PubMed Link to Article
Copin  BBrezin  APValtot  FDascotte  JCBechetoille  AGarchon  HJ Apolipoprotein E–promoter single-nucleotide polymorphisms affectthe phenotype of primary open-angle glaucoma and demonstrate interaction withthe myocilin gene. Am J Hum Genet. 2002;701575- 1581
PubMed Link to Article

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