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Prospective case control study on genetic assocation of apolipoprotein ε2 with intraocular pressure
  1. A Jünemann1,
  2. N Wakili1,
  3. C Mardin1,
  4. G O H Naumann1,
  5. S Bleich2,
  6. K Henkel2,
  7. G Beck2,
  8. J Kornhuber2,
  9. U Reulbach3,
  10. B Rautenstrauss4 and
  11. A Reis4
  1. 1Department of Ophthalmology, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany
  2. 2Department of Psychiatry and Psychotherapy, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany
  3. 3Department of Medical Informatics, Biometry and Epidemiology, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany
  4. 4Department of Human Genetics, Friedrich-Alexander-University, Erlangen-Nuremberg, Germany
  1. Correspondence to: Dr A Jüneman Department of Ophthalmology, Friedrich-Alexander-University, Erlangen-Nuremberg, Schwabachanlage 6 Erlangen, Germany; anselm.juenemannaugen.imed.uni-erlangen

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Glaucomas are a leading cause of blindness throughout the world. This group of diseases has a common characteristic: degeneration of the optic nerve that is usually associated with increased intraocular pressure (IOP). Increased IOP is one of the major risk factors for developing glaucomatous damage, whereby the loss of retinal ganglion cells is the typical pathological finding. However, the pathophysiology of pressure induced glaucomatous optic neuropathy remains unclear and is still a matter for debate. Genome scans have been performed to identify the genomic locations of glaucoma susceptibility genes.1

Apolipoprotein E (APOE), a lipid transporting protein produced in the liver and brain, is unique among apolipoproteins in that it has particular relevance to nervous tissue. It is involved in the mobilisation and redistribution of cholesterol in repair, growth, and maintenance of myelin and neuronal membranes during development or after injury. Recently it has been shown that the APOE ε4 allele is associated with elevated risk of normal tension glaucoma.2 The APOE ε2 allele was shown to be significantly associated with an elevated risk of age related macular degeneration (AMD).3

Material and methods

This prospective case control study included 32 controls (IOP <22 mm Hg, normal optic disc, normal visual field), 54 patients with ocular hypertension (OHT, IOP >21 mm Hg, normal optic disc, normal visual field), 96 patients with primary open angle glaucoma (POAG, 55 patients with preperimetric open angle glaucoma (pre-OAG, IOP >21 mm Hg, glaucomatous optic disc, normal visual field), and 41 patients with perimetric open angle glaucoma (OAG, IOP >21 mm Hg, glaucomatous optic disc, visual field defects). All individuals included in the study were unrelated, white, and had open anterior chamber angles, clear optic media, and a visual acuity of 20/25 or better. Exclusion criteria were all eye diseases other than glaucoma, diabetes mellitus, myopic refractive error exceeding −8 diopters, and visual acuity less than 0.7.

The study followed the tenets of the declaration of Helsinki for research involving human subjects and informed consent was obtained from all participants.

All control subjects and patients were thoroughly examined by clinical biomicroscopy including slit lamp inspection, gonioscopy and ophthalmoscopy, applanation tonometry, perimetry (Octopus G1 program, 3 phases), and pachymetry (Tomey AL-1100). In addition, a 24 hours IOP curve with measurements at 7 am, 12 am, 5 pm, 9 pm, 12 pm, 7 am was measured in all patients.

For a classification of study groups the 15° colour stereo photographs were evaluated qualitatively by two observers. Criteria for the diagnosis in all glaucomas were increased IOP and glaucomatous changes of the optic nerve head, including abnormally small neuroretinal rim area in relation to the optic disc size, abnormal neuroretinal rim shape, cup:disc ratios being higher vertically compared with horizontally, and localised or diffuse loss of retinal nerve fibre layer.

All subjects were familiar with visual field testing. Subjects with a higher than 12% rate of false-positive or false-negative responses were excluded. A “perimetric” glaucomatous visual field was defined as an Octopus G1 field with (a) at least three adjacent test points having a deviation of equal to or greater than 5 dB and with one test point with a deviation greater than 10 dB lower than normal; (b) at least two adjacent test points with a deviation equal to or greater than 10 dB; (c) at least three adjacent test points with a deviation equal to or greater than 5 dB abutting the nasal horizontal meridian, or (d) a mean visual field defect of more than 2.6 dB.

For APOE genotyping, genomic DNA was extracted from anticoagulated blood after isolation of peripheral lymphocytes following the “salting out” method. The APOE gene shows a polymorphism with three alleles (ε2, ε3, ε4) (table 1). As allele ε3 is considered to be the ancestral allele, and ε2 and ε4 are considered as variants on the basis of single point mutations, the ε3ε3 genotype was used as reference.

Table 1

Distribution of APOE genotypes and allele frequency

Results

The mean (SD) IOP of the 24 h diurnal curve was significantly higher in subjects with the ε2 allele (independent samples t test, t = −2.57, p = 0.011, 17.7 (2.7) v 16.4 (2.4) mm Hg) (fig 1). The maximum and minimum IOP were also increased or decreased, but not significantly (Mann-Whitney U, p = 0.052, 20.5 (3.2) v 19.1 (3.0) mm Hg, respectively. p = 0.178, 14.8 (2.7) v 14.0 (2.5) mm Hg). This was approximately continuous in the different study groups (normals, OHT, pre-OAG, and OAG); however it was only significant in the normal subjects for mean (t = −2.183, p = 0.043, 18.0 (4.9) v 14.3 (2.5) mm Hg) and minimum IOP (U = 15, p = 0.031, 15.0 (3.9) v 11.7 (2.5) mm Hg). The central corneal thickness was not different between the subjects with the ε2 allele and the reference group with ε3ε3 genotype (t = −0.035, p = 0.973, 587 (33) v 586 (51) μm).

Figure 1

Maximal and mean IOP of the 24 hour diurnal curve of 130 individuals (normal controls, OHT, pre-OAG, and OAG; + cases with more than 1.5 box lengths from the upper or lower edge of the box. The box length is the interquartile range.

Discussion

The results of this study show a significant association between the level of IOP and the APO ε2 allele. This may be supported by the recent findings that the APO ε4 allele is associated with higher risk for glaucomatous changes that are not related to increased IOP.2

It is not yet obvious how the APOE alleles may be a source of genetic risk for glaucoma and increased IOP. It will be intriguing to investigate whether there is increased expression of APOE in trabecular meshwork in glaucoma or an isoform dependent expression in different types of glaucoma. A possible role for ApoE promoter single nucleotide polymorphisms as modifiers of the POAG phenotype has been hypothesised.4

To conclude, we have shown a significant association between APOE and glaucoma and IOP. Quite recently it was argued that an IOP reduction of 1 mm Hg from baseline will decrease the risk of progression by about 10%.5 Although in need of confirmation, our data emphasise the role of APOE in regulation of IOP and may indicate that we have identified a susceptibility gene for glaucoma.

As future perspective for the APOE alleles, analysis of a larger number of glaucoma patients—taking into account family history, age, and sex—will provide more detailed insight.

References

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  • Author Correction

    PLease not that the author list published is not correct. The correct listing is shown below:

    A. Jünemann1, S. Bleich2, U. Reulbach3, K. Henkel2, N. Wakili1, G. Beck2, B. Rautenstrauss4, C. Mardin1, G.O.H. Naumann1, A. Reis4, J. Kornhuber2

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