Apolipoprotein E polymorphism in patients with cataract
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《英国眼科学杂志》
1 Institute of Clinical Neuroscience, Section of Ophthalmology, Sahlgrenska University Hospital, G?teborg University, M?lndal, Sweden
2 Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, G?teborg University, G?teborg, Sweden
3 Department of Human Biology and Genetics, University of Tartu, Tartu, Estonia
4 Department of Ophthalmology, University of Tartu, Tartu, Estonia
5 Department of Anatomy and Cell Biology, Medical Faculty, G?teborg University, G?teborg, Sweden
6 Institute of Clinical Neuroscience, Department of Experimental Neuroscience, Sahlgrenska University Hospital, G?teborg University, G?teborg, Sweden
Correspondence to:
Dr Madeleine Zetterberg
Institute of Clinical Neuroscience, Section of Ophthalmology, Sahlgrenska University Hospital, SE-431 80 M?lndal, Sweden; madeleine.zetterberg@anatcell.gu.se
Accepted for publication 1 September 2003
Keywords: Alzheimer’s disease; apolipoprotein E; cataract; polymorphism
Based on similarities in epidemiology and biochemistry, it has been suggested that cataract and Alzheimer’s disease (AD) share the same aetiological mechanisms. Comorbidity of cataract and AD in trisomy 21 (Down’s syndrome) is well known1,2 and both diseases are characterised by aggregated proteins exhibiting excessive glycation and racemisation of aspartyl residues.3 Several AD related proteins—amyloid precursor protein (APP), ? amyloid (A?), and presenilin (PS)—are expressed in the lens4,5 and A? is accumulated in the cytosol of lens fibres in cataractous lenses of people with AD.6
Human apolipoprotein E (apoE) exists in three major isoforms encoded by distinct alleles (APOE 2, 3, and 4). The different APOE alleles have been studied in relation to several human age related diseases: inheritance of the 4 allele is a strong risk factor for AD and influences A? metabolism.7,8 The purpose of this study was to investigate the APOE 2/3/4 polymorphism in patients with cataract.
After informed consent, patients with senile cataract and control individuals were recruited from two ophthalmic clinics in Tartu and the south Estonian area. The study was approved by the ethics committee at the University of Tartu, Estonia. Before surgery, the type of cataract was determined using biomicroscopy and ophthalmoscopy. Secondary cataracts were excluded. The case group included 502 patients; 77 with nuclear, 155 with cortical, 119 with posterior subcapsular, and 151 with mixed opacities. Mean age was 72.0 (SD 8.7) years (range 47–93 years) and 348 (69.3%) were women. The control group consisted of 187 individuals without cataract, uveitis, or glaucoma. Mean age was 65.8 (SD 6.9) years (range 43–90 years) and 136 (72.7%) were women. The power of the study was >99% as calculated according to Altman9 on the basis of APOE 4 allele frequencies in a recent study on AD.10
The APOE alleles and genotypes were determined as previously described.11 The allele and genotype frequencies of cataract cases and controls were compared using a two tailed Fisher’s exact test, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.9 All statistical analyses were performed using SYSTAT as software (SPSS Inc, Chicago, IL, USA). Statistical significance was defined as p<0.05.
APOE allele and genotype frequencies found in this study are well in accordance with those reported in other Northern European populations.12 No significant differences were seen between the control and cataract groups for any of the APOE alleles (table 1) or APOE genotypes (table 2). Neither were there any differences between the control group and the specific cataract subgroups. In order to prevent the data from being influenced by age differences between the groups studied, age matched control individuals were selected and compared with the cataract group and vice versa, without resulting in any significant changes in APOE allele or genotype frequencies.
Table 1 APOE allele frequencies for control and cataract groups
Table 2 APOE genotype distributions for control and cataract groups
Alzheimer’s disease and cataract both exhibit large aggregates of aberrant proteins, senile plaques composed of A? and neurofibrillary tangles containing the cytoskeletal protein tau in the former case, and light scattering high molecular weight aggregates of crystallins in the latter. Together with several other diseases characterised by protein aggregates, such as amyloidosis and prion diseases, the term "conformational disease" has been created, suggesting a common aetiology.3,13
The APOE 4 allele is a strong risk factor for AD, and it is believed that in neuronal tissue, apoE is important for mobilisation and redistribution of lipids, and for maintenance and repair of neuronal cell membranes.14 However, in age related macular degeneration (AMD)—a condition characterised by accumulation of extracellular deposits termed drusen, containing among other things neutral lipids, cholesterol, and apoE—the 4 allele appears to confer protection, whereas the 2 allele is associated with a moderately increased risk of AMD.15,16 The APOE 4 allele also seems to play a protective role during embryogenesis,17 suggesting different effects of the gene early and late in life.
To our knowledge, this is the first study to investigate the APOE polymorphism in cataract patients. No differences in the distribution of APOE alleles and genotypes could be seen between controls and cataract patients in spite of a large number of participants and a very high power. This indicates that if there is a common pathogenic mechanism for cataract and AD, it does not involve the APOE polymorphism. Of course the results need to be confirmed by other groups before the APOE polymorphism can be regarded as insignificant in cataractogenesis. Bearing in mind the similarities between cataract and AD is very important, however, as progress in aetiological research of one disease may contribute to elucidating the pathogenesis of the other.
ACKNOWLEDGEMENTS
This work was supported by grants from the Swedish Medical Research Council (projects #02226, #5932, and #12103), the Sahlgrenska University Hospital, the G?teborg Medical Society, Stiftelsen Kronprinsessan Margaretas Arbetsn?mnd f?r Synskadade, De Blindas V?nner, Stiftelsen Hjalmar Svenssons forskningsfond, and Tore Nilsons Stiftelse f?r Medicinsk Forskning.
References
da Cunha RP, Moreira JB. Ocular findings in Down’s syndrome. Am J Ophthalmol 1996;122:236–44.
Lott IT. Down’s syndrome, aging, and Alzheimer’s disease: a clinical review. Ann N Y Acad Sci 1982;396:15–27.
Harding J. Cataract, Alzheimer’s disease, and other conformational diseases. Curr Opin Ophthalmol 1998;9:10–13.
Frederikse PH, Zigler Jr JS. Presenilin expresssion in the ocular lens. Curr Eye Res 1998;17:947–52.
Frederikse PH, Garland D, Zigler J Jr, et al. Oxidative stress increases production of ?-amyloid (A?) in mammalian lenses, and A? has toxic effects on lens epithelial cells. J Biol Chem 1996;271:10169–74.
Goldstein LE, Muffat JA, Cherny RA, et al. Cytosolic ?-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer’s disease. Lancet 2003;361:1258–64.
Holtzman DM, Bales KR, Tenkova T, et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 2000;97:2892–7.
Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;261:921–3.
Altman DG. Practical Statistics for Medical Research. First edition. London: Chapman and Hall/CRC, 1991.
Johansson A, Hampel H, Faltraco F, et al. Increased frequency of a new polymorphism in the cell division cycle 2 (cdc2) gene in patients with Alzheimer’s disease and frontotemporal dementia. Neurosci Lett 2003;340:69–73.
Blennow K, Ricksten A, Prince JA, et al. No association between the 2-macroglobulin (2M) deletion and Alzheimer’s disease, and no change in 2M mRNA, protein, or protein expression. J Neural Transm 2000;107:1065–79.
Eichner JE, Dunn ST, Perveen G, et al. Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 2002;155:487–95.
Carrell RW, Lomas DA. Conformational disease. Lancet 1997;350:134–8.
Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988;240:622–30.
Souied EH, Benlian P, Amouyel P, et al. The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. Am J Ophthalmol 1998;125:353–9.
Klaver CCW, Kliffen M, van Duijn CM, et al. Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet 1998;63:200–6.
Zetterberg H, Palmér M, Ricksten A, et al. Influence of the apolipoprotein E e4 allele on human embryonic development. Neurosci Lett 2002;324:189–92.(M Zetterberg1,5, H Zetter)
2 Department of Clinical Chemistry and Transfusion Medicine, Sahlgrenska University Hospital, G?teborg University, G?teborg, Sweden
3 Department of Human Biology and Genetics, University of Tartu, Tartu, Estonia
4 Department of Ophthalmology, University of Tartu, Tartu, Estonia
5 Department of Anatomy and Cell Biology, Medical Faculty, G?teborg University, G?teborg, Sweden
6 Institute of Clinical Neuroscience, Department of Experimental Neuroscience, Sahlgrenska University Hospital, G?teborg University, G?teborg, Sweden
Correspondence to:
Dr Madeleine Zetterberg
Institute of Clinical Neuroscience, Section of Ophthalmology, Sahlgrenska University Hospital, SE-431 80 M?lndal, Sweden; madeleine.zetterberg@anatcell.gu.se
Accepted for publication 1 September 2003
Keywords: Alzheimer’s disease; apolipoprotein E; cataract; polymorphism
Based on similarities in epidemiology and biochemistry, it has been suggested that cataract and Alzheimer’s disease (AD) share the same aetiological mechanisms. Comorbidity of cataract and AD in trisomy 21 (Down’s syndrome) is well known1,2 and both diseases are characterised by aggregated proteins exhibiting excessive glycation and racemisation of aspartyl residues.3 Several AD related proteins—amyloid precursor protein (APP), ? amyloid (A?), and presenilin (PS)—are expressed in the lens4,5 and A? is accumulated in the cytosol of lens fibres in cataractous lenses of people with AD.6
Human apolipoprotein E (apoE) exists in three major isoforms encoded by distinct alleles (APOE 2, 3, and 4). The different APOE alleles have been studied in relation to several human age related diseases: inheritance of the 4 allele is a strong risk factor for AD and influences A? metabolism.7,8 The purpose of this study was to investigate the APOE 2/3/4 polymorphism in patients with cataract.
After informed consent, patients with senile cataract and control individuals were recruited from two ophthalmic clinics in Tartu and the south Estonian area. The study was approved by the ethics committee at the University of Tartu, Estonia. Before surgery, the type of cataract was determined using biomicroscopy and ophthalmoscopy. Secondary cataracts were excluded. The case group included 502 patients; 77 with nuclear, 155 with cortical, 119 with posterior subcapsular, and 151 with mixed opacities. Mean age was 72.0 (SD 8.7) years (range 47–93 years) and 348 (69.3%) were women. The control group consisted of 187 individuals without cataract, uveitis, or glaucoma. Mean age was 65.8 (SD 6.9) years (range 43–90 years) and 136 (72.7%) were women. The power of the study was >99% as calculated according to Altman9 on the basis of APOE 4 allele frequencies in a recent study on AD.10
The APOE alleles and genotypes were determined as previously described.11 The allele and genotype frequencies of cataract cases and controls were compared using a two tailed Fisher’s exact test, and odds ratios (ORs) and 95% confidence intervals (CIs) were calculated.9 All statistical analyses were performed using SYSTAT as software (SPSS Inc, Chicago, IL, USA). Statistical significance was defined as p<0.05.
APOE allele and genotype frequencies found in this study are well in accordance with those reported in other Northern European populations.12 No significant differences were seen between the control and cataract groups for any of the APOE alleles (table 1) or APOE genotypes (table 2). Neither were there any differences between the control group and the specific cataract subgroups. In order to prevent the data from being influenced by age differences between the groups studied, age matched control individuals were selected and compared with the cataract group and vice versa, without resulting in any significant changes in APOE allele or genotype frequencies.
Table 1 APOE allele frequencies for control and cataract groups
Table 2 APOE genotype distributions for control and cataract groups
Alzheimer’s disease and cataract both exhibit large aggregates of aberrant proteins, senile plaques composed of A? and neurofibrillary tangles containing the cytoskeletal protein tau in the former case, and light scattering high molecular weight aggregates of crystallins in the latter. Together with several other diseases characterised by protein aggregates, such as amyloidosis and prion diseases, the term "conformational disease" has been created, suggesting a common aetiology.3,13
The APOE 4 allele is a strong risk factor for AD, and it is believed that in neuronal tissue, apoE is important for mobilisation and redistribution of lipids, and for maintenance and repair of neuronal cell membranes.14 However, in age related macular degeneration (AMD)—a condition characterised by accumulation of extracellular deposits termed drusen, containing among other things neutral lipids, cholesterol, and apoE—the 4 allele appears to confer protection, whereas the 2 allele is associated with a moderately increased risk of AMD.15,16 The APOE 4 allele also seems to play a protective role during embryogenesis,17 suggesting different effects of the gene early and late in life.
To our knowledge, this is the first study to investigate the APOE polymorphism in cataract patients. No differences in the distribution of APOE alleles and genotypes could be seen between controls and cataract patients in spite of a large number of participants and a very high power. This indicates that if there is a common pathogenic mechanism for cataract and AD, it does not involve the APOE polymorphism. Of course the results need to be confirmed by other groups before the APOE polymorphism can be regarded as insignificant in cataractogenesis. Bearing in mind the similarities between cataract and AD is very important, however, as progress in aetiological research of one disease may contribute to elucidating the pathogenesis of the other.
ACKNOWLEDGEMENTS
This work was supported by grants from the Swedish Medical Research Council (projects #02226, #5932, and #12103), the Sahlgrenska University Hospital, the G?teborg Medical Society, Stiftelsen Kronprinsessan Margaretas Arbetsn?mnd f?r Synskadade, De Blindas V?nner, Stiftelsen Hjalmar Svenssons forskningsfond, and Tore Nilsons Stiftelse f?r Medicinsk Forskning.
References
da Cunha RP, Moreira JB. Ocular findings in Down’s syndrome. Am J Ophthalmol 1996;122:236–44.
Lott IT. Down’s syndrome, aging, and Alzheimer’s disease: a clinical review. Ann N Y Acad Sci 1982;396:15–27.
Harding J. Cataract, Alzheimer’s disease, and other conformational diseases. Curr Opin Ophthalmol 1998;9:10–13.
Frederikse PH, Zigler Jr JS. Presenilin expresssion in the ocular lens. Curr Eye Res 1998;17:947–52.
Frederikse PH, Garland D, Zigler J Jr, et al. Oxidative stress increases production of ?-amyloid (A?) in mammalian lenses, and A? has toxic effects on lens epithelial cells. J Biol Chem 1996;271:10169–74.
Goldstein LE, Muffat JA, Cherny RA, et al. Cytosolic ?-amyloid deposition and supranuclear cataracts in lenses from people with Alzheimer’s disease. Lancet 2003;361:1258–64.
Holtzman DM, Bales KR, Tenkova T, et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer’s disease. Proc Natl Acad Sci U S A 2000;97:2892–7.
Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 1993;261:921–3.
Altman DG. Practical Statistics for Medical Research. First edition. London: Chapman and Hall/CRC, 1991.
Johansson A, Hampel H, Faltraco F, et al. Increased frequency of a new polymorphism in the cell division cycle 2 (cdc2) gene in patients with Alzheimer’s disease and frontotemporal dementia. Neurosci Lett 2003;340:69–73.
Blennow K, Ricksten A, Prince JA, et al. No association between the 2-macroglobulin (2M) deletion and Alzheimer’s disease, and no change in 2M mRNA, protein, or protein expression. J Neural Transm 2000;107:1065–79.
Eichner JE, Dunn ST, Perveen G, et al. Apolipoprotein E polymorphism and cardiovascular disease: a HuGE review. Am J Epidemiol 2002;155:487–95.
Carrell RW, Lomas DA. Conformational disease. Lancet 1997;350:134–8.
Mahley RW. Apolipoprotein E: cholesterol transport protein with expanding role in cell biology. Science 1988;240:622–30.
Souied EH, Benlian P, Amouyel P, et al. The epsilon4 allele of the apolipoprotein E gene as a potential protective factor for exudative age-related macular degeneration. Am J Ophthalmol 1998;125:353–9.
Klaver CCW, Kliffen M, van Duijn CM, et al. Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet 1998;63:200–6.
Zetterberg H, Palmér M, Ricksten A, et al. Influence of the apolipoprotein E e4 allele on human embryonic development. Neurosci Lett 2002;324:189–92.(M Zetterberg1,5, H Zetter)