Ophthalmology

The Rotterdam Study: 2012 objectives and design update (Article)

Hofman, A. — 2011-08-31T00:00:00Z

Abstract The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, oncological, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in over a 1,000 research articles and reports (see www.erasmus-epidemiology.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.

Trajectories of CBCL Attention Problems in childhood (Article)

Robbers, S.C.C. — 2011-06-29T00:00:00Z

The first aim of this study was to identify developmental trajectories of Attention Problems in twins followed from age 6 to 12 years. Second, we investigated whether singletons follow similar trajectories. Maternal longitudinal ratings on the Attention Problems (AP) subscale of the Child Behavior Checklist were obtained for a sample of 12,486 twins from the Netherlands Twin Register and for a general population sample of 1,346 singletons. Trajectories were analyzed by growth mixture modeling in twins, and compared with singletons. Teacher ratings on the AP subscale of the Teachers' Report Form were available for 7,179 twins and 1,211 singletons, and were used for cross-sectional mean comparisons at each age. All analyses were conducted for boys and girls separately. We identified three linear trajectories in both boys and girls, i.e., stable low (62-71%), low-increasing (15-18%), and high-decreasing (14-21%). Singletons followed three identical trajectories, with similar class proportions. Teacher ratings yielded no differences in mean levels of Attention Problems between twins and singletons. The development of Attention Problems from age 6 to 12 years can be characterized by stable low, low-increasing, and high-decreasing developmental trajectories. Twins and singletons are comparable with respect to the development of Attention Problems in childhood.

The neonatal Fc receptor is expressed by human retinal pigment epithelial cells and is downregulated by tumour necrosis factor-alpha (Article)

Van Bilsen, K. — 2011-06-01T00:00:00Z

Background/aims: The neonatal Fc receptor (FcRn) protects immunoglobulin G (IgG) from catabolism, controls its transport between cell layers and extends its serum half-life. In the human, vitreous IgG can be found, but how vitreous IgG is processed or transported is currently unknown. The FcRn is a candidate molecule to regulate these processes. The authors examined FcRn expression and regulation in human retinal pigment epithelium (RPE) cells. Methods: In three primary RPE cell cultures (from three donor eyes) and in the human RPE cell line ARPE-19, FcRn and beta-2-microglobulin (β2M) mRNA levels were determined by real-time quantitative PCR. FcRn protein expression was analysed by western blot studies. Stimulation experiments were performed with recombinant human tumour necrosis factor (TNF)-α and interferon (IFN)-γ. HT-29, THP-1 and HeLa cell lines were used as FcRn positive and negative non-ocular controls, respectively. Results: Expression of FcRn mRNA and protein was demonstrated in all three RPE cultures. After stimulation with TNF-α, FcRn expression is downregulated in RPE cells and upregulated in HT-29 and THP-1 cells. IFN-γ has no effect on FcRn expression in RPE cells. Conclusions: Human RPE cells express FcRn. The proinflammatory cytokine TNF-α downregulates FcRn expression. The authors speculate that the FcRn may play a pivotal role in the immune privilege of the human eye.

Genetic Etiology and Clinical Consequences of Cone Disorders (Doctoral Thesis)

Thiadens, A.A.H.J. — 2011-05-18T00:00:00Z

Hereditary retinal disorders constitute a large heterogeneous group of diseases in which the photoreceptors are primarily aff ected. When cone cells are aff ected, one cannot see details or perceive color. In this thesis, we focused on the three most important diseases in which the cones are primarily aff ected: achromatopsia (ACHM), cone dystrophy (CD), and cone-rod dystrophy (CRD). Although cone disorders account for only a small portion of all retinal disorders, they have a great impact on daily life. This is mainly due to the early onset of disease, severe visual outcome, and lack of therapeutic options. Cone disorders can have an autosomal recessive, autosomal dominant or X-linked inheritance, but unfortunately the genetic etiology is still largely unknown. This hampers clinical and genetic counseling and the development of therapeutic options. This gap of knowledge encouraged us to initiate a multicenter study with the aim to investigate the clinical course of cone disorders and to unravel the genetic causes.

Whole orbital tissue culture identifies imatinib mesylate and adalimumab as potential therapeutics for Graves' ophthalmopathy (Article)

Steensel, L. van — 2011-05-01T00:00:00Z

Background and aims: Biologicals and small inhibitory molecules are used to treat inflammatory diseases, but their efficacy varies upon clinical application. Using a whole orbital tissue culture system, we tested the potential efficacy of imatinib mesylate (a tyrosine kinase inhibitor that blocks platelet-derived growth factor (PDGF)-receptor, c-Abl and c-Kit activity) and adalimumab (an anti-TNF-α antibody) for the treatment of Graves' ophthalmopathy (GO). Methods: Orbital fat tissue from GO patients (n=10) was cultured with or without imatinib mesylate or adalimumab. PDGF-B and tumour necrosis factor (TNF)-α mRNA expression levels were determined in the primary orbital tissue, and interleukin (IL)-6 and hyaluronan were measured in tissue-culture supernatants. Results: Imatinib mesylate significantly (p=0.005) reduced IL-6 and hyaluronan production. The inhibition of hyaluronan production correlated positively and significantly (p<0.05) with the PDGF-B mRNA level in the primary tissue. Adalimumab also significantly (p=0.005) reduced IL-6 production. The amount of IL-6 inhibition correlated positively with the TNF-α mRNA level in the primary tissue, but this was not significant. Conclusions: Imatinib mesylate can be expected to reduce inflammation and tissue remodelling in GO, while adalimumab can be mainly expected to reduce inflammation. This in vitro tissue-culture model may, in future, prove valuable to test novel therapeutics for their presumed effect in GO as well as in other inflammatory diseases.

Pre-divorce problems in 3-year-olds: A prospective study in boys and girls (Article)

Robbers, S.C.C. — 2011-04-01T00:00:00Z

Objective: We examined to what extent internalizing and externalizing problems at age 3 preceded and predicted parental divorce, and if divorce and the time lapse since divorce were related to internalizing and externalizing problems at age 12. Methods: Parental ratings of internalizing and externalizing problems were collected with the Child Behavior Checklist (CBCL) in a large sample (N = 6,426) of 3-yearold children. All these children were followed through the age of 12 years, at which parents completed the CBCL again, while teachers completed the Teacher's Report Form. Children whose parents divorced between age 3 and age 12 were compared with children whose families remained intact. Results: Girls whose parents divorced between ages 3 and 12 already showed more externalizing problems at age 3 than girls whose parents stayed married. Higher levels of externalizing problems in girls at age 3 predicted later parental divorce. Parental reports indicated that 12-year-olds with divorced parents showed more internalizing and externalizing problems than children with married parents. Levels of teacher-reported problems were not different between children with married versus divorced parents. However, children whose parents divorced between ages 3 and 12 showed more teacher-rated internalizing problems at age 12 when the divorce was more recent than when the divorce was less recent. Parental ratings of both internalizing and externalizing problems at age 12 were not associated with the time lapse since divorce. Conclusion: Externalizing problems in girls precede and predict later parental divorce. Post-divorce problems in children vary by raters, and may depend on the time lapse since divorce.

Ptosis, extraocular motility disorder, and myopia as features of pompe disease (Article)

Slingerland, N.W.R. — 2011-03-01T00:00:00Z

Purpose: The assets of this report are a thorough description of new clinical findings, namely the combination of ptosis, extraocular motility disorder and myopia, in consequence of prolonged survival in classic infantile-onset Pompe disease through enzyme therapy. Design: Single case description. Results: This manuscript describes a combination of ptosis, extraocular motility disorder and myopia in a 4.5-year-old patient with classic infantile-onset Pompe disease, who survived through enzyme therapy. This patient was treated with a bilateral frontalis suspension (modified Crawford technique) using prolene 3-0 sutures. Conclusions: The combination of ptosis, extraocular motility disorder and myopia, is a new clinical finding in children with classic infantile-onset Pompe disease.

Overexpression of full-length ETV1 transcripts in clinical prostate cancer due to gene translocation (Article)

Gasi, D. — 2011-02-07T00:00:00Z

ETV1 is overexpressed in a subset of clinical prostate cancers as a fusion transcript with many different partners. However, ETV1 can also be overexpressed as a full-length transcript. Full-length ETV1 protein functions differently from truncated ETV1 produced by fusion genes. In this study we describe the genetic background of full-length ETV1 overexpression and the biological properties of different full-length ETV1 isoforms in prostate cancer. Break-apart FISH showed in five out of six patient samples with overexpression of full-length ETV1 a genomic rearrangement of the gene, indicating frequent translocation. We were able to study the rearrangements in more detail in two tumors. In the first tumor 59′-RACE on cDNA showed linkage of the complete ETV1 transcript to the first exon of a prostate-specific two exon ncRNA gene that maps on chromosome 14 (EST14). This resulted in the expression of both full-length ETV1 transcripts and EST14-ETV1 fusion transcripts. In chromosome spreads of a xenograft derived from the second prostate cancer we observed a complex ETV1 translocation involving a chromosome 7 fragment that harbors ETV1 and fragments of chromosomes 4 and 10. Further studies revealed the overexpression of several different full-length transcripts, giving rise to four protein isoforms with different N-terminal regions. Even the shortest isoform synthesized by full-length ETV1 stimulated in vitro anchorage-independent growth of PNT2C2 prostate cells. This contrasts the lack of activity of even shorter N-truncated ETV1 produced by fusion transcripts. Our findings that in clinical prostate cancer overexpression of full-length ETV1 is due to genomic rearrangements involving different chromosomes and the identification of a shortened biologically active ETV1 isoform are highly relevant for understanding the mechanism of ETV1 function in prostate cancer.

A posterior khodadoust line in a graft rejection episode after descemet stripping automated endothelial keratoplasty (Article)

Saelens, I.E.Y. — 2011-02-01T00:00:00Z

Purpose: To describe the presence of an endothelial rejection line in immunological graft rejection after Descemet stripping automated endothelial keratoplasty (DSAEK). Methods: Case report. Results: A 77-year-old woman underwent DSAEK procedure of the left eye because of visual limiting bullous keratopathy. One week postoperatively, the donor lamella was partially detached and an additional air bubble was injected into the anterior chamber. Thereafter, complete adherence of the lamella was seen. Four months after surgery, vision deteriorated, and a transient immunological graft rejection episode with endothelial rejection line was seen. Conclusions: In contrast to other reports, an endothelial rejection line (Khodadoust line) can be seen during the endothelial rejection episode after DSAEK.

Genetic architecture of open angle glaucoma and related determinants (Article)

Ramdas, W.D. — 2011-01-01T00:00:00Z

Background: Although the vertical cup-disc ratio (VCDR) and intraocular pressure (IOP) are important determinants of open angle glaucoma (OAG), it is unclear to what extent the genetic origin of these traits overlap with those of OAG. We evaluated whether the same genes that determine VCDR and IOP also predict OAG. Methods: Genetic risk scores were constructed from single nucleotide polymorphisms (SNPs) using genome wide association data of 9326 participants from the Rotterdam Study cohorts (mean±SD age: 64.6±9.1 years). These risk scores were used to calculate the explained variance of VCDR and IOP in an independent cohort (Erasmus Rucphen Family study) consisting of 1646 participants (mean±SD age: 46.8614.1 years) and the OAG risk in a subset of the Rotterdam Study cohorts. To evaluate false positive findings, we generated two new variables containing randomly sampled values to serve as a negative control. Results: The explained variance of VCDR increased when increasing the number of SNPs included in the risk score, suggesting a polygenic model. We found no clear evidence for a similar model for IOP, suggesting that a small number of SNPs determine the susceptibility to IOP. The SNPs related to IOP in terms of p values contributed little to VCDR. The risk scores associated with VCDR were also associated significantly with OAG. This suggests a common polygenic background for VCDR and OAG Conclusions: We found evidence for a polygenic model underlying one of the major traits of OAG, VCDR, and OAG itself. The IOP did not show any evidence for such a model.

Utility analysis of disability caused by amblyopia and/or strabismus in a population-based, historic cohort (Article)

Graaf, E.S. van de — 2010-12-01T00:00:00Z

Background: Amblyopia (prevalence 3.4%) is in principle treatable, but approximately one quarter of children do not reach reading acuity in the amblyopic eye. Adults with persistent amblyopia and/or strabismus experience a decrease in quality of life. This was now quantified by patient-perceived utility values. Methods: Subjects were born 1962-1972 and had been treated by occlusion therapy for amblyopia by one orthoptist 30-35 years ago. All children in Waterland with amblyopia and/or strabismus had been referred to this orthoptist. Utilities were derived by methods of time trade-off, TTO (lifetime traded against perfect vision) and standard gamble, SG (death risk accepted for perfect vision). Most troubling eye disorder (low acuity of the amblyopic eye, lacking stereopsis or strabismus) was chosen and ranked among nine chronic disorders according to the subject's perceived severity. Results: From 201 patients that could be contacted 35 years after occlusion therapy - out of 471 who had been occluded - 135 were included: 17 could not be reached, 34 refused, and 15 had other reasons to not participate. Mean age was 40.86 years; 53% were male. Seventy percent were willing to trade lifetime according to the TTO method; its mean (log) utility was 0.963, i.e., a decrease in quality of life of 3.7%. Thirty-seven percent accepted death risk according to the SG method; its mean utility was 0.9996. TTO outcomes correlated with current near and distance visual acuity. Low acuity of the amblyopic eye, chosen as most troubling eye disorder, ranked slightly less severe than tooth decay. Conclusion: Amblyopia and/or strabismus patients had a slightly decreased utility. The decrease is small but still important in the cost-effectiveness of vision screening because these conditions occur very frequently.

Long-term follow-up of hydrogel intracorneal lenses in 2 aphakic eyes (Article)

Saelens, I.E.Y. — 2010-12-01T00:00:00Z

We report the outcome of hydrogel intracorneal lens implantation in 2 patients. The lenses were implanted at approximately 50% depth in the cornea to correct high hyperopic refractive errors of 10.5 diopters (D) and 14.0 D, respectively. Both patients were contact lens intolerant and not suitable for intraocular lens implantation. Surgery was performed in 1988, and the patients were followed until early 2010. The patients showed good tolerance for the intracorneal lenses, but both developed opacities around the implant, leading to reduced visual acuity in 1 patient. Long-term patient monitoring is essential since corneal opacities can develop after many years. Removing the implant is not necessary as the lens can easily be rinsed by lifting the corneal cap. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned.

How Dutch orthoptists deal with noncompliance with occlusion therapy for amblyopia (Article)

Tijam, A.M. — 2010-12-01T00:00:00Z

Background: We previously found that compliance with occlusion therapy for amblyopia is poor, especially among children of non-native parents who spoke Dutch poorly and who were low educated. We investigated conception, awareness, attitude, and actions to deal with noncompliance among Dutch orthoptists. Methods: Orthoptists working in non-native, low socioeconomic status (SES) areas and a selection of orthoptists working elsewhere in the Netherlands were studied. They were observed in their practice, received a structured questionnaire, and underwent a semi-structured interview. Finally, a short survey was sent to all working orthoptists in the Netherlands. Results: Nine orthoptists working in non-native, low-SES areas and 23 working elsewhere in the Netherlands participated. One hundred and fifty-one orthoptists returned the short survey. Major discrepancies existed in conception, awareness, and attitude. Opinions differed on what should be defined as noncompliance and on what causes noncompliance. Some orthoptists found noncompliance annoying, unpleasant, and hard to imagine, others were more understanding. Many pitied the noncompliant child. Almost all thought that the success of occlusion therapy lies both with the parents and the orthoptist, but one third thought that noncompliance was not solely their responsibility. Patients' compliance was estimated at 69.3% in non-native, low-SES areas (electronically, 52% had been measured), at 74.1% by the other 23 orthoptists, and at 73.8% in the short survey. Actions to improve compliance were diverse; some increased occlusion hours whereas others decreased them. In non-native, low-SES areas, 22% spoke Dutch moderately to none; the allotted time for a patient's first visit was 21'; the time spent on explaining to the parents was 2'30" and to the child 10". In practices of the other 23 orthoptists, 6% spoke Dutch moderately to none (P<0.0001), the time for a patient's first visit was 27'24" (P=0.47), and the periods spent explaining were 2'51" (P=0.59) and 26" (P=0.17), respectively. Conclusion: Conception, awareness, attitude, and actions to deal with noncompliance varied among orthoptists. In non-native, low-SES areas, time spent on explanation was shorter, despite a lower fluency in Dutch among the parents.

Pain management in intellectually disabled children: Assessment, treatment, and translational research (Article)

Valkenburg, A.J. — 2010-12-01T00:00:00Z

The primary focus of pain research in intellectually disabled individuals is still on pain assessment. Several observational pain assessment scales are available, each with its own characteristics, its own target group and its own validated use. Observational studies report differences in the treatment of intra- and postoperative pain of intellectually disabled children and almost all children with intellectual disability have comorbidities that need to be addressed. The scope of research has started to broaden. In this review we aim to answer the question: Can we integrate validated ways of pain assessment and postoperative pain treatment in intellectually disabled children to develop specific analgesic algorithms? Regrettably there is little knowledge on possible interaction effects and other relevant pharmacological issues. Possible genotype-phenotype associations related to pain in children with Down syndrome have several promises as six possible candidate genes are located on chromosome 21. In conclusion, the pain assessment tools for intellectually disabled children are there. We should now focus on tailoring the pain treatment. To this aim we need to perform pharmacokinetic and pharmacodynamic studies of analgesics and obtain information about the genotype-phenotype relationships for pain. This can lead to the development of specific analgesic algorithms.

Amblyopia and strabismus questionnaire: Rasch analysis (Article)

Graaf, E.S. van de — 2010-12-01T00:00:00Z

Retinal vascular calibers and the risk of intracerebral hemorrhage and cerebral infarction: The rotterdam study (Article)

Wieberdink, R.G. — 2010-12-01T00:00:00Z

Background and Purpose- Narrower retinal arteriolar calibers and wider venular calibers are associated with cardiovascular disease, including cerebral infarction. We investigated the association between retinal vascular calibers and the long-term risk for stroke and its subtypes with particular focus on intracerebral hemorrhage. Methods- We included 5518 participants (aged ≥55 years) from the prospective population-based Rotterdam Study who were stroke-free at baseline (1990-1993) and of whom digital retinal images were available. Follow-up for incident stroke was complete up to January 1, 2007. Data were analyzed with Cox proportional hazards models adjusted for age and sex and additionally for potential confounders. Arteriolar and venular calibers were entered both separately and simultaneously in the models. Results- During an average follow-up of 11.5 years, 623 participants developed a first-ever stroke (50 hemorrhagic, 361 ischemic, 212 unspecified). Larger venular caliber was independently associated with an increased risk for stroke (hazard ratio [HR] per SD increase: 1.20; 95% confidence interval [CI]: 1.09 to 1.33), cerebral infarction (HR: 1.28; 95% CI: 1.13 to 1.46), and intracerebral hemorrhage (HR: 1.53; 95% CI: 1.09 to 2.15). Much weaker, only borderline significant associations were found between arteriolar caliber and risk for stroke (HR per SD decrease: 1.12; 95% CI: 0.99 to 1.23), cerebral infarction (HR: 1.12; 95% CI, 0.98 to 1.27), and intracerebral hemorrhage (HR: 1.25; 95% CI: 0.87 to 1.79). Retinal vascular calibers were strongly associated with lobar hemorrhages and oral anticoagulant-related hemorrhages. Conclusion- Larger retinal venular caliber is associated with an increased risk for stroke in the general population and, in particular, with an increased risk for intracerebral hemorrhage.

Genetic testing and clinical characterization of patients with cone-rod dystrophy (Article)

Thiadens, A.A.H.J. — 2010-12-01T00:00:00Z

Zipper cell endotheliopathy: A new subset of idiopathic corneal edema (Article)

Hillenaar, T. — 2010-12-01T00:00:00Z

Purpose: To report the clinical and histologic findings of a new subset of idiopathic corneal edema: zipper cell endotheliopathy. Design: Observational case report. Participant: A 55-year-old woman with unilateral bullous keratopathy. Methods: Clinical observation consisted of slit-lamp examination and in vivo confocal microscopy (IVCM). Aqueous humor samples and the excised corneal button were analyzed for the presence of herpes viruses. The excised cornea was subjected to detailed immunohistochemistry (IHC) and scanning and transmission electron microscopy. Main Outcome Measures: Clinical and pathologic characteristics of zipper cell endotheliopathy. Results: In vivo confocal microscopy revealed unique morphologic alterations of the corneal endothelial layer. Focal areas of denudation were surrounded by endothelial cells with zipper-like cell borders and intercellular structures. Besides central corneal edema, no other signs of corneal inflammation were detected. A herpes virus origin for the bullous keratopathy was excluded. The IHC analysis disclosed positive staining for cytokeratin (CK) 7, CK8/18, and CK19, suggesting epithelial metaplasia of the endothelial cells. Ultrastructural examination confirmed the IVCM findings by showing large areas of endothelial denudation and vacuolated endothelial cells with large, broad-based extensions that partially overlapped neighboring cells. Despite extensive complementary research and review of the literature, the endothelial alterations could not be attributed to any known corneal disorder. Conclusions: To the authors' knowledge, zipper cell endotheliopathy is a new subset of idiopathic corneal edema. The case report presented illustrates the potential use of IVCM to differentiate the spectrum of corneal disorders and to discover new corneal diseases. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Comparable low-level mosaicism in affected and non affected tissue of a complex CDH patient (Article)

Veenma, D.C.M. — 2010-12-01T00:00:00Z

In this paper we present the detailed clinical and cytogenetic analysis of a prenatally detected complex Congenital Diaphragmatic Hernia (CDH) patient with a mosaic unbalanced translocation (5;12). High-resolution whole genome SNP array confirmed a low-level mosaicism (20%) in uncultured cells, underlining the value of array technology for identification studies. Subsequently, targeted Fluorescence In-Situ Hybridization in postmortem collected tissues demonstrated a similar low-level mosaicism, independently of the affected status of the tissue. Thus, a higher incidence of the genetic aberration in affected organs as lung and diaphragm cannot explain the severe phenotype of this complex CDH patient. Comparison with other described chromosome 5p and 12p anomalies indicated that half of the features presented in our patient (including the diaphragm defect) could be attributed to both chromosomal areas. In contrast, a few features such as the palpebral downslant, the broad nasal bridge, the micrognathia, microcephaly, abnormal dermatoglyphics and IUGR better fitted the 5p associated syndromes only. This study underlines the fact that low-level mosaicism can be associated with severe birth defects including CDH. The contribution of mosaicism to human diseases and specifically to congenital anomalies and spontaneous abortions becomes more and more accepted, although its phenotypic consequences are poorly described phenomena leading to counseling issues. Therefore, thorough follow-up of mosaic aberrations such as presented here is indicated in order to provide genetic counselors a more evidence based prediction of fetal prognosis in the future.

The ERCC6 Gene and Age-Related Macular Degeneration (Article)

Baas, D.C. — 2010-11-19T00:00:00Z

Background: Age-related macular degeneration (AMD) is the leading cause of irreversible visual loss in the developed countries and is caused by both environmental and genetic factors. A recent study (Tuo et al., PNAS) reported an association between AMD and a single nucleotide polymorphism (SNP) (rs3793784) in the ERCC6 (NM_000124) gene. The risk allele also increased ERCC6 expression. ERCC6 is involved in DNA repair and mutations in ERCC6 cause Cockayne syndrome (CS). Amongst others, photosensitivity and pigmentary retinopathy are hallmarks of CS. Methodology/Principal Findings: Separate and combined data from three large AMD case-control studies and a prospective population-based study (The Rotterdam Study) were used to analyse the genetic association between ERCC6 and AMD (2682 AMD cases and 3152 controls). We also measured ERCC6 mRNA levels in retinal pigment epithelium (RPE) cells of healthy and early AMD affected human donor eyes. Rs3793784 conferred a small increase in risk for late AMD in the Dutch population (The Rotterdam and AMRO-NL study), but this was not replicated in two non-European studies (AREDS, Columbia University). In addition, the AMRO-NL study revealed no significant association for 9 other variants spanning ERCC6. Finally, we determined that ERCC6 expression in the human RPE did not depend on rs3793784 genotype, but, interestingly, on AMD status: Early AMD-affected donor eyes had a 50% lower ERCC6 expression than healthy donor eyes (P = 0.018). Conclusions/Significance: Our meta analysis of four Caucasian cohorts does not replicate the reported association between SNPs in ERCC6 and AMD. Nevertheless, our findings on ERCC6 expression in the RPE suggest that ERCC6 may be functionally involved in AMD. Combining our data with those of the literature, we hypothesize that the AMD-related reduced transcriptional activity of ERCC6 may be caused by diverse, small and heterogeneous genetic and/or environmental determinants.