The ERCC6 gene and age-related macular degeneration.
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.


RESULTS
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
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.
Department of Clinical and Molecular Ophthalmogenetics, The Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands.
Dominique C
DC
Baas
Dominiek D
DD
Despriet
Theo G M F
TG
Gorgels
Julie
J
Bergeron-Sawitzke
André G
AG
Uitterlinden
Albert
A
Hofman
Cornelia M
CM
van Duijn
Joanna E
JE
Merriam
R Theodore
RT
Smith
Gaetano R
GR
Barile
Jacoline B
JB
ten Brink
Johannes R
JR
Vingerling
Caroline C W
CC
Klaver
Rando
R
Allikmets
Michael
M
Dean
Arthur A B
AA
Bergen
D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D016022:Case-Control Studies; D004265:DNA Helicases / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008268:Macular Degeneration / Q000235:genetics* / Q000473:pathology; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D000075223:Poly-ADP-Ribose Binding Proteins; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011446:Prospective Studies; D012307:Risk Factors
D000075223:Poly-ADP-Ribose Binding Proteins; D004265:DNA Helicases; C078673:ERCC6 protein, human; D045643:DNA Repair Enzymes