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The ERCC6 gene and age-related macular degeneration.

Baas DC, Despriet DD, Gorgels TG, Bergeron-Sawitzke J, Uitterlinden AG, Hofman A, van Duijn CM, Merriam JE, Smith RT, Barile GR, ten Brink JB, Vingerling JR, Klaver CC, Allikmets R, Dean M, Bergen AA - PLoS ONE (2010)

Bottom Line: 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).Our meta-analysis of four Caucasian cohorts does not replicate the reported association between SNPs in ERCC6 and 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Molecular Ophthalmogenetics, The Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands.

ABSTRACT

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.

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Related in: MedlinePlus

Linkage disequilibrium (LD) display in Haploview of SNPs encompassing the ERCC6 gene.SNP selection was based on criteria like functional relevance, minor allele frequency (MAF)>10%, coverage of the main linkage disequilibrium (LD) blocks and tagging of the most common haplotypes. Tag SNPs were selected by use of Tagger, an option of Haploview [1] (all SNPs were captured with a LD tagging criteria of r2>0.8). Figure 1 displays the 5 distinct haplotype blocks and all SNPs that were tested in the AMRO-NL study population (A). LD scores (D' and R2) between markers genotyped. Note D' above the diagonal and R2 scores below the diagonal (B).
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pone-0013786-g001: Linkage disequilibrium (LD) display in Haploview of SNPs encompassing the ERCC6 gene.SNP selection was based on criteria like functional relevance, minor allele frequency (MAF)>10%, coverage of the main linkage disequilibrium (LD) blocks and tagging of the most common haplotypes. Tag SNPs were selected by use of Tagger, an option of Haploview [1] (all SNPs were captured with a LD tagging criteria of r2>0.8). Figure 1 displays the 5 distinct haplotype blocks and all SNPs that were tested in the AMRO-NL study population (A). LD scores (D' and R2) between markers genotyped. Note D' above the diagonal and R2 scores below the diagonal (B).

Mentions: We next selected nine other ERCC6 SNPs that span and tag the entire ERCC6 gene. The LD plot and the distinct haplotype blocks for the nine selected SNPs, as generated by Haploview [31], are presented in Figure 1a. The nine variants spanned two different haplotype blocks of the ERCC6 gene. Corresponding LD scores (D' and R2) for each selected marker of the ERCC6 gene with a MAF>10% are also given (Figure 1b). The potential association of the SNPs with early and late AMD was analyzed in the AMRO-NL cohort. Genotype frequencies for all SNPs followed HWE (data not shown). None of the selected SNPs, including one in full LD with rs3793784 (rs2229760), showed a significant association with early or late AMD (Table S3).


The ERCC6 gene and age-related macular degeneration.

Baas DC, Despriet DD, Gorgels TG, Bergeron-Sawitzke J, Uitterlinden AG, Hofman A, van Duijn CM, Merriam JE, Smith RT, Barile GR, ten Brink JB, Vingerling JR, Klaver CC, Allikmets R, Dean M, Bergen AA - PLoS ONE (2010)

Linkage disequilibrium (LD) display in Haploview of SNPs encompassing the ERCC6 gene.SNP selection was based on criteria like functional relevance, minor allele frequency (MAF)>10%, coverage of the main linkage disequilibrium (LD) blocks and tagging of the most common haplotypes. Tag SNPs were selected by use of Tagger, an option of Haploview [1] (all SNPs were captured with a LD tagging criteria of r2>0.8). Figure 1 displays the 5 distinct haplotype blocks and all SNPs that were tested in the AMRO-NL study population (A). LD scores (D' and R2) between markers genotyped. Note D' above the diagonal and R2 scores below the diagonal (B).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2967476&req=5

pone-0013786-g001: Linkage disequilibrium (LD) display in Haploview of SNPs encompassing the ERCC6 gene.SNP selection was based on criteria like functional relevance, minor allele frequency (MAF)>10%, coverage of the main linkage disequilibrium (LD) blocks and tagging of the most common haplotypes. Tag SNPs were selected by use of Tagger, an option of Haploview [1] (all SNPs were captured with a LD tagging criteria of r2>0.8). Figure 1 displays the 5 distinct haplotype blocks and all SNPs that were tested in the AMRO-NL study population (A). LD scores (D' and R2) between markers genotyped. Note D' above the diagonal and R2 scores below the diagonal (B).
Mentions: We next selected nine other ERCC6 SNPs that span and tag the entire ERCC6 gene. The LD plot and the distinct haplotype blocks for the nine selected SNPs, as generated by Haploview [31], are presented in Figure 1a. The nine variants spanned two different haplotype blocks of the ERCC6 gene. Corresponding LD scores (D' and R2) for each selected marker of the ERCC6 gene with a MAF>10% are also given (Figure 1b). The potential association of the SNPs with early and late AMD was analyzed in the AMRO-NL cohort. Genotype frequencies for all SNPs followed HWE (data not shown). None of the selected SNPs, including one in full LD with rs3793784 (rs2229760), showed a significant association with early or late AMD (Table S3).

Bottom Line: 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).Our meta-analysis of four Caucasian cohorts does not replicate the reported association between SNPs in ERCC6 and 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical and Molecular Ophthalmogenetics, The Netherlands Institute for Neuroscience, Royal Netherlands Academy of Arts and Sciences (KNAW), Amsterdam, The Netherlands.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus