Multicenter cohort association study of SLC2A1 single nucleotide polymorphisms and age-related macular degeneration

Abstract

Purpose: Age-related macular degeneration (AMD) is a major cause of blindness in older adults and has a genetically complex background. This study examines the potential association between single nucleotide polymorphisms (SNPs) in the glucose transporter 1 (SLC2A1) gene and AMD. SLC2A1 regulates the bioavailability of glucose in the retinal pigment epithelium (RPE), which might influence oxidative stress-mediated AMD pathology.

Methods: Twenty-two SNPs spanning the SLC2A1 gene were genotyped in 375 cases and 199 controls from an initial discovery cohort (the Amsterdam-Rotterdam-Netherlands study). Replication testing was performed in The Rotterdam Study (the Netherlands) and study populations from Würzburg (Germany), the Age Related Eye Disease Study (AREDS; United States), Columbia University (United States), and Iowa University (United States). Subsequently, a meta-analysis of SNP association was performed.

Results: In the discovery cohort, significant genotypic association between three SNPs (rs3754219, rs4660687, and rs841853) and AMD was found. Replication in five large independent (Caucasian) cohorts (4,860 cases and 4,004 controls) did not yield consistent association results. The genotype frequencies for these SNPs were significantly different for the controls and/or cases among the six individual populations. Meta-analysis revealed significant heterogeneity of effect between the studies.

Conclusions: No overall association between SLC2A1 SNPs and AMD was demonstrated. Since the genotype frequencies for the three SLC2A1 SNPs were significantly different for the controls and/or cases between the six cohorts, this study corroborates previous evidence that population dependent genetic risk heterogeneity in AMD exists.

Figure 1

Linkage disequilibrium (LD) display in Haploview of (A) the three SLC2A1 single nucleotide polymorphisms (SNPs) rs3754219, rs4660687, and rs841853. Left: D’(D prime), Right: r² (r square) (B) all the 22 SNPs in the SLC2A1 gene with minor allele frequency>10% screened in this study and illustrating the nine distinct haplotype blocks. LD scores: D' (D prime) displays the raw D' value, which is the normalized covariance for a given marker pair and the correlation coefficient r² (r square). Darker shades represent stronger LD.

Figure 2

Meta-analysis of rs3754219 for its association with all AMD cases (A), early (B), GA (C), CNV (D), mixed (E), CNV + mixed (F), and late AMD (G) cases in six independent study populations. AMD=age-related macular degeneration; GA=geographic atrophy; CNV=choroidal neovascularization; Mixed cases (combination of GA + CNV). Odds ratios (ORs, squares) and 95% confidence intervals (CI; horizontal lines) are presented for each study. Also shown is the black diamond of the summary OR using either the additive Mantel-Haenszel fixed effects model when heterogeneity was absent (I² <25%) or the additive DerSimonian and Laird random effects model when heterogeneity was present (I² >25%). Heterogeneity between studies was tested using Cochran's Q statistic and the I-square statistic for inconsistency.

Figure 3

Meta-analysis of rs4660687 for its association with all AMD cases (A), early (B), GA (C), CNV (D), mixed (E), CNV + mixed (F), and late AMD (G) cases in six independent study populations. AMD=age-related macular degeneration; GA=geographic atrophy; CNV=choroidal neovascularization; Mixed cases (combination of GA + CNV). Odds ratios (ORs, squares) and 95% confidence intervals (CI; horizontal lines) are presented for each study. Also shown is the black diamond of the summary OR using either the additive Mantel-Haenszel fixed effects model when heterogeneity was absent (I² <25%) or the additive DerSimonian and Laird random effects model when heterogeneity was present (I² >25%). Heterogeneity between studies was tested using Cochran's Q statistic and the I-square statistic for inconsistency.

Figure 4

Meta-analysis of rs841853 for its association with all AMD cases (A), early (B), GA (C), CNV (D), mixed (E), CNV + mixed (F), and late AMD (G) cases in six independent study populations. AMD=age-related macular degeneration; GA=geographic atrophy; CNV=choroidal neovascularization; Mixed cases (combination of GA + CNV). Odds ratios (ORs, squares) and 95% confidence intervals (CI; horizontal lines) are presented for each study. Also shown is the black diamond of the summary OR using either the additive Mantel-Haenszel fixed effects model when heterogeneity was absent (I² <25%) or the additive DerSimonian and Laird random effects model when heterogeneity was present (I² >25%). Heterogeneity between studies was tested using Cochran's Q statistic and the I-square statistic for inconsistency.