Submitted to: Investigative Ophthalmology and Visual Science
Publication Type: Peer reviewed journal
Publication Acceptance Date: 10/19/2011
Publication Date: 11/25/2011
Citation: Chiu, C., Conley, Y., Gorin, M., Gensler, G., Lai, C., Shang, F., Taylor, A. 2011. Associations between genetic polymorphisms of insulin-like growth factor axis genes and risk for age-related macular degeneration. Investigative Ophthalmology and Visual Science. 52(12):9099-9107. Interpretive Summary: In this study, we used a case-control design with 962 subjects to investigate if insulin-like growth factor (IGF) axis genes, together with a novel dietary risk factor, dietary glycemic index (dGI), and body mass index (BMI) affect the risk for age-related macular degeneration (AMD). We found that a single nucleotide polymorphism (rs 2872060) in IGF1 receptor gene (IGF1R) is significantly associated with risk for advanced AMD. The risk allele (G) suggests an additive effect on advanced AMD risk (i.e. the risk for people with GG genotype (OR=2.93; 95% CI: 1.60-5.36) is almost twice the risk for people with GT genotype (OR=1.67; 95% CI: 1.03-2.71)). While obesity has long been recognized as a risk factor for AMD, interestingly we also found that obese people will predispose additional risk if carrying the risk G allele. These findings will be helpful in designing intervention strategies, furthering our understanding of the underlying pathogenesis, and would inform about the designs of new therapeutics for AMD.
Technical Abstract: Purpose: Our objective was to investigate if insulin-like growth factor (IGF) axis genes affect the risk for age-related macular degeneration (AMD). Methods: 864 Caucasian non-diabetic participants from the Age-Related Eye Disease Study (AREDS) Genetic Repository were used in this case control study, including 209 AREDS category 1 participants (control), 354 category 2 or 3 participants (drusen), and 301 category 4 participants (advanced AMD). 25 single nucleotide polymorphisms (SNPs) selected from IGF-1 (n=9), IGF-2 (n=1), IGF binding protein 1 (IGFBP1) (n=3), IGFBP3 (n=3), acid-labile subunit of IGFBP (IGFALS) (n=2), IGF1 receptor (IGF1R) (n=4), and IGF2R (n=3) were genotyped. SNP-AMD associations were measured with genotype-, allele X2 tests and Armitage’s trend test. Odds ratios (OR), 95% confidence intervals (CIs) and SNP-exposure interactions were evaluated by multivariate logistic regression. Results: One SNP (rs2872060) in IGF1R revealed a significant association with advanced AMD (P-Allele=0.0009, P-Trend=0.0008; significance level was set at 0.05/25=0.002 for multiple comparisons). The risk allele (G) in the heterozygous and homozygous state (OR=1.67 and 2.93; 95% CI: 1.03-2.71 and 1.60-5.36, respectively) suggests susceptibility and suggests an additive effect. Further stratification analysis remained significant for both neovascularization (OR=1.49 and 2.61; 95% CI: 0.90-2.48 and 1.39-4.90, respectively) and geographic atrophy (OR=2.57 and 4.52; 95% CI: 0.99-6.71 and 1.49-13.74, respectively). The G allele interaction analysis with body mass index was significant for neovascularization (P=0.042) but not for geographic atrophy (P=0.47). No significant interaction was found with dietary glycemic index. Conclusion: These data suggest a role of IGF1R on the risk for advanced AMD in this group of subjects.